红霉素对香烟刺激的人巨噬细胞组蛋白去乙酰化酶和核因子-κB的影响及机制研究
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摘要
第一部分:红霉素对香烟烟雾刺激的人巨噬细胞释放炎症介质的影响的实验研究
目的(一)探讨香烟烟雾诱导人巨噬细胞产生炎症反应的分子学机制。(二)从抗炎的角度来探讨红霉素(EM)对香烟烟雾诱导的人巨噬细胞释放炎症介质的影响。
方法体外培养人类单核细胞系U937细胞,用佛波脂(PMA,10ng/ml)将其诱导分化为人巨噬细胞。按传统方法制备好香烟烟雾提取物(CSE)用于实验。将传代后的细胞分组:①对照组,②CSE组(加入1%CSE孵育24h),③红霉素+CSE组(1μg/ml红霉素预孵育24h后,加入1%CSE继续孵育24h)。采用酶联免疫吸附试验(ELISA)检测细胞培养上清液的细胞因子白介素-8(IL-8)和肿瘤坏死因子-α(TNF-а)的浓度。数据用均数±标准差(?x±s)表示,两组间比较采用成组计量资料t检验,多组间比较采用方差分析(ANOVA分析),P <0.05表示差异有统计学意义。
结果(一) 1%CSE刺激人巨噬细胞24小时后,与对照组比较,巨噬细胞释放IL-8的含量(ng/L: CSE组281.53±89.98,对照组217.82±83.01;n=7,P <0.05;)和TNF-а的含量(pg/mL: CSE组729.25±44.17,对照组316.60±224.89;n=6,P <0.05;)均明显增高。
(二)红霉素(1ug/ml)预孵育24小时后再予1%CSE刺激人巨噬细胞24小时,与CSE组比较,巨噬细胞释放IL-8的含量(ng/L: CSE+EM组203.14±95.77,CSE组281.53±89.98;n=7,P <0.05)和TNF-а的含量(pg/mL: CSE+EM组510.29±309.83,CSE组281.53±89.98;n=6,P<0.05)均明显下降。
结论香烟烟雾通过刺激人巨噬细胞释放IL-8和TNF-а等炎症介质引起炎症,这提示是香烟烟雾引起炎症的机制之一。红霉素对香烟烟雾所导致的炎症起重要的调控作用(抑制作用),其作用部分是通过对炎性细胞因子IL-8和TNF-α的抑制而实现的,这是红霉素抗炎作用机制之一。
第二部分:红霉素对香烟烟雾刺激的人巨噬细胞核因子-κB活性的影响的实验研究
目的(一)探讨香烟烟雾对人巨噬细胞核转录因子核因子-κB(NF-κB)活性的影响及其与炎症介质的关系。(二)从抗炎的角度来探讨红霉素对香烟烟雾刺激的人巨噬细胞NF-κB活性的影响。
方法体外培养人类单核细胞系U937细胞,用PMA将其诱导分化为人巨噬细胞。按传统方法制备好CSE用于实验。将传代后的细胞分组:①对照组,②CSE组(加入1%CSE孵育24h),③红霉素+CSE组(1μg/ml红霉素预孵育24h后,加入1%CSE继续孵育24h),④吡咯烷二硫氨基甲酸(PDTC)组(加入20nM PDTC预孵育24h后,加入1%CSE继续孵育24h)。细胞提取核蛋白,采用电泳迁移率改变分析法(EMSA)检测NF-κB的活性。采用ELISA法检测细胞上清液IL-8的浓度。数据用均数±标准差(x±s)表示,两组间比较采用成组计量资料t检验,多组间比较采用方差分析(ANOVA分析),P <0.05表示差异有统计学意义。
结果(一)1%CSE刺激人巨噬细胞24小时后,巨噬细胞核转录因子NF-κB活性显著增强。红霉素(1ug/ml)预孵育24小时后再予1%CSE刺激巨噬细胞24小时,NF-κB活性被抑制;当红霉素预孵育时间延长至48小时,NF-κB活性被抑制更明显。作为阴性对照组,NF-κB的特异性抑制剂PDTC组的NF-κB活性明显被抑制。
(二)1%CSE刺激人巨噬细胞24小时后,细胞释放IL-8含量增高(ng/L: CSE组264.93±14.89,对照组103.52±3.33;n=6,P <0.05)。红霉素(1ug/ml)预孵育24小时后再予1%CSE刺激人巨噬细胞24小时,细胞释放IL-8含量下降(ng/L: CSE+EM组196.70±14.13,CSE组264.93±14.89;n=6,P <0.05)。NF-κB特异性抑制剂PDTC抑制香烟烟雾刺激的人巨噬细胞释放IL-8的含量(ng/L: PDTC组95.06±5.86,CSE组264.93±14.89;n=6,P <0.05)。
结论实验结果提示香烟烟雾诱导人巨噬细胞发生炎症的分子学机制之一是通过激活巨噬细胞的核转录因子NF-κB继而促使炎症介质IL-8的释放实现的。红霉素抑制香烟烟雾诱导的炎症的途径之一是通过抑制NF-κB活性从而抑制炎症细胞因子IL-8的表达,这是红霉素抗炎作用的部分分子学机制之一。
第三部分:红霉素对香烟烟雾刺激的人巨噬细胞核组蛋白去乙酰化酶表达的影响的实验研究
目的(一)探讨香烟烟雾对人巨噬细胞组蛋白去乙酰化酶(HDAC)表达的影响及其与NF-κB,炎症介质的关系。(二)从抗炎的角度来探讨红霉素对香烟烟雾刺激的人巨噬细胞HDAC总活性和HDAC1,2,3蛋白表达的影响其与NF-κB,炎症介质的关系。
方法体外培养人类单核细胞系U937细胞,用PMA将其诱导分化为人巨噬细胞。按传统方法制备好CSE用于实验。将传代后的细胞分组:对照组、CSE组(加入1%CSE孵育24h)、红霉素+CSE组(1μg/ml红霉素预孵育24h后,加入1%CSE继续孵育24h)、HDAC的特异性抑制剂曲古霉素(TSA)组(加入TSA100ng/ml孵育24h),细胞提取核蛋白,采用比色法检测细胞HDAC活性和Western blot法检测细胞HDAC1,HDAC2,和HDAC3和NF-κB蛋白表达。采用ELISA法检测细胞培养上清液的细胞因子IL-8和TNF-а的浓度。数据用均数±标准差(x±s)表示,两组间比较采用成组计量资料t检验,多组间比较采用方差分析(ANOVA分析),P <0.05表示差异有统计学意义。
结果(一)1%CSE刺激人巨噬细胞24小时后,巨噬细胞释放IL-8的含量(ng/L: CSE组281.53±89.98,对照组217.82±83.01;n=7,P <0.05)和TNF-а的含量(pg/mL: CSE组729.25±444.17,对照组316.60±224.89;n=7,P <0.05;)均明显增高。红霉素(1ug/ml)预孵育24小时后再予1%CSE刺激人巨噬细胞24小时,巨噬细胞释放IL-8的含量(ng/L: CSE+EM组203.14±95.77,CSE组281.53±89.98;n=7,P <0.05)和TNF-а的含量(pg/mL: CSE+EM组510.29±309.83,CSE组281.53±89.98;n=7,P <0.05)均明显下降。此外,HDAC的特异性抑制剂TSA组的人巨噬细胞释放IL-8的含量(ng/L: TSA组232.21±109.67,对照组217.82±83.01;n=7,P <0.05)和TNF-а的含量(pg/mL: TSA组428.71±371.00,对照组316.60±224.89;n=7,P <0.05)均明显升高。
(二)1%CSE刺激人巨噬细胞24小时后,与阳性对照组比较,巨噬细胞HDAC总活性明显减弱(微摩尔对硝基苯/分钟: CSE组0.0803±0.0431,阳性对照组0.2455±0.0595;n=4,P <0.05)。红霉素(1ug/ml)预孵育24小时后再予1%CSE刺激巨噬细胞24小时,与CSE组比较,巨噬细胞HDAC总活性增强(微摩尔对硝基苯/分钟: CSE+EM组0.0865±0.05081,CSE组0.0803±0.0431;n=4,P <0.05)。作为阴性对照组,HDAC的特异性抑制剂TSA组的HDAC总活性被抑制。
(三)1%CSE刺激人巨噬细胞24小时后,与对照组比较,巨噬细胞HDAC1,2,3表达水平均下降,以HDAC2改变明显。红霉素(1ug/ml)预孵育24小时后再予1%CSE刺激巨噬细胞24小时,与CSE组比较,巨噬细胞HDAC1,2,3表达均增强,以HDAC2改变明显。作为阴性对照组,HDAC的特异性抑制剂TSA组的HDAC1,2,3表达明显被抑制。
(四) 1%CSE刺激巨噬细胞24小时后,细胞NF-КB蛋白表达增强。红霉素(1ug/ml)预孵育24小时后再予1%CSE刺激巨噬细胞24小时,细胞NF-КB蛋白表达水平下降。HDAC的特异性抑制剂TSA组细胞的NF-КB蛋白表达增强。
结论实验结果提示香烟烟雾诱导人巨噬细胞发生炎症的分子学机制之一是通过抑制巨噬细胞HDAC活性和HDAC1,HDAC2和HDAC3蛋白表达水平(尤其是HDAC2水平)继而激活NF-кB,使NF-кB蛋白表达增加,促使炎症介质的释放实现的。红霉素通过提高HDAC活性及HDAC1,2,3,特别是HDAC2蛋白表达,继而抑制NF-κB的活性和蛋白表达从而抑制炎症基因表达,下调炎症反应,这一机制是红霉素具有免疫调节和抗炎作用的分子学机制之一。
Chapter 1
Effect of Erythromycin on the release of proinflammatory cytokines induced by Cigarette Smoke in Human Macrophages
Objectives:
The aim of this study was to investigate the molecular mechanism of inflammatory responses caused by cigarette smoke and the effect of erythromycin (EM) on proinflammatory cytokine induced by CSE in human macrophages.
Methods:
The Aqueous cigarette smoke extract (CSE) was always prepared fresh on the day of the experiment. The human monocytic cell line (U937), obtained from the ATCC, were grown in RPMI 1640 medium supplemented with 10% fetal bovine serum. The U937 monocytic cells were differentiated into macrophages using phorbol 12-myristate 13-acetate (PMA) according to standard procedures. The U937 differentiated cells were treated with either CSE (1%) or EM (1μg/ml) pretreatment for 24 h at 37°C with 5% CO2. The levels of interleukin-8 (IL-8) and tumor necrosis factor-а(TNF-а) release in the supernatant were determined by sandwich ELISA, using the respective dual antibody kits (R&D Systems) according to the manufacturer’s instructions.
Results:
CSE 1% treatment significantly increased IL-8 release (ng/L: CSE1% 281.53±89.98, controls 217.82±83.01; n=7, P<0.05) and TNF-аrelease(pg/ml: CSE1% 729.25±444.17, controls 316.60±224.89; n=6, P<0.05) from human macrophages cells at 24h of treatment. To find out the role of EM on CSE-mediated proinflammatory cytokine release, we pretreated macrophages with EM for 24 h and then washed cells, then incubated with CSE 1% for 24 h. EM significantly inhibited CSE-mediated IL-8 release (ng/L: CSE1% 281.53±89.98, CSE1% + EM1μg/ml 203.144±95.77, n=7, P<0.05) and TNF-аrelease (pg/ml: CSE1% 729.25±444.17, CSE1% + EM1μg/ml 510.29±309.83, n=6, P<0.05).
Conclusions:
Our studies show that cigarette smoke induces an inflammatory response by driving proinflammatory gene transcription and stimulating the release of proinflammatory cytokines in human macrophages. EM is able to decrease CSE-induced release of proinflammatory cytokines, such as IL-8 and TNF-а. This suggests that EM protects against the proinflammatory effects of CSE in macrophages cells.
Chapter 2
Effect of Erythromycin on the transcriptional activity of NF-КB activated by Cigarette Smoke in Human Macrophages
Objectives:
The aim of this study was to investigate the molecular mechanism of inflammatory responses caused by cigarette smoke and the effect of erythromycin on the transcriptional activity of nuclear factor-КB (NF-КB) activated by cigarette smoke in human macrophages cells.
Methods:
The Aqueous CSE was always prepared fresh on the day of the experiment. The human monocytic cell line (U937), obtained from the ATCC, were grown in RPMI 1640 medium supplemented with 10% fetal bovine serum. The U937 monocytic cells were differentiated into macrophages using PMA according to standard procedures. The U937 differentiated cells were treated with either CSE (1%) or EM (1μg/ml) pretreatment , and NF-КB inhibitor pyrrolidine dithiocarbamate (PDTC) for 24 h at 37°C with 5% CO2. NF-КB was assessed by electrophoretic mobility-shift assay(EMSA). Briefly, nuclear extracts were prepared according to a method described previously. Protein concentration was determined by the Bradford method. EMSA was done with the Gel-Shift Assay System following the manufacturer′s instructions. The levels of IL-8 release in the supernatant were determined by sandwich ELISA, using the respective dual antibody kits (R&D Systems) according to the manufacturer’s instructions.
Results:
Treatment with CSE1% for 24h increased NF-КB nuclear binding and IL-8 release in human macrophage cells. EM pretreatment has inhibitory effect on CSE-induced NF-КB transcription activity and IL-8 release in human macrophage cells. As a negative control, PTDC inhibit NF-КB activation and IL-8 release.
Conclusions:
Our data show that cigarette smoke induces an inflammatory response by activating transcription factor NF-КB in human macrophages cells, which maybe results in increasing IL-8 release. EM has an anti-inflammatory action, presumably via an interaction with the NF-КB signaling pathway. Our data suggest that Erythromycin inhibited NF-КB transcriptional activity resulting in decreasing cigarette smoke-induced IL-8 release to exert anti-inflammatory effect.
Chapter 3
Effect of Erythromycin on Histone Deacetylase Activity Decreased by Cigarette Smoke in Human Macrophages
Objectives:
The aim of this study was to investigate the molecular mechanism of inflammatory responses caused by cigarette smoke and the effect of erythromycin on histone deacetylase (HDAC) activity and HDAC1, HDAC2, and HDAC3 protein expression, correlation with NF-КB expression and inflammatory mediators release in human macrophages cells.
Methods:
The Aqueous CSE was always prepared fresh on the day of the experiment. The human monocytic cell line (U937), obtained from the ATCC, were grown in RPMI 1640 medium supplemented with 10% fetal bovine serum. The U937 monocytic cells were differentiated into macrophages using PMA according to standard procedures. The U937 differentiated cells were treated with either CSE (1%) or EM (1μg/ml) pretreatment , and HDAC inhibitor trichostatin A (TSA; 100 ng/ml) for 24 h at 37°C with 5% CO2. The levels of IL-8 and TNF-аrelease in the supernatant were determined by sandwich ELISA, using the respective dual antibody kits (R&D Systems) according to the manufacturer’s instructions. And the HDAC activity was measured with a colorimetric assay kit and Western Blot was used for HDAC1, 2, 3 and NF-КB protein assays.
Results:
1. CSE 1% treatment significantly increased IL-8 release (ng/L: CSE1% 281.53±89.98, controls 217.82±83.01; n=7, P<0.05) and TNF-аrelease(pg/ml: CSE1% 729.25±444.17, controls 316.60±224.89; n=6, P<0.05) from human macrophages cells at 24h of treatment. Pretreatment with EM significantly inhibited CSE-mediated IL-8 release (ng/L: CSE1% 281.53±89.98, CSE1% + EM1μg/ml 203.144±95.77, n=7, P<0.05) and TNF-аrelease (pg/ml: CSE1% 729.25±444.17, CSE1% + EM1μg/ml 510.29±309.83, n=6, P<0.05). Further, TSA treatment significantly increased IL-8 release (ng/L: TSA 232.21±109.67, controls217.82±83.01; n=7, P<0.05) and TNF-аrelease(pg/ml: TSA 428.71±371.00, controls 316.60±224.89; n=6, P<0.05) from human macrophages cells at 24h of treatment. 2. CSE 1% significantly decreased HDAC activity and HDAC1, 2, 3 protein levels at 24h, which were associated with the increased protein expression of NF-КB. We also showed that CSE-mediated inhibition of HDAC activity and HDAC1, 2, 3 protein levels and increase of NF-КB protein expression were restored by EM pretreatment at 24h . We further showed that CSE particularly decreased HDAC2 protein level, which was significantly restored by EM pretreatment. As a positive control, TSA decreased HDAC activity and HDAC1, -2, and -3 protein levels and increased NF-КB protein expression.
Conclusions:
Cigarette smoke reduced HDAC expression and decreased the protein levels of HDAC1, HDAC2 and HDAC3 in human macrophages cells. Particularly, cigarette smoke caused a decline in HDAC2 protein expression. The decrease of HDAC activity and HDAC1, 2, 3 expression may be responsible for the increased inflammatory gene transcription. EM is able to restore HDAC activity and HDAC1, HDAC2, HDAC3 levels decreased by cigarette smoke and inhibite NF-КB activity resulting in decreasing CSE-mediated IL-8 and TNF-аrelease, which has shown an important explanation that EM possess the anti-inflammatory effect induced by cigarette smoke.
目的(一)探讨香烟烟雾诱导人巨噬细胞产生炎症反应的分子学机制。(二)从抗炎的角度来探讨红霉素(EM)对香烟烟雾诱导的人巨噬细胞释放炎症介质的影响。
方法体外培养人类单核细胞系U937细胞,用佛波脂(PMA,10ng/ml)将其诱导分化为人巨噬细胞。按传统方法制备好香烟烟雾提取物(CSE)用于实验。将传代后的细胞分组:①对照组,②CSE组(加入1%CSE孵育24h),③红霉素+CSE组(1μg/ml红霉素预孵育24h后,加入1%CSE继续孵育24h)。采用酶联免疫吸附试验(ELISA)检测细胞培养上清液的细胞因子白介素-8(IL-8)和肿瘤坏死因子-α(TNF-а)的浓度。数据用均数±标准差(?x±s)表示,两组间比较采用成组计量资料t检验,多组间比较采用方差分析(ANOVA分析),P <0.05表示差异有统计学意义。
结果(一) 1%CSE刺激人巨噬细胞24小时后,与对照组比较,巨噬细胞释放IL-8的含量(ng/L: CSE组281.53±89.98,对照组217.82±83.01;n=7,P <0.05;)和TNF-а的含量(pg/mL: CSE组729.25±44.17,对照组316.60±224.89;n=6,P <0.05;)均明显增高。
(二)红霉素(1ug/ml)预孵育24小时后再予1%CSE刺激人巨噬细胞24小时,与CSE组比较,巨噬细胞释放IL-8的含量(ng/L: CSE+EM组203.14±95.77,CSE组281.53±89.98;n=7,P <0.05)和TNF-а的含量(pg/mL: CSE+EM组510.29±309.83,CSE组281.53±89.98;n=6,P<0.05)均明显下降。
结论香烟烟雾通过刺激人巨噬细胞释放IL-8和TNF-а等炎症介质引起炎症,这提示是香烟烟雾引起炎症的机制之一。红霉素对香烟烟雾所导致的炎症起重要的调控作用(抑制作用),其作用部分是通过对炎性细胞因子IL-8和TNF-α的抑制而实现的,这是红霉素抗炎作用机制之一。
第二部分:红霉素对香烟烟雾刺激的人巨噬细胞核因子-κB活性的影响的实验研究
目的(一)探讨香烟烟雾对人巨噬细胞核转录因子核因子-κB(NF-κB)活性的影响及其与炎症介质的关系。(二)从抗炎的角度来探讨红霉素对香烟烟雾刺激的人巨噬细胞NF-κB活性的影响。
方法体外培养人类单核细胞系U937细胞,用PMA将其诱导分化为人巨噬细胞。按传统方法制备好CSE用于实验。将传代后的细胞分组:①对照组,②CSE组(加入1%CSE孵育24h),③红霉素+CSE组(1μg/ml红霉素预孵育24h后,加入1%CSE继续孵育24h),④吡咯烷二硫氨基甲酸(PDTC)组(加入20nM PDTC预孵育24h后,加入1%CSE继续孵育24h)。细胞提取核蛋白,采用电泳迁移率改变分析法(EMSA)检测NF-κB的活性。采用ELISA法检测细胞上清液IL-8的浓度。数据用均数±标准差(x±s)表示,两组间比较采用成组计量资料t检验,多组间比较采用方差分析(ANOVA分析),P <0.05表示差异有统计学意义。
结果(一)1%CSE刺激人巨噬细胞24小时后,巨噬细胞核转录因子NF-κB活性显著增强。红霉素(1ug/ml)预孵育24小时后再予1%CSE刺激巨噬细胞24小时,NF-κB活性被抑制;当红霉素预孵育时间延长至48小时,NF-κB活性被抑制更明显。作为阴性对照组,NF-κB的特异性抑制剂PDTC组的NF-κB活性明显被抑制。
(二)1%CSE刺激人巨噬细胞24小时后,细胞释放IL-8含量增高(ng/L: CSE组264.93±14.89,对照组103.52±3.33;n=6,P <0.05)。红霉素(1ug/ml)预孵育24小时后再予1%CSE刺激人巨噬细胞24小时,细胞释放IL-8含量下降(ng/L: CSE+EM组196.70±14.13,CSE组264.93±14.89;n=6,P <0.05)。NF-κB特异性抑制剂PDTC抑制香烟烟雾刺激的人巨噬细胞释放IL-8的含量(ng/L: PDTC组95.06±5.86,CSE组264.93±14.89;n=6,P <0.05)。
结论实验结果提示香烟烟雾诱导人巨噬细胞发生炎症的分子学机制之一是通过激活巨噬细胞的核转录因子NF-κB继而促使炎症介质IL-8的释放实现的。红霉素抑制香烟烟雾诱导的炎症的途径之一是通过抑制NF-κB活性从而抑制炎症细胞因子IL-8的表达,这是红霉素抗炎作用的部分分子学机制之一。
第三部分:红霉素对香烟烟雾刺激的人巨噬细胞核组蛋白去乙酰化酶表达的影响的实验研究
目的(一)探讨香烟烟雾对人巨噬细胞组蛋白去乙酰化酶(HDAC)表达的影响及其与NF-κB,炎症介质的关系。(二)从抗炎的角度来探讨红霉素对香烟烟雾刺激的人巨噬细胞HDAC总活性和HDAC1,2,3蛋白表达的影响其与NF-κB,炎症介质的关系。
方法体外培养人类单核细胞系U937细胞,用PMA将其诱导分化为人巨噬细胞。按传统方法制备好CSE用于实验。将传代后的细胞分组:对照组、CSE组(加入1%CSE孵育24h)、红霉素+CSE组(1μg/ml红霉素预孵育24h后,加入1%CSE继续孵育24h)、HDAC的特异性抑制剂曲古霉素(TSA)组(加入TSA100ng/ml孵育24h),细胞提取核蛋白,采用比色法检测细胞HDAC活性和Western blot法检测细胞HDAC1,HDAC2,和HDAC3和NF-κB蛋白表达。采用ELISA法检测细胞培养上清液的细胞因子IL-8和TNF-а的浓度。数据用均数±标准差(x±s)表示,两组间比较采用成组计量资料t检验,多组间比较采用方差分析(ANOVA分析),P <0.05表示差异有统计学意义。
结果(一)1%CSE刺激人巨噬细胞24小时后,巨噬细胞释放IL-8的含量(ng/L: CSE组281.53±89.98,对照组217.82±83.01;n=7,P <0.05)和TNF-а的含量(pg/mL: CSE组729.25±444.17,对照组316.60±224.89;n=7,P <0.05;)均明显增高。红霉素(1ug/ml)预孵育24小时后再予1%CSE刺激人巨噬细胞24小时,巨噬细胞释放IL-8的含量(ng/L: CSE+EM组203.14±95.77,CSE组281.53±89.98;n=7,P <0.05)和TNF-а的含量(pg/mL: CSE+EM组510.29±309.83,CSE组281.53±89.98;n=7,P <0.05)均明显下降。此外,HDAC的特异性抑制剂TSA组的人巨噬细胞释放IL-8的含量(ng/L: TSA组232.21±109.67,对照组217.82±83.01;n=7,P <0.05)和TNF-а的含量(pg/mL: TSA组428.71±371.00,对照组316.60±224.89;n=7,P <0.05)均明显升高。
(二)1%CSE刺激人巨噬细胞24小时后,与阳性对照组比较,巨噬细胞HDAC总活性明显减弱(微摩尔对硝基苯/分钟: CSE组0.0803±0.0431,阳性对照组0.2455±0.0595;n=4,P <0.05)。红霉素(1ug/ml)预孵育24小时后再予1%CSE刺激巨噬细胞24小时,与CSE组比较,巨噬细胞HDAC总活性增强(微摩尔对硝基苯/分钟: CSE+EM组0.0865±0.05081,CSE组0.0803±0.0431;n=4,P <0.05)。作为阴性对照组,HDAC的特异性抑制剂TSA组的HDAC总活性被抑制。
(三)1%CSE刺激人巨噬细胞24小时后,与对照组比较,巨噬细胞HDAC1,2,3表达水平均下降,以HDAC2改变明显。红霉素(1ug/ml)预孵育24小时后再予1%CSE刺激巨噬细胞24小时,与CSE组比较,巨噬细胞HDAC1,2,3表达均增强,以HDAC2改变明显。作为阴性对照组,HDAC的特异性抑制剂TSA组的HDAC1,2,3表达明显被抑制。
(四) 1%CSE刺激巨噬细胞24小时后,细胞NF-КB蛋白表达增强。红霉素(1ug/ml)预孵育24小时后再予1%CSE刺激巨噬细胞24小时,细胞NF-КB蛋白表达水平下降。HDAC的特异性抑制剂TSA组细胞的NF-КB蛋白表达增强。
结论实验结果提示香烟烟雾诱导人巨噬细胞发生炎症的分子学机制之一是通过抑制巨噬细胞HDAC活性和HDAC1,HDAC2和HDAC3蛋白表达水平(尤其是HDAC2水平)继而激活NF-кB,使NF-кB蛋白表达增加,促使炎症介质的释放实现的。红霉素通过提高HDAC活性及HDAC1,2,3,特别是HDAC2蛋白表达,继而抑制NF-κB的活性和蛋白表达从而抑制炎症基因表达,下调炎症反应,这一机制是红霉素具有免疫调节和抗炎作用的分子学机制之一。
Chapter 1
Effect of Erythromycin on the release of proinflammatory cytokines induced by Cigarette Smoke in Human Macrophages
Objectives:
The aim of this study was to investigate the molecular mechanism of inflammatory responses caused by cigarette smoke and the effect of erythromycin (EM) on proinflammatory cytokine induced by CSE in human macrophages.
Methods:
The Aqueous cigarette smoke extract (CSE) was always prepared fresh on the day of the experiment. The human monocytic cell line (U937), obtained from the ATCC, were grown in RPMI 1640 medium supplemented with 10% fetal bovine serum. The U937 monocytic cells were differentiated into macrophages using phorbol 12-myristate 13-acetate (PMA) according to standard procedures. The U937 differentiated cells were treated with either CSE (1%) or EM (1μg/ml) pretreatment for 24 h at 37°C with 5% CO2. The levels of interleukin-8 (IL-8) and tumor necrosis factor-а(TNF-а) release in the supernatant were determined by sandwich ELISA, using the respective dual antibody kits (R&D Systems) according to the manufacturer’s instructions.
Results:
CSE 1% treatment significantly increased IL-8 release (ng/L: CSE1% 281.53±89.98, controls 217.82±83.01; n=7, P<0.05) and TNF-аrelease(pg/ml: CSE1% 729.25±444.17, controls 316.60±224.89; n=6, P<0.05) from human macrophages cells at 24h of treatment. To find out the role of EM on CSE-mediated proinflammatory cytokine release, we pretreated macrophages with EM for 24 h and then washed cells, then incubated with CSE 1% for 24 h. EM significantly inhibited CSE-mediated IL-8 release (ng/L: CSE1% 281.53±89.98, CSE1% + EM1μg/ml 203.144±95.77, n=7, P<0.05) and TNF-аrelease (pg/ml: CSE1% 729.25±444.17, CSE1% + EM1μg/ml 510.29±309.83, n=6, P<0.05).
Conclusions:
Our studies show that cigarette smoke induces an inflammatory response by driving proinflammatory gene transcription and stimulating the release of proinflammatory cytokines in human macrophages. EM is able to decrease CSE-induced release of proinflammatory cytokines, such as IL-8 and TNF-а. This suggests that EM protects against the proinflammatory effects of CSE in macrophages cells.
Chapter 2
Effect of Erythromycin on the transcriptional activity of NF-КB activated by Cigarette Smoke in Human Macrophages
Objectives:
The aim of this study was to investigate the molecular mechanism of inflammatory responses caused by cigarette smoke and the effect of erythromycin on the transcriptional activity of nuclear factor-КB (NF-КB) activated by cigarette smoke in human macrophages cells.
Methods:
The Aqueous CSE was always prepared fresh on the day of the experiment. The human monocytic cell line (U937), obtained from the ATCC, were grown in RPMI 1640 medium supplemented with 10% fetal bovine serum. The U937 monocytic cells were differentiated into macrophages using PMA according to standard procedures. The U937 differentiated cells were treated with either CSE (1%) or EM (1μg/ml) pretreatment , and NF-КB inhibitor pyrrolidine dithiocarbamate (PDTC) for 24 h at 37°C with 5% CO2. NF-КB was assessed by electrophoretic mobility-shift assay(EMSA). Briefly, nuclear extracts were prepared according to a method described previously. Protein concentration was determined by the Bradford method. EMSA was done with the Gel-Shift Assay System following the manufacturer′s instructions. The levels of IL-8 release in the supernatant were determined by sandwich ELISA, using the respective dual antibody kits (R&D Systems) according to the manufacturer’s instructions.
Results:
Treatment with CSE1% for 24h increased NF-КB nuclear binding and IL-8 release in human macrophage cells. EM pretreatment has inhibitory effect on CSE-induced NF-КB transcription activity and IL-8 release in human macrophage cells. As a negative control, PTDC inhibit NF-КB activation and IL-8 release.
Conclusions:
Our data show that cigarette smoke induces an inflammatory response by activating transcription factor NF-КB in human macrophages cells, which maybe results in increasing IL-8 release. EM has an anti-inflammatory action, presumably via an interaction with the NF-КB signaling pathway. Our data suggest that Erythromycin inhibited NF-КB transcriptional activity resulting in decreasing cigarette smoke-induced IL-8 release to exert anti-inflammatory effect.
Chapter 3
Effect of Erythromycin on Histone Deacetylase Activity Decreased by Cigarette Smoke in Human Macrophages
Objectives:
The aim of this study was to investigate the molecular mechanism of inflammatory responses caused by cigarette smoke and the effect of erythromycin on histone deacetylase (HDAC) activity and HDAC1, HDAC2, and HDAC3 protein expression, correlation with NF-КB expression and inflammatory mediators release in human macrophages cells.
Methods:
The Aqueous CSE was always prepared fresh on the day of the experiment. The human monocytic cell line (U937), obtained from the ATCC, were grown in RPMI 1640 medium supplemented with 10% fetal bovine serum. The U937 monocytic cells were differentiated into macrophages using PMA according to standard procedures. The U937 differentiated cells were treated with either CSE (1%) or EM (1μg/ml) pretreatment , and HDAC inhibitor trichostatin A (TSA; 100 ng/ml) for 24 h at 37°C with 5% CO2. The levels of IL-8 and TNF-аrelease in the supernatant were determined by sandwich ELISA, using the respective dual antibody kits (R&D Systems) according to the manufacturer’s instructions. And the HDAC activity was measured with a colorimetric assay kit and Western Blot was used for HDAC1, 2, 3 and NF-КB protein assays.
Results:
1. CSE 1% treatment significantly increased IL-8 release (ng/L: CSE1% 281.53±89.98, controls 217.82±83.01; n=7, P<0.05) and TNF-аrelease(pg/ml: CSE1% 729.25±444.17, controls 316.60±224.89; n=6, P<0.05) from human macrophages cells at 24h of treatment. Pretreatment with EM significantly inhibited CSE-mediated IL-8 release (ng/L: CSE1% 281.53±89.98, CSE1% + EM1μg/ml 203.144±95.77, n=7, P<0.05) and TNF-аrelease (pg/ml: CSE1% 729.25±444.17, CSE1% + EM1μg/ml 510.29±309.83, n=6, P<0.05). Further, TSA treatment significantly increased IL-8 release (ng/L: TSA 232.21±109.67, controls217.82±83.01; n=7, P<0.05) and TNF-аrelease(pg/ml: TSA 428.71±371.00, controls 316.60±224.89; n=6, P<0.05) from human macrophages cells at 24h of treatment. 2. CSE 1% significantly decreased HDAC activity and HDAC1, 2, 3 protein levels at 24h, which were associated with the increased protein expression of NF-КB. We also showed that CSE-mediated inhibition of HDAC activity and HDAC1, 2, 3 protein levels and increase of NF-КB protein expression were restored by EM pretreatment at 24h . We further showed that CSE particularly decreased HDAC2 protein level, which was significantly restored by EM pretreatment. As a positive control, TSA decreased HDAC activity and HDAC1, -2, and -3 protein levels and increased NF-КB protein expression.
Conclusions:
Cigarette smoke reduced HDAC expression and decreased the protein levels of HDAC1, HDAC2 and HDAC3 in human macrophages cells. Particularly, cigarette smoke caused a decline in HDAC2 protein expression. The decrease of HDAC activity and HDAC1, 2, 3 expression may be responsible for the increased inflammatory gene transcription. EM is able to restore HDAC activity and HDAC1, HDAC2, HDAC3 levels decreased by cigarette smoke and inhibite NF-КB activity resulting in decreasing CSE-mediated IL-8 and TNF-аrelease, which has shown an important explanation that EM possess the anti-inflammatory effect induced by cigarette smoke.
引文
1. Barnes PJ. Chronic obstructive pulmonary disease. N Engl J Med. Jul 27 2000;343(4):269-280.
2. Donnelly LE, Rogers DF. Therapy for chronic obstructive pulmonary disease in the 21st century. Drugs. 2003;63(19):1973-1998.
3. Gulsvik A. The global burden and impact of chronic obstructive pulmonary disease worldwide. Monaldi Arch Chest Dis. Jun 2001;56(3):261-264.
4. Ward SA, Casaburi R. 21st century perspective on chronic obstructive pulmonary disease. Respiration. 2001;68(6):557-561.
5. Rahman I, MacNee W. Lung glutathione and oxidative stress: implications in cigarette smoke-induced airway disease. Am J Physiol. Dec 1999;277(6 Pt 1):L1067-1088.
6. Rytila P, Rehn T, Ilumets H, et al. Increased oxidative stress in asymptomatic current chronic smokers and GOLD stage 0 COPD. Respir Res. 2006;7:69.
7. Marwick JA, Kirkham PA, Stevenson CS, et al. Cigarette smoke alters chromatin remodeling and induces proinflammatory genes in rat lungs. Am J Respir Cell Mol Biol. Dec 2004;31(6):633-642.
8. Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. Jun 24 2004;350(26):2645-2653.
9. Saetta M, Turato G, Maestrelli P, Mapp CE, Fabbri LM. Cellular andstructural bases of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. May 2001;163(6):1304-1309.
10. Kirkham P, Rahman I. Oxidative stress in asthma and COPD: antioxidants as a therapeutic strategy. Pharmacol Ther. Aug 2006;111(2):476-494.
11. Mahfouz M, Qi Z, Kummerow FA. Inhibition of prostacyclin release by cigarette smoke extract in endothelial cells is not related to enhanced superoxide generation and NADPH-oxidase activation. J Environ Pathol Toxicol Oncol. 2006;25(3):585-595.
12. Proulx LI, Pare G, Bissonnette EY. Alveolar macrophage cytotoxic activity is inhibited by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a carcinogenic component of cigarette smoke. Cancer Immunol Immunother. Jun 2007;56(6):831-838.
13. Rahman I. Oxidative stress, chromatin remodeling and gene transcription in inflammation and chronic lung diseases. J Biochem Mol Biol. Jan 31 2003;36(1):95-109.
14. Adcock IM, Cosio B, Tsaprouni L, Barnes PJ, Ito K. Redox regulation of histone deacetylases and glucocorticoid-mediated inhibition of the inflammatory response. Antioxid Redox Signal. Jan-Feb 2005;7(1-2):144-152.
15. Rahman I, Adcock IM. Oxidative stress and redox regulation of lung inflammation in COPD. Eur Respir J. Jul 2006;28(1):219-242.
16. Urnov FD, Wolffe AP. Chromatin remodeling and transcriptional activation: the cast (in order of appearance). Oncogene. May 28 2001;20(24):2991-3006.
17. Gilmour PS, Rahman I, Donaldson K, MacNee W. Histone acetylation regulates epithelial IL-8 release mediated by oxidative stress fromenvironmental particles. Am J Physiol Lung Cell Mol Physiol. Mar 2003;284(3):L533-540.
18. Iwata K, Tomita K, Sano H, Fujii Y, Yamasaki A, Shimizu E. Trichostatin A, a histone deacetylase inhibitor, down-regulates interleukin-12 transcription in SV-40-transformed lung epithelial cells. Cell Immunol. Jul-Aug 2002;218(1-2):26-33.
19. Tomita K, Barnes PJ, Adcock IM. The effect of oxidative stress on histone acetylation and IL-8 release. Biochem Biophys Res Commun. Feb 7 2003;301(2):572-577.
20. Ito K, Ito M, Elliott WM, et al. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N Engl J Med. May 12 2005;352(19):1967-1976.
21. Barnes PJ. Reduced histone deacetylase in COPD: clinical implications. Chest. Jan 2006;129(1):151-155.
22. de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J. Mar 15 2003;370(Pt 3):737-749.
23. Ito K, Lim S, Caramori G, et al. A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression. Proc Natl Acad Sci U S A. Jun 25 2002;99(13):8921-8926.
24. Ito K, Barnes PJ, Adcock IM. Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1beta-induced histone H4 acetylation on lysines 8 and 12. Mol Cell Biol. Sep 2000;20(18):6891-6903.
25. Barnes PJ, Ito K, Adcock IM. Corticosteroid resistance in chronicobstructive pulmonary disease: inactivation of histone deacetylase. Lancet. Feb 28 2004;363(9410):731-733.
26. Parnham MJ. Inflammation 2005 - Seventh World Congress. Respiratory inflammation. IDrugs. Oct 2005;8(10):783-786.
27. Barnes PJ. Targeting histone deacetylase 2 in chronic obstructive pulmonary disease treatment. Expert Opin Ther Targets. Dec 2005;9(6):1111-1121.
28. Barnes PJ. Transcription factors in airway diseases. Lab Invest. Sep 2006;86(9):867-872.
29. Barnes PJ. Role of HDAC2 in the pathophysiology of COPD. Annu Rev Physiol. 2009;71:451-464.
30. Barnes PJ, Adcock IM, Ito K. Histone acetylation and deacetylation: importance in inflammatory lung diseases. Eur Respir J. Mar 2005;25(3):552-563.
31. Adcock IM, Ito K, Barnes PJ. Histone deacetylation: an important mechanism in inflammatory lung diseases. COPD. Dec 2005;2(4):445-455.
32. Barnes PJ. Alveolar macrophages in chronic obstructive pulmonary disease (COPD). Cell Mol Biol (Noisy-le-grand). 2004;50 Online Pub:OL627-637.
33. Barnes PJ. How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Br J Pharmacol. Jun 2006;148(3):245-254.
34. Barnes PJ. New concepts in chronic obstructive pulmonary disease. Annu Rev Med. 2003;54:113-129.
35. Culpitt SV, Rogers DF, Shah P, et al. Impaired inhibition by dexamethasone of cytokine release by alveolar macrophages from patientswith chronic obstructive pulmonary disease. Am J Respir Crit Care Med. Jan 1 2003;167(1):24-31.
36. Cosio MG, Saetta M, Agusti A. Immunologic aspects of chronic obstructive pulmonary disease. N Engl J Med. Jun 4 2009;360(23):2445-2454.
37. Cosio BG, Tsaprouni L, Ito K, Jazrawi E, Adcock IM, Barnes PJ. Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med. Sep 6 2004;200(5):689-695.
38. Barnes PJ, Hansel TT. Prospects for new drugs for chronic obstructive pulmonary disease. Lancet. Sep 11-17 2004;364(9438):985-996.
39. Shinkai M, Rubin BK. Macrolides and airway inflammation in children. Paediatr Respir Rev. Sep 2005;6(3):227-235.
40. Henke MO, Shah SA, Rubin BK. The role of airway secretions in COPD--clinical applications. COPD. Sep 2005;2(3):377-390.
41. Rubin BK, Henke MO. Immunomodulatory activity and effectiveness of macrolides in chronic airway disease. Chest. Feb 2004;125(2 Suppl):70S-78S.
42. Johnston SL. Macrolide antibiotics and asthma treatment. J Allergy Clin Immunol. Jun 2006;117(6):1233-1236.
43. Parnham MJ. Immunomodulatory effects of antimicrobials in the therapy of respiratory tract infections. Curr Opin Infect Dis. Apr 2005;18(2):125-131.
44. Giamarellos-Bourboulis EJ. Macrolides beyond the conventional antimicrobials: a class of potent immunomodulators. Int J Antimicrob Agents. Jan 2008;31(1):12-20.
45. Gotfried MH. Macrolides for the treatment of chronic sinusitis, asthma,and COPD. Chest. Feb 2004;125(2 Suppl):52S-60S; quiz 60S-61S.
46. Kikuchi T, Hagiwara K, Honda Y, et al. Clarithromycin suppresses lipopolysaccharide-induced interleukin-8 production by human monocytes through AP-1 and NF-kappa B transcription factors. J Antimicrob Chemother. May 2002;49(5):745-755.
47. Banerjee D, Honeybourne D, Khair OA. The effect of oral clarithromycin on bronchial airway inflammation in moderate-to-severe stable COPD: a randomized controlled trial. Treat Respir Med. 2004;3(1):59-65.
48. Basyigit I, Yildiz F, Ozkara SK, Yildirim E, Boyaci H, Ilgazli A. The effect of clarithromycin on inflammatory markers in chronic obstructive pulmonary disease: preliminary data. Ann Pharmacother. Sep 2004;38(9):1400-1405.
49. Parnham MJ, Culic O, Erakovic V, et al. Modulation of neutrophil and inflammation markers in chronic obstructive pulmonary disease by short-term azithromycin treatment. Eur J Pharmacol. Jul 4 2005;517(1-2):132-143.
50. Seemungal TA, Hurst JR, Wedzicha JA. Exacerbation rate, health status and mortality in COPD--a review of potential interventions. Int J Chron Obstruct Pulmon Dis. 2009;4:203-223.
51. Suzuki T, Yanai M, Yamaya M, et al. Erythromycin and common cold in COPD. Chest. Sep 2001;120(3):730-733.
52. Gomez J, Banos V, Simarro E, et al. [Prospective, comparative study (1994-1998) of the influence of short-term prophylactic treatment with azithromycin on patients with advanced COPD]. Rev Esp Quimioter. Dec 2000;13(4):379-383.
53. Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ,Wedzicha JA. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. Dec 1 2008;178(11):1139-1147.
54. Wilkinson TM, Donaldson GC, Hurst JR, Seemungal TA, Wedzicha JA. Early therapy improves outcomes of exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. Jun 15 2004;169(12):1298-1303.
55. Culic O, Erakovic V, Parnham MJ. Anti-inflammatory effects of macrolide antibiotics. Eur J Pharmacol. Oct 19 2001;429(1-3):209-229.
56. Schultz MJ. Macrolide activities beyond their antimicrobial effects: macrolides in diffuse panbronchiolitis and cystic fibrosis. J Antimicrob Chemother. Jul 2004;54(1):21-28.
57. Tsai WC, Standiford TJ. Immunomodulatory effects of macrolides in the lung: lessons from in-vitro and in-vivo models. Curr Pharm Des. 2004;10(25):3081-3093.
58. Zalewska-Kaszubska J, Gorska D. Anti-inflammatory capabilities of macrolides. Pharmacol Res. Dec 2001;44(6):451-454.
59. Desaki M, Okazaki H, Sunazuka T, Omura S, Yamamoto K, Takizawa H. Molecular mechanisms of anti-inflammatory action of erythromycin in human bronchial epithelial cells: possible role in the signaling pathway that regulates nuclear factor-kappaB activation. Antimicrob Agents Chemother. May 2004;48(5):1581-1585.
1. Gotfried MH. Macrolides for the treatment of chronic sinusitis, asthma, and COPD. Chest. Feb 2004;125(2 Suppl):52S-60S; quiz 60S-61S.
2. Kikuchi T, Hagiwara K, Honda Y, et al. Clarithromycin suppresses lipopolysaccharide-induced interleukin-8 production by human monocytes through AP-1 and NF-kappa B transcription factors. J Antimicrob Chemother. May 2002;49(5):745-755.
3. Banerjee D, Honeybourne D, Khair OA. The effect of oral clarithromycin on bronchial airway inflammation in moderate-to-severe stable COPD: a randomized controlled trial. Treat Respir Med. 2004;3(1):59-65.
4. Basyigit I, Yildiz F, Ozkara SK, Yildirim E, Boyaci H, Ilgazli A. The effect of clarithromycin on inflammatory markers in chronic obstructive pulmonary disease: preliminary data. Ann Pharmacother. Sep 2004;38(9):1400-1405.
5. Parnham MJ, Culic O, Erakovic V, et al. Modulation of neutrophil and inflammation markers in chronic obstructive pulmonary disease by short-term azithromycin treatment. Eur J Pharmacol. Jul 4 2005;517(1-2):132-143.
6. Suzuki T, Yanai M, Yamaya M, et al. Erythromycin and common cold in COPD. Chest. Sep 2001;120(3):730-733.
7. Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ, Wedzicha JA. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. Dec 1 2008;178(11):1139-1147.
8. Sundstrom C, Nilsson K. Establishment and characterization of a human histiocytic lymphoma cell line (U-937). Int J Cancer. May 151976;17(5):565-577.
9. Verhoeckx KC, Bijlsma S, de Groene EM, Witkamp RF, van der Greef J, Rodenburg RJ. A combination of proteomics, principal component analysis and transcriptomics is a powerful tool for the identification of biomarkers for macrophage maturation in the U937 cell line. Proteomics. Apr 2004;4(4):1014-1028.
10. Izeboud CA, Vermeulen RM, Zwart A, Voss HP, van Miert AS, Witkamp RF. Stereoselectivity at the beta2-adrenoceptor on macrophages is a major determinant of the anti-inflammatory effects of beta2-agonists. Naunyn Schmiedebergs Arch Pharmacol. Aug 2000;362(2):184-189.
11. Martey CA, Pollock SJ, Turner CK, et al. Cigarette smoke induces cyclooxygenase-2 and microsomal prostaglandin E2 synthase in human lung fibroblasts: implications for lung inflammation and cancer. Am J Physiol Lung Cell Mol Physiol. Nov 2004;287(5):L981-991.
12. Moodie FM, Marwick JA, Anderson CS, et al. Oxidative stress and cigarette smoke alter chromatin remodeling but differentially regulate NF-kappaB activation and proinflammatory cytokine release in alveolar epithelial cells. FASEB J. Dec 2004;18(15):1897-1899.
13. Carp H, Janoff A. Possible mechanisms of emphysema in smokers. In vitro suppression of serum elastase-inhibitory capacity by fresh cigarette smoke and its prevention by antioxidants. Am Rev Respir Dis. Sep 1978;118(3):617-621.
14. Yang SR, Chida AS, Bauter MR, et al. Cigarette smoke induces proinflammatory cytokine release by activation of NF-kappaB and posttranslational modifications of histone deacetylase in macrophages. Am J Physiol Lung Cell Mol Physiol. Jul 2006;291(1):L46-57.
15. Barnes PJ. Immunology of asthma and chronic obstructive pulmonary disease. Nat Rev Immunol. Mar 2008;8(3):183-192.
16. Cosio MG, Saetta M, Agusti A. Immunologic aspects of chronic obstructive pulmonary disease. N Engl J Med. Jun 4 2009;360(23):2445-2454.
17. Chung KF. Inflammatory mediators in chronic obstructive pulmonary disease. Curr Drug Targets Inflamm Allergy. Dec 2005;4(6):619-625.
18. Tetley TD. Macrophages and the pathogenesis of COPD. Chest. May 2002;121(5 Suppl):156S-159S.
19. Moretto N, Facchinetti F, Southworth T, Civelli M, Singh D, Patacchini R. alpha,beta-Unsaturated aldehydes contained in cigarette smoke elicit IL-8 release in pulmonary cells through mitogen-activated protein kinases. Am J Physiol Lung Cell Mol Physiol. May 2009;296(5):L839-848.
20. Yang SR, Wright J, Bauter M, Seweryniak K, Kode A, Rahman I. Sirtuin regulates cigarette smoke-induced proinflammatory mediator release via RelA/p65 NF-kappaB in macrophages in vitro and in rat lungs in vivo: implications for chronic inflammation and aging. Am J Physiol Lung Cell Mol Physiol. Feb 2007;292(2):L567-576.
21. Mukhopadhyay S, Hoidal JR, Mukherjee TK. Role of TNFalpha in pulmonary pathophysiology. Respir Res. 2006;7:125.
22. Zhang X, Wang L, Zhang H, et al. The effects of cigarette smoke extract on the endothelial production of soluble intercellular adhesion molecule-1 are mediated through macrophages, possibly by inducing TNF-alpha release. Methods Find Exp Clin Pharmacol. Jun 2002;24(5):261-265.
23. Demirjian L, Abboud RT, Li H, Duronio V. Acute effect of cigarette smoke on TNF-alpha release by macrophages mediated through theerk1/2 pathway. Biochim Biophys Acta. Jun 2006;1762(6):592-597.
24. Churg A, Wang X, Wang RD, Meixner SC, Pryzdial EL, Wright JL. Alpha1-antitrypsin suppresses TNF-alpha and MMP-12 production by cigarette smoke-stimulated macrophages. Am J Respir Cell Mol Biol. Aug 2007;37(2):144-151.
25. Barnes PJ, Shapiro SD, Pauwels RA. Chronic obstructive pulmonary disease: molecular and cellular mechanisms. Eur Respir J. Oct 2003;22(4):672-688.
26. Barnes PJ. Alveolar macrophages in chronic obstructive pulmonary disease (COPD). Cell Mol Biol (Noisy-le-grand). 2004;50 Online Pub:OL627-637.
27. Marwick JA, Kirkham PA, Stevenson CS, et al. Cigarette smoke alters chromatin remodeling and induces proinflammatory genes in rat lungs. Am J Respir Cell Mol Biol. Dec 2004;31(6):633-642.
28. Rajendrasozhan S, Yao H, Rahman I. Current perspectives on role of chromatin modifications and deacetylases in lung inflammation in COPD. COPD. Aug 2009;6(4):291-297.
29. Kirkham P, Rahman I. Oxidative stress in asthma and COPD: antioxidants as a therapeutic strategy. Pharmacol Ther. Aug 2006;111(2):476-494.
30. Marwick JA, Ito K, Adcock IM, Kirkham PA. Oxidative stress and steroid resistance in asthma and COPD: pharmacological manipulation of HDAC-2 as a therapeutic strategy. Expert Opin Ther Targets. Jun 2007;11(6):745-755.
31. Adcock IM, Cosio B, Tsaprouni L, Barnes PJ, Ito K. Redox regulation of histone deacetylases and glucocorticoid-mediated inhibition of the inflammatory response. Antioxid Redox Signal. Jan-Feb2005;7(1-2):144-152.
32. Adcock IM, Ito K, Barnes PJ. Histone deacetylation: an important mechanism in inflammatory lung diseases. COPD. Dec 2005;2(4):445-455.
33. Rahman I, Adcock IM. Oxidative stress and redox regulation of lung inflammation in COPD. Eur Respir J. Jul 2006;28(1):219-242.
34. Adcock IM, Ito K. Glucocorticoid pathways in chronic obstructive pulmonary disease therapy. Proc Am Thorac Soc. 2005;2(4):313-319; discussion 340-311.
35. Rahman I, Gilmour PS, Jimenez LA, MacNee W. Oxidative stress and TNF-alpha induce histone acetylation and NF-kappaB/AP-1 activation in alveolar epithelial cells: potential mechanism in gene transcription in lung inflammation. Mol Cell Biochem. May-Jun 2002;234-235(1-2):239-248.
36. Rahman I, Gilmour PS, Jimenez LA, Biswas SK, Antonicelli F, Aruoma OI. Ergothioneine inhibits oxidative stress- and TNF-alpha-induced NF-kappa B activation and interleukin-8 release in alveolar epithelial cells. Biochem Biophys Res Commun. Mar 21 2003;302(4):860-864.
37. Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. Jun 24 2004;350(26):2645-2653.
38. Swords WE, Rubin BK. Macrolide antibiotics, bacterial populations and inflammatory airway disease. Neth J Med. Jul 2003;61(7):242-248.
39. Amsden GW. Anti-inflammatory effects of macrolides--an underappreciated benefit in the treatment of community-acquired respiratory tract infections and chronic inflammatory pulmonary conditions? J Antimicrob Chemother. Jan 2005;55(1):10-21.
1. Gotfried MH. Macrolides for the treatment of chronic sinusitis, asthma, and COPD. Chest. Feb 2004;125(2 Suppl):52S-60S; quiz 60S-61S.
2. Kikuchi T, Hagiwara K, Honda Y, et al. Clarithromycin suppresses lipopolysaccharide-induced interleukin-8 production by human monocytes through AP-1 and NF-kappa B transcription factors. J Antimicrob Chemother. May 2002;49(5):745-755.
3. Banerjee D, Honeybourne D, Khair OA. The effect of oral clarithromycin on bronchial airway inflammation in moderate-to-severe stable COPD: a randomized controlled trial. Treat Respir Med. 2004;3(1):59-65.
4. Basyigit I, Yildiz F, Ozkara SK, Yildirim E, Boyaci H, Ilgazli A. The effect of clarithromycin on inflammatory markers in chronic obstructive pulmonary disease: preliminary data. Ann Pharmacother. Sep 2004;38(9):1400-1405.
5. Parnham MJ, Culic O, Erakovic V, et al. Modulation of neutrophil and inflammation markers in chronic obstructive pulmonary disease by short-term azithromycin treatment. Eur J Pharmacol. Jul 4 2005;517(1-2):132-143.
6. Suzuki T, Yanai M, Yamaya M, et al. Erythromycin and common cold in COPD. Chest. Sep 2001;120(3):730-733.
7. Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ, Wedzicha JA. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. Dec 1 2008;178(11):1139-1147.
8. McDonald PP, Bald A, Cassatella MA. Activation of the NF-kappaBpathway by inflammatory stimuli in human neutrophils. Blood. May 1 1997;89(9):3421-3433.
9. Sundstrom C, Nilsson K. Establishment and characterization of a human histiocytic lymphoma cell line (U-937). Int J Cancer. May 15 1976;17(5):565-577.
10. Verhoeckx KC, Bijlsma S, de Groene EM, Witkamp RF, van der Greef J, Rodenburg RJ. A combination of proteomics, principal component analysis and transcriptomics is a powerful tool for the identification of biomarkers for macrophage maturation in the U937 cell line. Proteomics. Apr 2004;4(4):1014-1028.
11. Izeboud CA, Vermeulen RM, Zwart A, Voss HP, van Miert AS, Witkamp RF. Stereoselectivity at the beta2-adrenoceptor on macrophages is a major determinant of the anti-inflammatory effects of beta2-agonists. Naunyn Schmiedebergs Arch Pharmacol. Aug 2000;362(2):184-189.
12. Martey CA, Pollock SJ, Turner CK, et al. Cigarette smoke induces cyclooxygenase-2 and microsomal prostaglandin E2 synthase in human lung fibroblasts: implications for lung inflammation and cancer. Am J Physiol Lung Cell Mol Physiol. Nov 2004;287(5):L981-991.
13. Moodie FM, Marwick JA, Anderson CS, et al. Oxidative stress and cigarette smoke alter chromatin remodeling but differentially regulate NF-kappaB activation and proinflammatory cytokine release in alveolar epithelial cells. FASEB J. Dec 2004;18(15):1897-1899.
14. Carp H, Janoff A. Possible mechanisms of emphysema in smokers. In vitro suppression of serum elastase-inhibitory capacity by fresh cigarette smoke and its prevention by antioxidants. Am Rev Respir Dis. Sep 1978;118(3):617-621.
15. Yang SR, Chida AS, Bauter MR, et al. Cigarette smoke induces proinflammatory cytokine release by activation of NF-kappaB and posttranslational modifications of histone deacetylase in macrophages. Am J Physiol Lung Cell Mol Physiol. Jul 2006;291(1):L46-57.
16. Wald NJ, Hackshaw AK. Cigarette smoking: an epidemiological overview. Br Med Bull. Jan 1996;52(1):3-11.
17. Barnes PJ. Transcription factors in airway diseases. Lab Invest. Sep 2006;86(9):867-872.
18. Barnes PJ. How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Br J Pharmacol. Jun 2006;148(3):245-254.
19. Anto RJ, Mukhopadhyay A, Shishodia S, Gairola CG, Aggarwal BB. Cigarette smoke condensate activates nuclear transcription factor-kappaB through phosphorylation and degradation of IkappaB(alpha): correlation with induction of cyclooxygenase-2. Carcinogenesis. Sep 2002;23(9):1511-1518.
20. Gebel S, Muller T. The activity of NF-kappaB in Swiss 3T3 cells exposed to aqueous extracts of cigarette smoke is dependent on thioredoxin. Toxicol Sci. Jan 2001;59(1):75-81.
21. Laan M, Bozinovski S, Anderson GP. Cigarette smoke inhibits lipopolysaccharide-induced production of inflammatory cytokines by suppressing the activation of activator protein-1 in bronchial epithelial cells. J Immunol. Sep 15 2004;173(6):4164-4170.
22. Tamaoki J, Kadota J, Takizawa H. Clinical implications of the immunomodulatory effects of macrolides. Am J Med. Nov 8 2004;117 Suppl 9A:5S-11S.
23. Rahman I, MacNee W. Oxidative stress and regulation of glutathione inlung inflammation. Eur Respir J. Sep 2000;16(3):534-554.
24. Adcock IM, Cosio B, Tsaprouni L, Barnes PJ, Ito K. Redox regulation of histone deacetylases and glucocorticoid-mediated inhibition of the inflammatory response. Antioxid Redox Signal. Jan-Feb 2005;7(1-2):144-152.
25. Rahman I, Adcock IM. Oxidative stress and redox regulation of lung inflammation in COPD. Eur Respir J. Jul 2006;28(1):219-242.
26. Rahman I, Gilmour PS, Jimenez LA, MacNee W. Oxidative stress and TNF-alpha induce histone acetylation and NF-kappaB/AP-1 activation in alveolar epithelial cells: potential mechanism in gene transcription in lung inflammation. Mol Cell Biochem. May-Jun 2002;234-235(1-2):239-248.
27. Nishikawa M, Kakemizu N, Ito T, et al. Superoxide mediates cigarette smoke-induced infiltration of neutrophils into the airways through nuclear factor-kappaB activation and IL-8 mRNA expression in guinea pigs in vivo. Am J Respir Cell Mol Biol. Feb 1999;20(2):189-198.
28. Desaki M, Takizawa H, Ohtoshi T, et al. Erythromycin suppresses nuclear factor-kappaB and activator protein-1 activation in human bronchial epithelial cells. Biochem Biophys Res Commun. Jan 7 2000;267(1):124-128.
29. Desaki M, Okazaki H, Sunazuka T, Omura S, Yamamoto K, Takizawa H. Molecular mechanisms of anti-inflammatory action of erythromycin in human bronchial epithelial cells: possible role in the signaling pathway that regulates nuclear factor-kappaB activation. Antimicrob Agents Chemother. May 2004;48(5):1581-1585.
30. Wu L, Lin JH, Bao K, Li PF, Zhang WG. In vitro effects of erythromycin on RANKL and nuclear factor-kappa B by human TNF-alpha stimulatedJurkat cells. Int Immunopharmacol. Aug 2009;9(9):1105-1109.
31. Wu L, Zhang W, Tian L, Bao K, Li P, Lin J. Immunomodulatory effects of erythromycin and its derivatives on human T-lymphocyte in vitro. Immunopharmacol Immunotoxicol. 2007;29(3-4):587-596.
32. He JX, Zhao SY, Jiang ZF. [Demonstration of a mechanism of anti-inflammatory effect of erythromycin on allergic airway inflammation in rat]. Zhonghua Er Ke Za Zhi. Mar 2005;43(3):196-198.
33. Nordskog BK, Fields WR, Hellmann GM. Kinetic analysis of cytokine response to cigarette smoke condensate by human endothelial and monocytic cells. Toxicology. Sep 1 2005;212(2-3):87-97.
1. Gotfried MH. Macrolides for the treatment of chronic sinusitis, asthma, and COPD. Chest. Feb 2004;125(2 Suppl):52S-60S; quiz 60S-61S.
2. Kikuchi T, Hagiwara K, Honda Y, et al. Clarithromycin suppresses lipopolysaccharide-induced interleukin-8 production by human monocytes through AP-1 and NF-kappa B transcription factors. J Antimicrob Chemother. May 2002;49(5):745-755.
3. Banerjee D, Honeybourne D, Khair OA. The effect of oral clarithromycin on bronchial airway inflammation in moderate-to-severe stable COPD: a randomized controlled trial. Treat Respir Med. 2004;3(1):59-65.
4. Basyigit I, Yildiz F, Ozkara SK, Yildirim E, Boyaci H, Ilgazli A. The effect of clarithromycin on inflammatory markers in chronic obstructive pulmonary disease: preliminary data. Ann Pharmacother. Sep 2004;38(9):1400-1405.
5. Parnham MJ, Culic O, Erakovic V, et al. Modulation of neutrophil and inflammation markers in chronic obstructive pulmonary disease by short-term azithromycin treatment. Eur J Pharmacol. Jul 4 2005;517(1-2):132-143.
6. Suzuki T, Yanai M, Yamaya M, et al. Erythromycin and common cold in COPD. Chest. Sep 2001;120(3):730-733.
7. Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ, Wedzicha JA. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. Dec 1 2008;178(11):1139-1147.
8. Moodie FM, Marwick JA, Anderson CS, et al. Oxidative stress andcigarette smoke alter chromatin remodeling but differentially regulate NF-kappaB activation and proinflammatory cytokine release in alveolar epithelial cells. FASEB J. Dec 2004;18(15):1897-1899.
9. Sundstrom C, Nilsson K. Establishment and characterization of a human histiocytic lymphoma cell line (U-937). Int J Cancer. May 15 1976;17(5):565-577.
10. Verhoeckx KC, Bijlsma S, de Groene EM, Witkamp RF, van der Greef J, Rodenburg RJ. A combination of proteomics, principal component analysis and transcriptomics is a powerful tool for the identification of biomarkers for macrophage maturation in the U937 cell line. Proteomics. Apr 2004;4(4):1014-1028.
11. Izeboud CA, Vermeulen RM, Zwart A, Voss HP, van Miert AS, Witkamp RF. Stereoselectivity at the beta2-adrenoceptor on macrophages is a major determinant of the anti-inflammatory effects of beta2-agonists. Naunyn Schmiedebergs Arch Pharmacol. Aug 2000;362(2):184-189.
12. Carp H, Janoff A. Possible mechanisms of emphysema in smokers. In vitro suppression of serum elastase-inhibitory capacity by fresh cigarette smoke and its prevention by antioxidants. Am Rev Respir Dis. Sep 1978;118(3):617-621.
13. Yang SR, Chida AS, Bauter MR, et al. Cigarette smoke induces proinflammatory cytokine release by activation of NF-kappaB and posttranslational modifications of histone deacetylase in macrophages. Am J Physiol Lung Cell Mol Physiol. Jul 2006;291(1):L46-57.
14. Martey CA, Pollock SJ, Turner CK, et al. Cigarette smoke induces cyclooxygenase-2 and microsomal prostaglandin E2 synthase in human lung fibroblasts: implications for lung inflammation and cancer. Am JPhysiol Lung Cell Mol Physiol. Nov 2004;287(5):L981-991.
15. Barnes PJ, Adcock IM, Ito K. Histone acetylation and deacetylation: importance in inflammatory lung diseases. Eur Respir J. Mar 2005;25(3):552-563.
16. Espino PS, Drobic B, Dunn KL, Davie JR. Histone modifications as a platform for cancer therapy. J Cell Biochem. Apr 15 2005;94(6):1088-1102.
17. Strahl BD, Allis CD. The language of covalent histone modifications. Nature. Jan 6 2000;403(6765):41-45.
18. Villar-Garea A, Imhof A. The analysis of histone modifications. Biochim Biophys Acta. Dec 2006;1764(12):1932-1939.
19. Adcock IM, Ford P, Ito K, Barnes PJ. Epigenetics and airways disease. Respir Res. 2006;7:21.
20. Barnes PJ. Reduced histone deacetylase in COPD: clinical implications. Chest. Jan 2006;129(1):151-155.
21. Girodet PO. [What is the therapeutic response to corticosteroid in smokers with asthma?]. Rev Mal Respir. Feb 2008;25(2):185-192.
22. Thomson NC, Chaudhuri R, Livingston E. Asthma and cigarette smoking. Eur Respir J. Nov 2004;24(5):822-833.
23. Van Overveld FJ, Demkow U, Gorecka D, De Backer WA, Zielinski J. Differences in responses upon corticosteroid therapy between smoking and non-smoking patients with COPD. J Physiol Pharmacol. Sep 2006;57 Suppl 4:273-282.
24. Cosio BG, Tsaprouni L, Ito K, Jazrawi E, Adcock IM, Barnes PJ. Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med. Sep 6 2004;200(5):689-695.
25. Rajendrasozhan S, Yao H, Rahman I. Current perspectives on role of chromatin modifications and deacetylases in lung inflammation in COPD. COPD. Aug 2009;6(4):291-297.
26. Meja KK, Rajendrasozhan S, Adenuga D, et al. Curcumin restores corticosteroid function in monocytes exposed to oxidants by maintaining HDAC2. Am J Respir Cell Mol Biol. Sep 2008;39(3):312-323.
27. Barnes PJ. Role of HDAC2 in the pathophysiology of COPD. Annu Rev Physiol. 2009;71:451-464.
28. Adcock IM, Tsaprouni L, Bhavsar P, Ito K. Epigenetic regulation of airway inflammation. Curr Opin Immunol. Dec 2007;19(6):694-700.
29. Barnes PJ. How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Br J Pharmacol. Jun 2006;148(3):245-254.
30. Barnes PJ, Ito K, Adcock IM. Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase. Lancet. Feb 28 2004;363(9410):731-733.
31. de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J. Mar 15 2003;370(Pt 3):737-749.
32. Gray SG, Ekstrom TJ. The human histone deacetylase family. Exp Cell Res. Jan 15 2001;262(2):75-83.
33. Ito K, Barnes PJ, Adcock IM. Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1beta-induced histone H4 acetylation on lysines 8 and 12. Mol Cell Biol. Sep 2000;20(18):6891-6903.
34. Ito K, Yamamura S, Essilfie-Quaye S, et al. Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enablesNF-kappaB suppression. J Exp Med. Jan 23 2006;203(1):7-13.
35. Ito K, Hanazawa T, Tomita K, Barnes PJ, Adcock IM. Oxidative stress reduces histone deacetylase 2 activity and enhances IL-8 gene expression: role of tyrosine nitration. Biochem Biophys Res Commun. Feb 27 2004;315(1):240-245.
36. Marwick JA, Kirkham PA, Stevenson CS, et al. Cigarette smoke alters chromatin remodeling and induces proinflammatory genes in rat lungs. Am J Respir Cell Mol Biol. Dec 2004;31(6):633-642.
37. Ito K, Ito M, Elliott WM, et al. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N Engl J Med. May 12 2005;352(19):1967-1976.
38. Ito K, Lim S, Caramori G, Chung KF, Barnes PJ, Adcock IM. Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions in alveolar macrophages. FASEB J. Apr 2001;15(6):1110-1112.
39. Barnes PJ. Targeting histone deacetylase 2 in chronic obstructive pulmonary disease treatment. Expert Opin Ther Targets. Dec 2005;9(6):1111-1121.
40. Barnes PJ. Theophylline in chronic obstructive pulmonary disease: new horizons. Proc Am Thorac Soc. 2005;2(4):334-339; discussion 340-331.
41. Barnes PJ. Transcription factors in airway diseases. Lab Invest. Sep 2006;86(9):867-872.
42. Rahman I, Marwick J, Kirkham P. Redox modulation of chromatin remodeling: impact on histone acetylation and deacetylation, NF-kappaB and pro-inflammatory gene expression. Biochem Pharmacol. Sep 15 2004;68(6):1255-1267.
43. Cosio BG, Mann B, Ito K, et al. Histone acetylase and deacetylase activity in alveolar macrophages and blood mononocytes in asthma. Am J Respir Crit Care Med. Jul 15 2004;170(2):141-147.
44. Rajendrasozhan S, Yang SR, Edirisinghe I, Yao H, Adenuga D, Rahman I. Deacetylases and NF-kappaB in redox regulation of cigarette smoke-induced lung inflammation: epigenetics in pathogenesis of COPD. Antioxid Redox Signal. Apr 2008;10(4):799-811.
45. Chen L, Fischle W, Verdin E, Greene WC. Duration of nuclear NF-kappaB action regulated by reversible acetylation. Science. Aug 31 2001;293(5535):1653-1657.
46. Zhong H, May MJ, Jimi E, Ghosh S. The phosphorylation status of nuclear NF-kappa B determines its association with CBP/p300 or HDAC-1. Mol Cell. Mar 2002;9(3):625-636.
47. Sengupta N, Seto E. Regulation of histone deacetylase activities. J Cell Biochem. Sep 1 2004;93(1):57-67.
1. Anto JM, Vermeire P, Vestbo J, Sunyer J. Epidemiology of chronic obstructive pulmonary disease. Eur Respir J. May 2001;17(5):982-994.
2. Ward MM, Javitz HS, Smith WM, Bakst A. Direct medical cost of chronic obstructive pulmonary disease in the U.S.A. Respir Med. Nov 2000;94(11):1123-1129.
3. Halbert RJ, Isonaka S, George D, Iqbal A. Interpreting COPD prevalence estimates: what is the true burden of disease? Chest. May 2003;123(5):1684-1692.
4. Halpern MT, Higashi MK, Bakst AW, Schmier JK. The economic impact of acute exacerbations of chronic bronchitis in the United States and Canada: a literature review. J Manag Care Pharm. Jul-Aug 2003;9(4):353-359.
5. Wouters EF. Economic analysis of the Confronting COPD survey: an overview of results. Respir Med. Mar 2003;97 Suppl C:S3-14.
6. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med. Apr 2001;163(5):1256-1276.
7. Mannino DM, Homa DM, Akinbami LJ, Ford ES, Redd SC. Chronic obstructive pulmonary disease surveillance--United States, 1971-2000. Respir Care. Oct 2002;47(10):1184-1199.
8. Petty TL. Scope of the COPD problem in North America: earlystudies of prevalence and NHANES III data: basis for early identification and intervention. Chest. May 2000;117(5 Suppl 2):326S-331S.
9. Stoller JK. Clinical practice. Acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med. Mar 28 2002;346(13):988-994.
10. Gulsvik A. The global burden and impact of chronic obstructive pulmonary disease worldwide. Monaldi Arch Chest Dis. Jun 2001;56(3):261-264.
11. Sethi S. Infectious etiology of acute exacerbations of chronic bronchitis. Chest. May 2000;117(5 Suppl 2):380S-385S.
12. Aaron SD, Angel JB, Lunau M, et al. Granulocyte inflammatory markers and airway infection during acute exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. Feb 2001;163(2):349-355.
13. Gompertz S, O'Brien C, Bayley DL, Hill SL, Stockley RA. Changes in bronchial inflammation during acute exacerbations of chronic bronchitis. Eur Respir J. Jun 2001;17(6):1112-1119.
14. Wedzicha JA. Exacerbations: etiology and pathophysiologic mechanisms. Chest. May 2002;121(5 Suppl):136S-141S.
15. Pietila MP, Thomas CF. Inflammation and infection in exacerbations of chronic obstructive pulmonary disease. Semin Respir Infect. Mar 2003;18(1):9-16.
16. White AJ, Gompertz S, Bayley DL, et al. Resolution of bronchial inflammation is related to bacterial eradication following treatment of exacerbations of chronic bronchitis. Thorax. Aug2003;58(8):680-685.
17. Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. Jun 24 2004;350(26):2645-2653.
18. Shapiro SD, Ingenito EP. The pathogenesis of chronic obstructive pulmonary disease: advances in the past 100 years. Am J Respir Cell Mol Biol. May 2005;32(5):367-372.
19. Wouters EF. Local and systemic inflammation in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2005;2(1):26-33.
20. Roland M, Bhowmik A, Sapsford RJ, et al. Sputum and plasma endothelin-1 levels in exacerbations of chronic obstructive pulmonary disease. Thorax. Jan 2001;56(1):30-35.
21. Fujimoto K, Yasuo M, Urushibata K, Hanaoka M, Koizumi T, Kubo K. Airway inflammation during stable and acutely exacerbated chronic obstructive pulmonary disease. Eur Respir J. Apr 2005;25(4):640-646.
22. Zhu J, Qiu YS, Majumdar S, et al. Exacerbations of Bronchitis: bronchial eosinophilia and gene expression for interleukin-4, interleukin-5, and eosinophil chemoattractants. Am J Respir Crit Care Med. Jul 1 2001;164(1):109-116.
23. Qiu Y, Zhu J, Bandi V, et al. Biopsy neutrophilia, neutrophil chemokine and receptor gene expression in severe exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. Oct 15 2003;168(8):968-975.
24. Drost EM, Skwarski KM, Sauleda J, et al. Oxidative stress andairway inflammation in severe exacerbations of COPD. Thorax. Apr 2005;60(4):293-300.
25. Ito K, Ito M, Elliott WM, et al. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N Engl J Med. May 12 2005;352(19):1967-1976.
26. Rutgers SR, Postma DS, ten Hacken NH, et al. Ongoing airway inflammation in patients with COPD who Do not currently smoke. Chest. May 2000;117(5 Suppl 1):262S.
27. Amin K, Ekberg-Jansson A, Lofdahl CG, Venge P. Relationship between inflammatory cells and structural changes in the lungs of asymptomatic and never smokers: a biopsy study. Thorax. Feb 2003;58(2):135-142.
28. Caramori G, Adcock I. Pharmacology of airway inflammation in asthma and COPD. Pulm Pharmacol Ther. 2003;16(5):247-277.
29. Di Stefano A, Caramori G, Ricciardolo FL, Capelli A, Adcock IM, Donner CF. Cellular and molecular mechanisms in chronic obstructive pulmonary disease: an overview. Clin Exp Allergy. Aug 2004;34(8):1156-1167.
30. Di Stefano A, Capelli A, Lusuardi M, et al. Decreased T lymphocyte infiltration in bronchial biopsies of subjects with severe chronic obstructive pulmonary disease. Clin Exp Allergy. Jun 2001;31(6):893-902.
31. Hill AT, Campbell EJ, Hill SL, Bayley DL, Stockley RA. Association between airway bacterial load and markers of airway inflammation in patients with stable chronic bronchitis. Am J Med. Sep 2000;109(4):288-295.
32. Turato G, Zuin R, Miniati M, et al. Airway inflammation in severe chronic obstructive pulmonary disease: relationship with lung function and radiologic emphysema. Am J Respir Crit Care Med. Jul 1 2002;166(1):105-110.
33. Russell RE, Culpitt SV, DeMatos C, et al. Release and activity of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 by alveolar macrophages from patients with chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol. May 2002;26(5):602-609.
34. Russell RE, Thorley A, Culpitt SV, et al. Alveolar macrophage-mediated elastolysis: roles of matrix metalloproteinases, cysteine, and serine proteases. Am J Physiol Lung Cell Mol Physiol. Oct 2002;283(4):L867-873.
35. Saetta M, Mariani M, Panina-Bordignon P, et al. Increased expression of the chemokine receptor CXCR3 and its ligand CXCL10 in peripheral airways of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. May 15 2002;165(10):1404-1409.
36. Majo J, Ghezzo H, Cosio MG. Lymphocyte population and apoptosis in the lungs of smokers and their relation to emphysema. Eur Respir J. May 2001;17(5):946-953.
37. Grumelli S, Corry DB, Song LZ, et al. An immune basis for lung parenchymal destruction in chronic obstructive pulmonary disease and emphysema. PLoS Med. Oct 2004;1(1):e8.
38. Barnes PJ, Shapiro SD, Pauwels RA. Chronic obstructive pulmonary disease: molecular and cellular mechanisms. EurRespir J. Oct 2003;22(4):672-688.
39. Agusti AG. COPD, a multicomponent disease: implications for management. Respir Med. Jun 2005;99(6):670-682.
40. Wedzicha JA. The heterogeneity of chronic obstructive pulmonary disease. Thorax. Aug 2000;55(8):631-632.
41. Hurst JR, Perera WR, Wilkinson TM, Donaldson GC, Wedzicha JA. Systemic and upper and lower airway inflammation at exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. Jan 1 2006;173(1):71-78.
42. Garcia-Aymerich J, Tobias A, Anto JM, Sunyer J. Air pollution and mortality in a cohort of patients with chronic obstructive pulmonary disease: a time series analysis. J Epidemiol Community Health. Jan 2000;54(1):73-74.
43. Sunyer J, Schwartz J, Tobias A, Macfarlane D, Garcia J, Anto JM. Patients with chronic obstructive pulmonary disease are at increased risk of death associated with urban particle air pollution: a case-crossover analysis. Am J Epidemiol. Jan 1 2000;151(1):50-56.
44. Sethi S. Bacteria in exacerbations of chronic obstructive pulmonary disease: phenomenon or epiphenomenon? Proc Am Thorac Soc. 2004;1(2):109-114.
45. Wilkinson TM, Donaldson GC, Hurst JR, Seemungal TA, Wedzicha JA. Early therapy improves outcomes of exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. Jun 15 2004;169(12):1298-1303.
46. Johnston SL. Overview of virus-induced airway disease. Proc AmThorac Soc. 2005;2(2):150-156.
47. Parnham MJ. Immunomodulatory effects of antimicrobials in the therapy of respiratory tract infections. Curr Opin Infect Dis. Apr 2005;18(2):125-131.
48. Culic O, Erakovic V, Cepelak I, et al. Azithromycin modulates neutrophil function and circulating inflammatory mediators in healthy human subjects. Eur J Pharmacol. Aug 30 2002;450(3):277-289.
49. Tsai WC, Standiford TJ. Immunomodulatory effects of macrolides in the lung: lessons from in-vitro and in-vivo models. Curr Pharm Des. 2004;10(25):3081-3093.
50. Parnham MJ, Culic O, Erakovic V, et al. Modulation of neutrophil and inflammation markers in chronic obstructive pulmonary disease by short-term azithromycin treatment. Eur J Pharmacol. Jul 4 2005;517(1-2):132-143.
51. Callard R, George AJ, Stark J. Cytokines, chaos, and complexity. Immunity. Nov 1999;11(5):507-513.
52. Shinkai M, Lopez-Boado YS, Rubin BK. Clarithromycin has an immunomodulatory effect on ERK-mediated inflammation induced by Pseudomonas aeruginosa flagellin. J Antimicrob Chemother. Jun 2007;59(6):1096-1101.
53. Shinkai M, Foster GH, Rubin BK. Macrolide antibiotics modulate ERK phosphorylation and IL-8 and GM-CSF production by human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol. Jan 2006;290(1):L75-85.
54. Shinkai M, Tamaoki J, Kobayashi H, et al. Clarithromycin delaysprogression of bronchial epithelial cells from G1 phase to S phase and delays cell growth via extracellular signal-regulated protein kinase suppression. Antimicrob Agents Chemother. May 2006;50(5):1738-1744.
55. Kikuchi T, Hagiwara K, Honda Y, et al. Clarithromycin suppresses lipopolysaccharide-induced interleukin-8 production by human monocytes through AP-1 and NF-kappa B transcription factors. J Antimicrob Chemother. May 2002;49(5):745-755.
56. Takaki M, Ushikai M, Deguchi K, Nishimoto K, Matsune S, Kurono Y. The role of nuclear factor-kappa B in interleukin-8 expression by human adenoidal fibroblasts. Laryngoscope. Aug 2003;113(8):1378-1385.
57. Desaki M, Okazaki H, Sunazuka T, Omura S, Yamamoto K, Takizawa H. Molecular mechanisms of anti-inflammatory action of erythromycin in human bronchial epithelial cells: possible role in the signaling pathway that regulates nuclear factor-kappaB activation. Antimicrob Agents Chemother. May 2004;48(5):1581-1585.
58. Reato G, Cuffini AM, Tullio V, et al. Immunomodulating effect of antimicrobial agents on cytokine production by human polymorphonuclear neutrophils. Int J Antimicrob Agents. Feb 2004;23(2):150-154.
59. Ishizawa K, Suzuki T, Yamaya M, et al. Erythromycin increases bactericidal activity of surface liquid in human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol. Oct 2005;289(4):L565-573.
60. Khan AA, Slifer TR, Araujo FG, Remington JS. Effect of clarithromycin and azithromycin on production of cytokines by human monocytes. Int J Antimicrob Agents. Feb 1999;11(2):121-132.
61. Suzaki H, Asano K, Ohki S, Kanai K, Mizutani T, Hisamitsu T. Suppressive activity of a macrolide antibiotic, roxithromycin, on pro-inflammatory cytokine production in vitro and in vivo. Mediators Inflamm. 1999;8(4-5):199-204.
62. Yamasawa H, Oshikawa K, Ohno S, Sugiyama Y. Macrolides inhibit epithelial cell-mediated neutrophil survival by modulating granulocyte macrophage colony-stimulating factor release. Am J Respir Cell Mol Biol. Apr 2004;30(4):569-575.
63. Hashimoto N, Kawabe T, Hara T, et al. Effect of erythromycin on matrix metalloproteinase-9 and cell migration. J Lab Clin Med. Mar 2001;137(3):176-183.
64. Kanai K, Asano K, Hisamitsu T, Suzaki H. Suppression of matrix metalloproteinase production from nasal fibroblasts by macrolide antibiotics in vitro. Eur Respir J. May 2004;23(5):671-678.
65. Villagrasa V, Berto L, Cortijo J, Perpina M, Sanz C, Morcillo EJ. Effects of erythromycin on chemoattractant-activated human polymorphonuclear leukocytes. Gen Pharmacol. Oct 1997;29(4):605-609.
66. Tsai WC, Rodriguez ML, Young KS, et al. Azithromycin blocks neutrophil recruitment in Pseudomonas endobronchial infection. Am J Respir Crit Care Med. Dec 15 2004;170(12):1331-1339.
67. Inamura K, Ohta N, Fukase S, Kasajima N, Aoyagi M. The effects of erythromycin on human peripheral neutrophil apoptosis. Rhinology. Sep 2000;38(3):124-129.
68. Ogawa N, Sugawara Y, Fujiwara Y, Noma T. Roxithromycin promotes lymphocyte apoptosis in Dermatophagoides-sensitive asthma patients. Eur J Pharmacol. Aug 8 2003;474(2-3):273-281.
69. Kadota J, Mizunoe S, Kishi K, Tokimatsu I, Nagai H, Nasu M. Antibiotic-induced apoptosis in human activated peripheral lymphocytes. Int J Antimicrob Agents. Mar 2005;25(3):216-220.
70. Shimizu T, Shimizu S, Hattori R, Gabazza EC, Majima Y. In vivo and in vitro effects of macrolide antibiotics on mucus secretion in airway epithelial cells. Am J Respir Crit Care Med. Sep 1 2003;168(5):581-587.
71. Imamura Y, Yanagihara K, Mizuta Y, et al. Azithromycin inhibits MUC5AC production induced by the Pseudomonas aeruginosa autoinducer N-(3-Oxododecanoyl) homoserine lactone in NCI-H292 Cells. Antimicrob Agents Chemother. Sep 2004;48(9):3457-3461.
72. Yatsunami J, Hayashi S. Fourteen-membered ring macrolides as anti-angiogenic compounds. Anticancer Res. Nov-Dec 2001;21(6B):4253-4258.
73. Desaki M, Takizawa H, Ohtoshi T, et al. Erythromycin suppresses nuclear factor-kappaB and activator protein-1 activation in human bronchial epithelial cells. Biochem Biophys Res Commun. Jan 7 2000;267(1):124-128.
74. Wozniak DJ, Keyser R. Effects of subinhibitory concentrations of macrolide antibiotics on Pseudomonas aeruginosa. Chest. Feb2004;125(2 Suppl):62S-69S; quiz 69S.
75. Pechere JC. New perspectives on macrolide antibiotics. Int J Antimicrob Agents. 2001;18 Suppl 1:S93-97.
76. Baumann U, Fischer JJ, Gudowius P, et al. Buccal adherence of Pseudomonas aeruginosa in patients with cystic fibrosis under long-term therapy with azithromycin. Infection. Jan-Feb 2001;29(1):7-11.
77. Tsang KW, Ng P, Ho PL, et al. Effects of erythromycin on Pseudomonas aeruginosa adherence to collagen and morphology in vitro. Eur Respir J. Mar 2003;21(3):401-406.
78. Tateda K, Comte R, Pechere JC, Kohler T, Yamaguchi K, Van Delden C. Azithromycin inhibits quorum sensing in Pseudomonas aeruginosa. Antimicrob Agents Chemother. Jun 2001;45(6):1930-1933.
79. Nagata T, Mukae H, Kadota J, et al. Effect of erythromycin on chronic respiratory infection caused by Pseudomonas aeruginosa with biofilm formation in an experimental murine model. Antimicrob Agents Chemother. Jun 2004;48(6):2251-2259.
80. Gillis RJ, Iglewski BH. Azithromycin retards Pseudomonas aeruginosa biofilm formation. J Clin Microbiol. Dec 2004;42(12):5842-5845.
81. Wagner T, Soong G, Sokol S, Saiman L, Prince A. Effects of azithromycin on clinical isolates of Pseudomonas aeruginosa from cystic fibrosis patients. Chest. Aug 2005;128(2):912-919.
82. Rubin BK. Immunomodulatory properties of macrolides: overview and historical perspective. Am J Med. Nov 8 2004;117 Suppl9A:2S-4S.
83. Labro MT. Macrolide antibiotics: current and future uses. Expert Opin Pharmacother. Mar 2004;5(3):541-550.
84. Shinkai M, Rubin BK. Macrolides and airway inflammation in children. Paediatr Respir Rev. Sep 2005;6(3):227-235.
85. Henke MO, Shah SA, Rubin BK. The role of airway secretions in COPD--clinical applications. COPD. Sep 2005;2(3):377-390.
86. Johnston SL. Macrolide antibiotics and asthma treatment. J Allergy Clin Immunol. Jun 2006;117(6):1233-1236.
87. Giamarellos-Bourboulis EJ. Macrolides beyond the conventional antimicrobials: a class of potent immunomodulators. Int J Antimicrob Agents. Jan 2008;31(1):12-20.
88. Wilson R, Kubin R, Ballin I, et al. Five day moxifloxacin therapy compared with 7 day clarithromycin therapy for the treatment of acute exacerbations of chronic bronchitis. J Antimicrob Chemother. Oct 1999;44(4):501-513.
89. Wilson KG, Aaron SD, Vandemheen KL, et al. Evaluation of a decision aid for making choices about intubation and mechanical ventilation in chronic obstructive pulmonary disease. Patient Educ Couns. Apr 2005;57(1):88-95.
90. Suzuki T, Yanai M, Yamaya M, et al. Erythromycin and common cold in COPD. Chest. Sep 2001;120(3):730-733.
91. Gomez J, Banos V, Simarro E, et al. [Prospective, comparative study (1994-1998) of the influence of short-term prophylactic treatment with azithromycin on patients with advanced COPD]. Rev Esp Quimioter. Dec 2000;13(4):379-383.
92. Basyigit I, Yildiz F, Ozkara SK, Yildirim E, Boyaci H, Ilgazli A. The effect of clarithromycin on inflammatory markers in chronic obstructive pulmonary disease: preliminary data. Ann Pharmacother. Sep 2004;38(9):1400-1405.
93. Banerjee D, Khair OA, Honeybourne D. The effect of oral clarithromycin on health status and sputum bacteriology in stable COPD. Respir Med. Feb 2005;99(2):208-215.
94. Banerjee D, Honeybourne D, Khair OA. The effect of oral clarithromycin on bronchial airway inflammation in moderate-to-severe stable COPD: a randomized controlled trial. Treat Respir Med. 2004;3(1):59-65.
95. Banerjee D, Khair OA, Honeybourne D. Impact of sputum bacteria on airway inflammation and health status in clinical stable COPD. Eur Respir J. May 2004;23(5):685-691.
96. Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ, Wedzicha JA. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. Dec 1 2008;178(11):1139-1147.
97. Tagaya E, Tamaoki J, Kondo M, Nagai A. Effect of a short course of clarithromycin therapy on sputum production in patients with chronic airway hypersecretion. Chest. Jul 2002;122(1):213-218.
2. Donnelly LE, Rogers DF. Therapy for chronic obstructive pulmonary disease in the 21st century. Drugs. 2003;63(19):1973-1998.
3. Gulsvik A. The global burden and impact of chronic obstructive pulmonary disease worldwide. Monaldi Arch Chest Dis. Jun 2001;56(3):261-264.
4. Ward SA, Casaburi R. 21st century perspective on chronic obstructive pulmonary disease. Respiration. 2001;68(6):557-561.
5. Rahman I, MacNee W. Lung glutathione and oxidative stress: implications in cigarette smoke-induced airway disease. Am J Physiol. Dec 1999;277(6 Pt 1):L1067-1088.
6. Rytila P, Rehn T, Ilumets H, et al. Increased oxidative stress in asymptomatic current chronic smokers and GOLD stage 0 COPD. Respir Res. 2006;7:69.
7. Marwick JA, Kirkham PA, Stevenson CS, et al. Cigarette smoke alters chromatin remodeling and induces proinflammatory genes in rat lungs. Am J Respir Cell Mol Biol. Dec 2004;31(6):633-642.
8. Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. Jun 24 2004;350(26):2645-2653.
9. Saetta M, Turato G, Maestrelli P, Mapp CE, Fabbri LM. Cellular andstructural bases of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. May 2001;163(6):1304-1309.
10. Kirkham P, Rahman I. Oxidative stress in asthma and COPD: antioxidants as a therapeutic strategy. Pharmacol Ther. Aug 2006;111(2):476-494.
11. Mahfouz M, Qi Z, Kummerow FA. Inhibition of prostacyclin release by cigarette smoke extract in endothelial cells is not related to enhanced superoxide generation and NADPH-oxidase activation. J Environ Pathol Toxicol Oncol. 2006;25(3):585-595.
12. Proulx LI, Pare G, Bissonnette EY. Alveolar macrophage cytotoxic activity is inhibited by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a carcinogenic component of cigarette smoke. Cancer Immunol Immunother. Jun 2007;56(6):831-838.
13. Rahman I. Oxidative stress, chromatin remodeling and gene transcription in inflammation and chronic lung diseases. J Biochem Mol Biol. Jan 31 2003;36(1):95-109.
14. Adcock IM, Cosio B, Tsaprouni L, Barnes PJ, Ito K. Redox regulation of histone deacetylases and glucocorticoid-mediated inhibition of the inflammatory response. Antioxid Redox Signal. Jan-Feb 2005;7(1-2):144-152.
15. Rahman I, Adcock IM. Oxidative stress and redox regulation of lung inflammation in COPD. Eur Respir J. Jul 2006;28(1):219-242.
16. Urnov FD, Wolffe AP. Chromatin remodeling and transcriptional activation: the cast (in order of appearance). Oncogene. May 28 2001;20(24):2991-3006.
17. Gilmour PS, Rahman I, Donaldson K, MacNee W. Histone acetylation regulates epithelial IL-8 release mediated by oxidative stress fromenvironmental particles. Am J Physiol Lung Cell Mol Physiol. Mar 2003;284(3):L533-540.
18. Iwata K, Tomita K, Sano H, Fujii Y, Yamasaki A, Shimizu E. Trichostatin A, a histone deacetylase inhibitor, down-regulates interleukin-12 transcription in SV-40-transformed lung epithelial cells. Cell Immunol. Jul-Aug 2002;218(1-2):26-33.
19. Tomita K, Barnes PJ, Adcock IM. The effect of oxidative stress on histone acetylation and IL-8 release. Biochem Biophys Res Commun. Feb 7 2003;301(2):572-577.
20. Ito K, Ito M, Elliott WM, et al. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N Engl J Med. May 12 2005;352(19):1967-1976.
21. Barnes PJ. Reduced histone deacetylase in COPD: clinical implications. Chest. Jan 2006;129(1):151-155.
22. de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J. Mar 15 2003;370(Pt 3):737-749.
23. Ito K, Lim S, Caramori G, et al. A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression. Proc Natl Acad Sci U S A. Jun 25 2002;99(13):8921-8926.
24. Ito K, Barnes PJ, Adcock IM. Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1beta-induced histone H4 acetylation on lysines 8 and 12. Mol Cell Biol. Sep 2000;20(18):6891-6903.
25. Barnes PJ, Ito K, Adcock IM. Corticosteroid resistance in chronicobstructive pulmonary disease: inactivation of histone deacetylase. Lancet. Feb 28 2004;363(9410):731-733.
26. Parnham MJ. Inflammation 2005 - Seventh World Congress. Respiratory inflammation. IDrugs. Oct 2005;8(10):783-786.
27. Barnes PJ. Targeting histone deacetylase 2 in chronic obstructive pulmonary disease treatment. Expert Opin Ther Targets. Dec 2005;9(6):1111-1121.
28. Barnes PJ. Transcription factors in airway diseases. Lab Invest. Sep 2006;86(9):867-872.
29. Barnes PJ. Role of HDAC2 in the pathophysiology of COPD. Annu Rev Physiol. 2009;71:451-464.
30. Barnes PJ, Adcock IM, Ito K. Histone acetylation and deacetylation: importance in inflammatory lung diseases. Eur Respir J. Mar 2005;25(3):552-563.
31. Adcock IM, Ito K, Barnes PJ. Histone deacetylation: an important mechanism in inflammatory lung diseases. COPD. Dec 2005;2(4):445-455.
32. Barnes PJ. Alveolar macrophages in chronic obstructive pulmonary disease (COPD). Cell Mol Biol (Noisy-le-grand). 2004;50 Online Pub:OL627-637.
33. Barnes PJ. How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Br J Pharmacol. Jun 2006;148(3):245-254.
34. Barnes PJ. New concepts in chronic obstructive pulmonary disease. Annu Rev Med. 2003;54:113-129.
35. Culpitt SV, Rogers DF, Shah P, et al. Impaired inhibition by dexamethasone of cytokine release by alveolar macrophages from patientswith chronic obstructive pulmonary disease. Am J Respir Crit Care Med. Jan 1 2003;167(1):24-31.
36. Cosio MG, Saetta M, Agusti A. Immunologic aspects of chronic obstructive pulmonary disease. N Engl J Med. Jun 4 2009;360(23):2445-2454.
37. Cosio BG, Tsaprouni L, Ito K, Jazrawi E, Adcock IM, Barnes PJ. Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med. Sep 6 2004;200(5):689-695.
38. Barnes PJ, Hansel TT. Prospects for new drugs for chronic obstructive pulmonary disease. Lancet. Sep 11-17 2004;364(9438):985-996.
39. Shinkai M, Rubin BK. Macrolides and airway inflammation in children. Paediatr Respir Rev. Sep 2005;6(3):227-235.
40. Henke MO, Shah SA, Rubin BK. The role of airway secretions in COPD--clinical applications. COPD. Sep 2005;2(3):377-390.
41. Rubin BK, Henke MO. Immunomodulatory activity and effectiveness of macrolides in chronic airway disease. Chest. Feb 2004;125(2 Suppl):70S-78S.
42. Johnston SL. Macrolide antibiotics and asthma treatment. J Allergy Clin Immunol. Jun 2006;117(6):1233-1236.
43. Parnham MJ. Immunomodulatory effects of antimicrobials in the therapy of respiratory tract infections. Curr Opin Infect Dis. Apr 2005;18(2):125-131.
44. Giamarellos-Bourboulis EJ. Macrolides beyond the conventional antimicrobials: a class of potent immunomodulators. Int J Antimicrob Agents. Jan 2008;31(1):12-20.
45. Gotfried MH. Macrolides for the treatment of chronic sinusitis, asthma,and COPD. Chest. Feb 2004;125(2 Suppl):52S-60S; quiz 60S-61S.
46. Kikuchi T, Hagiwara K, Honda Y, et al. Clarithromycin suppresses lipopolysaccharide-induced interleukin-8 production by human monocytes through AP-1 and NF-kappa B transcription factors. J Antimicrob Chemother. May 2002;49(5):745-755.
47. Banerjee D, Honeybourne D, Khair OA. The effect of oral clarithromycin on bronchial airway inflammation in moderate-to-severe stable COPD: a randomized controlled trial. Treat Respir Med. 2004;3(1):59-65.
48. Basyigit I, Yildiz F, Ozkara SK, Yildirim E, Boyaci H, Ilgazli A. The effect of clarithromycin on inflammatory markers in chronic obstructive pulmonary disease: preliminary data. Ann Pharmacother. Sep 2004;38(9):1400-1405.
49. Parnham MJ, Culic O, Erakovic V, et al. Modulation of neutrophil and inflammation markers in chronic obstructive pulmonary disease by short-term azithromycin treatment. Eur J Pharmacol. Jul 4 2005;517(1-2):132-143.
50. Seemungal TA, Hurst JR, Wedzicha JA. Exacerbation rate, health status and mortality in COPD--a review of potential interventions. Int J Chron Obstruct Pulmon Dis. 2009;4:203-223.
51. Suzuki T, Yanai M, Yamaya M, et al. Erythromycin and common cold in COPD. Chest. Sep 2001;120(3):730-733.
52. Gomez J, Banos V, Simarro E, et al. [Prospective, comparative study (1994-1998) of the influence of short-term prophylactic treatment with azithromycin on patients with advanced COPD]. Rev Esp Quimioter. Dec 2000;13(4):379-383.
53. Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ,Wedzicha JA. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. Dec 1 2008;178(11):1139-1147.
54. Wilkinson TM, Donaldson GC, Hurst JR, Seemungal TA, Wedzicha JA. Early therapy improves outcomes of exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. Jun 15 2004;169(12):1298-1303.
55. Culic O, Erakovic V, Parnham MJ. Anti-inflammatory effects of macrolide antibiotics. Eur J Pharmacol. Oct 19 2001;429(1-3):209-229.
56. Schultz MJ. Macrolide activities beyond their antimicrobial effects: macrolides in diffuse panbronchiolitis and cystic fibrosis. J Antimicrob Chemother. Jul 2004;54(1):21-28.
57. Tsai WC, Standiford TJ. Immunomodulatory effects of macrolides in the lung: lessons from in-vitro and in-vivo models. Curr Pharm Des. 2004;10(25):3081-3093.
58. Zalewska-Kaszubska J, Gorska D. Anti-inflammatory capabilities of macrolides. Pharmacol Res. Dec 2001;44(6):451-454.
59. Desaki M, Okazaki H, Sunazuka T, Omura S, Yamamoto K, Takizawa H. Molecular mechanisms of anti-inflammatory action of erythromycin in human bronchial epithelial cells: possible role in the signaling pathway that regulates nuclear factor-kappaB activation. Antimicrob Agents Chemother. May 2004;48(5):1581-1585.
1. Gotfried MH. Macrolides for the treatment of chronic sinusitis, asthma, and COPD. Chest. Feb 2004;125(2 Suppl):52S-60S; quiz 60S-61S.
2. Kikuchi T, Hagiwara K, Honda Y, et al. Clarithromycin suppresses lipopolysaccharide-induced interleukin-8 production by human monocytes through AP-1 and NF-kappa B transcription factors. J Antimicrob Chemother. May 2002;49(5):745-755.
3. Banerjee D, Honeybourne D, Khair OA. The effect of oral clarithromycin on bronchial airway inflammation in moderate-to-severe stable COPD: a randomized controlled trial. Treat Respir Med. 2004;3(1):59-65.
4. Basyigit I, Yildiz F, Ozkara SK, Yildirim E, Boyaci H, Ilgazli A. The effect of clarithromycin on inflammatory markers in chronic obstructive pulmonary disease: preliminary data. Ann Pharmacother. Sep 2004;38(9):1400-1405.
5. Parnham MJ, Culic O, Erakovic V, et al. Modulation of neutrophil and inflammation markers in chronic obstructive pulmonary disease by short-term azithromycin treatment. Eur J Pharmacol. Jul 4 2005;517(1-2):132-143.
6. Suzuki T, Yanai M, Yamaya M, et al. Erythromycin and common cold in COPD. Chest. Sep 2001;120(3):730-733.
7. Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ, Wedzicha JA. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. Dec 1 2008;178(11):1139-1147.
8. Sundstrom C, Nilsson K. Establishment and characterization of a human histiocytic lymphoma cell line (U-937). Int J Cancer. May 151976;17(5):565-577.
9. Verhoeckx KC, Bijlsma S, de Groene EM, Witkamp RF, van der Greef J, Rodenburg RJ. A combination of proteomics, principal component analysis and transcriptomics is a powerful tool for the identification of biomarkers for macrophage maturation in the U937 cell line. Proteomics. Apr 2004;4(4):1014-1028.
10. Izeboud CA, Vermeulen RM, Zwart A, Voss HP, van Miert AS, Witkamp RF. Stereoselectivity at the beta2-adrenoceptor on macrophages is a major determinant of the anti-inflammatory effects of beta2-agonists. Naunyn Schmiedebergs Arch Pharmacol. Aug 2000;362(2):184-189.
11. Martey CA, Pollock SJ, Turner CK, et al. Cigarette smoke induces cyclooxygenase-2 and microsomal prostaglandin E2 synthase in human lung fibroblasts: implications for lung inflammation and cancer. Am J Physiol Lung Cell Mol Physiol. Nov 2004;287(5):L981-991.
12. Moodie FM, Marwick JA, Anderson CS, et al. Oxidative stress and cigarette smoke alter chromatin remodeling but differentially regulate NF-kappaB activation and proinflammatory cytokine release in alveolar epithelial cells. FASEB J. Dec 2004;18(15):1897-1899.
13. Carp H, Janoff A. Possible mechanisms of emphysema in smokers. In vitro suppression of serum elastase-inhibitory capacity by fresh cigarette smoke and its prevention by antioxidants. Am Rev Respir Dis. Sep 1978;118(3):617-621.
14. Yang SR, Chida AS, Bauter MR, et al. Cigarette smoke induces proinflammatory cytokine release by activation of NF-kappaB and posttranslational modifications of histone deacetylase in macrophages. Am J Physiol Lung Cell Mol Physiol. Jul 2006;291(1):L46-57.
15. Barnes PJ. Immunology of asthma and chronic obstructive pulmonary disease. Nat Rev Immunol. Mar 2008;8(3):183-192.
16. Cosio MG, Saetta M, Agusti A. Immunologic aspects of chronic obstructive pulmonary disease. N Engl J Med. Jun 4 2009;360(23):2445-2454.
17. Chung KF. Inflammatory mediators in chronic obstructive pulmonary disease. Curr Drug Targets Inflamm Allergy. Dec 2005;4(6):619-625.
18. Tetley TD. Macrophages and the pathogenesis of COPD. Chest. May 2002;121(5 Suppl):156S-159S.
19. Moretto N, Facchinetti F, Southworth T, Civelli M, Singh D, Patacchini R. alpha,beta-Unsaturated aldehydes contained in cigarette smoke elicit IL-8 release in pulmonary cells through mitogen-activated protein kinases. Am J Physiol Lung Cell Mol Physiol. May 2009;296(5):L839-848.
20. Yang SR, Wright J, Bauter M, Seweryniak K, Kode A, Rahman I. Sirtuin regulates cigarette smoke-induced proinflammatory mediator release via RelA/p65 NF-kappaB in macrophages in vitro and in rat lungs in vivo: implications for chronic inflammation and aging. Am J Physiol Lung Cell Mol Physiol. Feb 2007;292(2):L567-576.
21. Mukhopadhyay S, Hoidal JR, Mukherjee TK. Role of TNFalpha in pulmonary pathophysiology. Respir Res. 2006;7:125.
22. Zhang X, Wang L, Zhang H, et al. The effects of cigarette smoke extract on the endothelial production of soluble intercellular adhesion molecule-1 are mediated through macrophages, possibly by inducing TNF-alpha release. Methods Find Exp Clin Pharmacol. Jun 2002;24(5):261-265.
23. Demirjian L, Abboud RT, Li H, Duronio V. Acute effect of cigarette smoke on TNF-alpha release by macrophages mediated through theerk1/2 pathway. Biochim Biophys Acta. Jun 2006;1762(6):592-597.
24. Churg A, Wang X, Wang RD, Meixner SC, Pryzdial EL, Wright JL. Alpha1-antitrypsin suppresses TNF-alpha and MMP-12 production by cigarette smoke-stimulated macrophages. Am J Respir Cell Mol Biol. Aug 2007;37(2):144-151.
25. Barnes PJ, Shapiro SD, Pauwels RA. Chronic obstructive pulmonary disease: molecular and cellular mechanisms. Eur Respir J. Oct 2003;22(4):672-688.
26. Barnes PJ. Alveolar macrophages in chronic obstructive pulmonary disease (COPD). Cell Mol Biol (Noisy-le-grand). 2004;50 Online Pub:OL627-637.
27. Marwick JA, Kirkham PA, Stevenson CS, et al. Cigarette smoke alters chromatin remodeling and induces proinflammatory genes in rat lungs. Am J Respir Cell Mol Biol. Dec 2004;31(6):633-642.
28. Rajendrasozhan S, Yao H, Rahman I. Current perspectives on role of chromatin modifications and deacetylases in lung inflammation in COPD. COPD. Aug 2009;6(4):291-297.
29. Kirkham P, Rahman I. Oxidative stress in asthma and COPD: antioxidants as a therapeutic strategy. Pharmacol Ther. Aug 2006;111(2):476-494.
30. Marwick JA, Ito K, Adcock IM, Kirkham PA. Oxidative stress and steroid resistance in asthma and COPD: pharmacological manipulation of HDAC-2 as a therapeutic strategy. Expert Opin Ther Targets. Jun 2007;11(6):745-755.
31. Adcock IM, Cosio B, Tsaprouni L, Barnes PJ, Ito K. Redox regulation of histone deacetylases and glucocorticoid-mediated inhibition of the inflammatory response. Antioxid Redox Signal. Jan-Feb2005;7(1-2):144-152.
32. Adcock IM, Ito K, Barnes PJ. Histone deacetylation: an important mechanism in inflammatory lung diseases. COPD. Dec 2005;2(4):445-455.
33. Rahman I, Adcock IM. Oxidative stress and redox regulation of lung inflammation in COPD. Eur Respir J. Jul 2006;28(1):219-242.
34. Adcock IM, Ito K. Glucocorticoid pathways in chronic obstructive pulmonary disease therapy. Proc Am Thorac Soc. 2005;2(4):313-319; discussion 340-311.
35. Rahman I, Gilmour PS, Jimenez LA, MacNee W. Oxidative stress and TNF-alpha induce histone acetylation and NF-kappaB/AP-1 activation in alveolar epithelial cells: potential mechanism in gene transcription in lung inflammation. Mol Cell Biochem. May-Jun 2002;234-235(1-2):239-248.
36. Rahman I, Gilmour PS, Jimenez LA, Biswas SK, Antonicelli F, Aruoma OI. Ergothioneine inhibits oxidative stress- and TNF-alpha-induced NF-kappa B activation and interleukin-8 release in alveolar epithelial cells. Biochem Biophys Res Commun. Mar 21 2003;302(4):860-864.
37. Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. Jun 24 2004;350(26):2645-2653.
38. Swords WE, Rubin BK. Macrolide antibiotics, bacterial populations and inflammatory airway disease. Neth J Med. Jul 2003;61(7):242-248.
39. Amsden GW. Anti-inflammatory effects of macrolides--an underappreciated benefit in the treatment of community-acquired respiratory tract infections and chronic inflammatory pulmonary conditions? J Antimicrob Chemother. Jan 2005;55(1):10-21.
1. Gotfried MH. Macrolides for the treatment of chronic sinusitis, asthma, and COPD. Chest. Feb 2004;125(2 Suppl):52S-60S; quiz 60S-61S.
2. Kikuchi T, Hagiwara K, Honda Y, et al. Clarithromycin suppresses lipopolysaccharide-induced interleukin-8 production by human monocytes through AP-1 and NF-kappa B transcription factors. J Antimicrob Chemother. May 2002;49(5):745-755.
3. Banerjee D, Honeybourne D, Khair OA. The effect of oral clarithromycin on bronchial airway inflammation in moderate-to-severe stable COPD: a randomized controlled trial. Treat Respir Med. 2004;3(1):59-65.
4. Basyigit I, Yildiz F, Ozkara SK, Yildirim E, Boyaci H, Ilgazli A. The effect of clarithromycin on inflammatory markers in chronic obstructive pulmonary disease: preliminary data. Ann Pharmacother. Sep 2004;38(9):1400-1405.
5. Parnham MJ, Culic O, Erakovic V, et al. Modulation of neutrophil and inflammation markers in chronic obstructive pulmonary disease by short-term azithromycin treatment. Eur J Pharmacol. Jul 4 2005;517(1-2):132-143.
6. Suzuki T, Yanai M, Yamaya M, et al. Erythromycin and common cold in COPD. Chest. Sep 2001;120(3):730-733.
7. Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ, Wedzicha JA. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. Dec 1 2008;178(11):1139-1147.
8. McDonald PP, Bald A, Cassatella MA. Activation of the NF-kappaBpathway by inflammatory stimuli in human neutrophils. Blood. May 1 1997;89(9):3421-3433.
9. Sundstrom C, Nilsson K. Establishment and characterization of a human histiocytic lymphoma cell line (U-937). Int J Cancer. May 15 1976;17(5):565-577.
10. Verhoeckx KC, Bijlsma S, de Groene EM, Witkamp RF, van der Greef J, Rodenburg RJ. A combination of proteomics, principal component analysis and transcriptomics is a powerful tool for the identification of biomarkers for macrophage maturation in the U937 cell line. Proteomics. Apr 2004;4(4):1014-1028.
11. Izeboud CA, Vermeulen RM, Zwart A, Voss HP, van Miert AS, Witkamp RF. Stereoselectivity at the beta2-adrenoceptor on macrophages is a major determinant of the anti-inflammatory effects of beta2-agonists. Naunyn Schmiedebergs Arch Pharmacol. Aug 2000;362(2):184-189.
12. Martey CA, Pollock SJ, Turner CK, et al. Cigarette smoke induces cyclooxygenase-2 and microsomal prostaglandin E2 synthase in human lung fibroblasts: implications for lung inflammation and cancer. Am J Physiol Lung Cell Mol Physiol. Nov 2004;287(5):L981-991.
13. Moodie FM, Marwick JA, Anderson CS, et al. Oxidative stress and cigarette smoke alter chromatin remodeling but differentially regulate NF-kappaB activation and proinflammatory cytokine release in alveolar epithelial cells. FASEB J. Dec 2004;18(15):1897-1899.
14. Carp H, Janoff A. Possible mechanisms of emphysema in smokers. In vitro suppression of serum elastase-inhibitory capacity by fresh cigarette smoke and its prevention by antioxidants. Am Rev Respir Dis. Sep 1978;118(3):617-621.
15. Yang SR, Chida AS, Bauter MR, et al. Cigarette smoke induces proinflammatory cytokine release by activation of NF-kappaB and posttranslational modifications of histone deacetylase in macrophages. Am J Physiol Lung Cell Mol Physiol. Jul 2006;291(1):L46-57.
16. Wald NJ, Hackshaw AK. Cigarette smoking: an epidemiological overview. Br Med Bull. Jan 1996;52(1):3-11.
17. Barnes PJ. Transcription factors in airway diseases. Lab Invest. Sep 2006;86(9):867-872.
18. Barnes PJ. How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Br J Pharmacol. Jun 2006;148(3):245-254.
19. Anto RJ, Mukhopadhyay A, Shishodia S, Gairola CG, Aggarwal BB. Cigarette smoke condensate activates nuclear transcription factor-kappaB through phosphorylation and degradation of IkappaB(alpha): correlation with induction of cyclooxygenase-2. Carcinogenesis. Sep 2002;23(9):1511-1518.
20. Gebel S, Muller T. The activity of NF-kappaB in Swiss 3T3 cells exposed to aqueous extracts of cigarette smoke is dependent on thioredoxin. Toxicol Sci. Jan 2001;59(1):75-81.
21. Laan M, Bozinovski S, Anderson GP. Cigarette smoke inhibits lipopolysaccharide-induced production of inflammatory cytokines by suppressing the activation of activator protein-1 in bronchial epithelial cells. J Immunol. Sep 15 2004;173(6):4164-4170.
22. Tamaoki J, Kadota J, Takizawa H. Clinical implications of the immunomodulatory effects of macrolides. Am J Med. Nov 8 2004;117 Suppl 9A:5S-11S.
23. Rahman I, MacNee W. Oxidative stress and regulation of glutathione inlung inflammation. Eur Respir J. Sep 2000;16(3):534-554.
24. Adcock IM, Cosio B, Tsaprouni L, Barnes PJ, Ito K. Redox regulation of histone deacetylases and glucocorticoid-mediated inhibition of the inflammatory response. Antioxid Redox Signal. Jan-Feb 2005;7(1-2):144-152.
25. Rahman I, Adcock IM. Oxidative stress and redox regulation of lung inflammation in COPD. Eur Respir J. Jul 2006;28(1):219-242.
26. Rahman I, Gilmour PS, Jimenez LA, MacNee W. Oxidative stress and TNF-alpha induce histone acetylation and NF-kappaB/AP-1 activation in alveolar epithelial cells: potential mechanism in gene transcription in lung inflammation. Mol Cell Biochem. May-Jun 2002;234-235(1-2):239-248.
27. Nishikawa M, Kakemizu N, Ito T, et al. Superoxide mediates cigarette smoke-induced infiltration of neutrophils into the airways through nuclear factor-kappaB activation and IL-8 mRNA expression in guinea pigs in vivo. Am J Respir Cell Mol Biol. Feb 1999;20(2):189-198.
28. Desaki M, Takizawa H, Ohtoshi T, et al. Erythromycin suppresses nuclear factor-kappaB and activator protein-1 activation in human bronchial epithelial cells. Biochem Biophys Res Commun. Jan 7 2000;267(1):124-128.
29. Desaki M, Okazaki H, Sunazuka T, Omura S, Yamamoto K, Takizawa H. Molecular mechanisms of anti-inflammatory action of erythromycin in human bronchial epithelial cells: possible role in the signaling pathway that regulates nuclear factor-kappaB activation. Antimicrob Agents Chemother. May 2004;48(5):1581-1585.
30. Wu L, Lin JH, Bao K, Li PF, Zhang WG. In vitro effects of erythromycin on RANKL and nuclear factor-kappa B by human TNF-alpha stimulatedJurkat cells. Int Immunopharmacol. Aug 2009;9(9):1105-1109.
31. Wu L, Zhang W, Tian L, Bao K, Li P, Lin J. Immunomodulatory effects of erythromycin and its derivatives on human T-lymphocyte in vitro. Immunopharmacol Immunotoxicol. 2007;29(3-4):587-596.
32. He JX, Zhao SY, Jiang ZF. [Demonstration of a mechanism of anti-inflammatory effect of erythromycin on allergic airway inflammation in rat]. Zhonghua Er Ke Za Zhi. Mar 2005;43(3):196-198.
33. Nordskog BK, Fields WR, Hellmann GM. Kinetic analysis of cytokine response to cigarette smoke condensate by human endothelial and monocytic cells. Toxicology. Sep 1 2005;212(2-3):87-97.
1. Gotfried MH. Macrolides for the treatment of chronic sinusitis, asthma, and COPD. Chest. Feb 2004;125(2 Suppl):52S-60S; quiz 60S-61S.
2. Kikuchi T, Hagiwara K, Honda Y, et al. Clarithromycin suppresses lipopolysaccharide-induced interleukin-8 production by human monocytes through AP-1 and NF-kappa B transcription factors. J Antimicrob Chemother. May 2002;49(5):745-755.
3. Banerjee D, Honeybourne D, Khair OA. The effect of oral clarithromycin on bronchial airway inflammation in moderate-to-severe stable COPD: a randomized controlled trial. Treat Respir Med. 2004;3(1):59-65.
4. Basyigit I, Yildiz F, Ozkara SK, Yildirim E, Boyaci H, Ilgazli A. The effect of clarithromycin on inflammatory markers in chronic obstructive pulmonary disease: preliminary data. Ann Pharmacother. Sep 2004;38(9):1400-1405.
5. Parnham MJ, Culic O, Erakovic V, et al. Modulation of neutrophil and inflammation markers in chronic obstructive pulmonary disease by short-term azithromycin treatment. Eur J Pharmacol. Jul 4 2005;517(1-2):132-143.
6. Suzuki T, Yanai M, Yamaya M, et al. Erythromycin and common cold in COPD. Chest. Sep 2001;120(3):730-733.
7. Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ, Wedzicha JA. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. Dec 1 2008;178(11):1139-1147.
8. Moodie FM, Marwick JA, Anderson CS, et al. Oxidative stress andcigarette smoke alter chromatin remodeling but differentially regulate NF-kappaB activation and proinflammatory cytokine release in alveolar epithelial cells. FASEB J. Dec 2004;18(15):1897-1899.
9. Sundstrom C, Nilsson K. Establishment and characterization of a human histiocytic lymphoma cell line (U-937). Int J Cancer. May 15 1976;17(5):565-577.
10. Verhoeckx KC, Bijlsma S, de Groene EM, Witkamp RF, van der Greef J, Rodenburg RJ. A combination of proteomics, principal component analysis and transcriptomics is a powerful tool for the identification of biomarkers for macrophage maturation in the U937 cell line. Proteomics. Apr 2004;4(4):1014-1028.
11. Izeboud CA, Vermeulen RM, Zwart A, Voss HP, van Miert AS, Witkamp RF. Stereoselectivity at the beta2-adrenoceptor on macrophages is a major determinant of the anti-inflammatory effects of beta2-agonists. Naunyn Schmiedebergs Arch Pharmacol. Aug 2000;362(2):184-189.
12. Carp H, Janoff A. Possible mechanisms of emphysema in smokers. In vitro suppression of serum elastase-inhibitory capacity by fresh cigarette smoke and its prevention by antioxidants. Am Rev Respir Dis. Sep 1978;118(3):617-621.
13. Yang SR, Chida AS, Bauter MR, et al. Cigarette smoke induces proinflammatory cytokine release by activation of NF-kappaB and posttranslational modifications of histone deacetylase in macrophages. Am J Physiol Lung Cell Mol Physiol. Jul 2006;291(1):L46-57.
14. Martey CA, Pollock SJ, Turner CK, et al. Cigarette smoke induces cyclooxygenase-2 and microsomal prostaglandin E2 synthase in human lung fibroblasts: implications for lung inflammation and cancer. Am JPhysiol Lung Cell Mol Physiol. Nov 2004;287(5):L981-991.
15. Barnes PJ, Adcock IM, Ito K. Histone acetylation and deacetylation: importance in inflammatory lung diseases. Eur Respir J. Mar 2005;25(3):552-563.
16. Espino PS, Drobic B, Dunn KL, Davie JR. Histone modifications as a platform for cancer therapy. J Cell Biochem. Apr 15 2005;94(6):1088-1102.
17. Strahl BD, Allis CD. The language of covalent histone modifications. Nature. Jan 6 2000;403(6765):41-45.
18. Villar-Garea A, Imhof A. The analysis of histone modifications. Biochim Biophys Acta. Dec 2006;1764(12):1932-1939.
19. Adcock IM, Ford P, Ito K, Barnes PJ. Epigenetics and airways disease. Respir Res. 2006;7:21.
20. Barnes PJ. Reduced histone deacetylase in COPD: clinical implications. Chest. Jan 2006;129(1):151-155.
21. Girodet PO. [What is the therapeutic response to corticosteroid in smokers with asthma?]. Rev Mal Respir. Feb 2008;25(2):185-192.
22. Thomson NC, Chaudhuri R, Livingston E. Asthma and cigarette smoking. Eur Respir J. Nov 2004;24(5):822-833.
23. Van Overveld FJ, Demkow U, Gorecka D, De Backer WA, Zielinski J. Differences in responses upon corticosteroid therapy between smoking and non-smoking patients with COPD. J Physiol Pharmacol. Sep 2006;57 Suppl 4:273-282.
24. Cosio BG, Tsaprouni L, Ito K, Jazrawi E, Adcock IM, Barnes PJ. Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med. Sep 6 2004;200(5):689-695.
25. Rajendrasozhan S, Yao H, Rahman I. Current perspectives on role of chromatin modifications and deacetylases in lung inflammation in COPD. COPD. Aug 2009;6(4):291-297.
26. Meja KK, Rajendrasozhan S, Adenuga D, et al. Curcumin restores corticosteroid function in monocytes exposed to oxidants by maintaining HDAC2. Am J Respir Cell Mol Biol. Sep 2008;39(3):312-323.
27. Barnes PJ. Role of HDAC2 in the pathophysiology of COPD. Annu Rev Physiol. 2009;71:451-464.
28. Adcock IM, Tsaprouni L, Bhavsar P, Ito K. Epigenetic regulation of airway inflammation. Curr Opin Immunol. Dec 2007;19(6):694-700.
29. Barnes PJ. How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Br J Pharmacol. Jun 2006;148(3):245-254.
30. Barnes PJ, Ito K, Adcock IM. Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase. Lancet. Feb 28 2004;363(9410):731-733.
31. de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J. Mar 15 2003;370(Pt 3):737-749.
32. Gray SG, Ekstrom TJ. The human histone deacetylase family. Exp Cell Res. Jan 15 2001;262(2):75-83.
33. Ito K, Barnes PJ, Adcock IM. Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1beta-induced histone H4 acetylation on lysines 8 and 12. Mol Cell Biol. Sep 2000;20(18):6891-6903.
34. Ito K, Yamamura S, Essilfie-Quaye S, et al. Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enablesNF-kappaB suppression. J Exp Med. Jan 23 2006;203(1):7-13.
35. Ito K, Hanazawa T, Tomita K, Barnes PJ, Adcock IM. Oxidative stress reduces histone deacetylase 2 activity and enhances IL-8 gene expression: role of tyrosine nitration. Biochem Biophys Res Commun. Feb 27 2004;315(1):240-245.
36. Marwick JA, Kirkham PA, Stevenson CS, et al. Cigarette smoke alters chromatin remodeling and induces proinflammatory genes in rat lungs. Am J Respir Cell Mol Biol. Dec 2004;31(6):633-642.
37. Ito K, Ito M, Elliott WM, et al. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N Engl J Med. May 12 2005;352(19):1967-1976.
38. Ito K, Lim S, Caramori G, Chung KF, Barnes PJ, Adcock IM. Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions in alveolar macrophages. FASEB J. Apr 2001;15(6):1110-1112.
39. Barnes PJ. Targeting histone deacetylase 2 in chronic obstructive pulmonary disease treatment. Expert Opin Ther Targets. Dec 2005;9(6):1111-1121.
40. Barnes PJ. Theophylline in chronic obstructive pulmonary disease: new horizons. Proc Am Thorac Soc. 2005;2(4):334-339; discussion 340-331.
41. Barnes PJ. Transcription factors in airway diseases. Lab Invest. Sep 2006;86(9):867-872.
42. Rahman I, Marwick J, Kirkham P. Redox modulation of chromatin remodeling: impact on histone acetylation and deacetylation, NF-kappaB and pro-inflammatory gene expression. Biochem Pharmacol. Sep 15 2004;68(6):1255-1267.
43. Cosio BG, Mann B, Ito K, et al. Histone acetylase and deacetylase activity in alveolar macrophages and blood mononocytes in asthma. Am J Respir Crit Care Med. Jul 15 2004;170(2):141-147.
44. Rajendrasozhan S, Yang SR, Edirisinghe I, Yao H, Adenuga D, Rahman I. Deacetylases and NF-kappaB in redox regulation of cigarette smoke-induced lung inflammation: epigenetics in pathogenesis of COPD. Antioxid Redox Signal. Apr 2008;10(4):799-811.
45. Chen L, Fischle W, Verdin E, Greene WC. Duration of nuclear NF-kappaB action regulated by reversible acetylation. Science. Aug 31 2001;293(5535):1653-1657.
46. Zhong H, May MJ, Jimi E, Ghosh S. The phosphorylation status of nuclear NF-kappa B determines its association with CBP/p300 or HDAC-1. Mol Cell. Mar 2002;9(3):625-636.
47. Sengupta N, Seto E. Regulation of histone deacetylase activities. J Cell Biochem. Sep 1 2004;93(1):57-67.
1. Anto JM, Vermeire P, Vestbo J, Sunyer J. Epidemiology of chronic obstructive pulmonary disease. Eur Respir J. May 2001;17(5):982-994.
2. Ward MM, Javitz HS, Smith WM, Bakst A. Direct medical cost of chronic obstructive pulmonary disease in the U.S.A. Respir Med. Nov 2000;94(11):1123-1129.
3. Halbert RJ, Isonaka S, George D, Iqbal A. Interpreting COPD prevalence estimates: what is the true burden of disease? Chest. May 2003;123(5):1684-1692.
4. Halpern MT, Higashi MK, Bakst AW, Schmier JK. The economic impact of acute exacerbations of chronic bronchitis in the United States and Canada: a literature review. J Manag Care Pharm. Jul-Aug 2003;9(4):353-359.
5. Wouters EF. Economic analysis of the Confronting COPD survey: an overview of results. Respir Med. Mar 2003;97 Suppl C:S3-14.
6. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med. Apr 2001;163(5):1256-1276.
7. Mannino DM, Homa DM, Akinbami LJ, Ford ES, Redd SC. Chronic obstructive pulmonary disease surveillance--United States, 1971-2000. Respir Care. Oct 2002;47(10):1184-1199.
8. Petty TL. Scope of the COPD problem in North America: earlystudies of prevalence and NHANES III data: basis for early identification and intervention. Chest. May 2000;117(5 Suppl 2):326S-331S.
9. Stoller JK. Clinical practice. Acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med. Mar 28 2002;346(13):988-994.
10. Gulsvik A. The global burden and impact of chronic obstructive pulmonary disease worldwide. Monaldi Arch Chest Dis. Jun 2001;56(3):261-264.
11. Sethi S. Infectious etiology of acute exacerbations of chronic bronchitis. Chest. May 2000;117(5 Suppl 2):380S-385S.
12. Aaron SD, Angel JB, Lunau M, et al. Granulocyte inflammatory markers and airway infection during acute exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. Feb 2001;163(2):349-355.
13. Gompertz S, O'Brien C, Bayley DL, Hill SL, Stockley RA. Changes in bronchial inflammation during acute exacerbations of chronic bronchitis. Eur Respir J. Jun 2001;17(6):1112-1119.
14. Wedzicha JA. Exacerbations: etiology and pathophysiologic mechanisms. Chest. May 2002;121(5 Suppl):136S-141S.
15. Pietila MP, Thomas CF. Inflammation and infection in exacerbations of chronic obstructive pulmonary disease. Semin Respir Infect. Mar 2003;18(1):9-16.
16. White AJ, Gompertz S, Bayley DL, et al. Resolution of bronchial inflammation is related to bacterial eradication following treatment of exacerbations of chronic bronchitis. Thorax. Aug2003;58(8):680-685.
17. Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. Jun 24 2004;350(26):2645-2653.
18. Shapiro SD, Ingenito EP. The pathogenesis of chronic obstructive pulmonary disease: advances in the past 100 years. Am J Respir Cell Mol Biol. May 2005;32(5):367-372.
19. Wouters EF. Local and systemic inflammation in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2005;2(1):26-33.
20. Roland M, Bhowmik A, Sapsford RJ, et al. Sputum and plasma endothelin-1 levels in exacerbations of chronic obstructive pulmonary disease. Thorax. Jan 2001;56(1):30-35.
21. Fujimoto K, Yasuo M, Urushibata K, Hanaoka M, Koizumi T, Kubo K. Airway inflammation during stable and acutely exacerbated chronic obstructive pulmonary disease. Eur Respir J. Apr 2005;25(4):640-646.
22. Zhu J, Qiu YS, Majumdar S, et al. Exacerbations of Bronchitis: bronchial eosinophilia and gene expression for interleukin-4, interleukin-5, and eosinophil chemoattractants. Am J Respir Crit Care Med. Jul 1 2001;164(1):109-116.
23. Qiu Y, Zhu J, Bandi V, et al. Biopsy neutrophilia, neutrophil chemokine and receptor gene expression in severe exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. Oct 15 2003;168(8):968-975.
24. Drost EM, Skwarski KM, Sauleda J, et al. Oxidative stress andairway inflammation in severe exacerbations of COPD. Thorax. Apr 2005;60(4):293-300.
25. Ito K, Ito M, Elliott WM, et al. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N Engl J Med. May 12 2005;352(19):1967-1976.
26. Rutgers SR, Postma DS, ten Hacken NH, et al. Ongoing airway inflammation in patients with COPD who Do not currently smoke. Chest. May 2000;117(5 Suppl 1):262S.
27. Amin K, Ekberg-Jansson A, Lofdahl CG, Venge P. Relationship between inflammatory cells and structural changes in the lungs of asymptomatic and never smokers: a biopsy study. Thorax. Feb 2003;58(2):135-142.
28. Caramori G, Adcock I. Pharmacology of airway inflammation in asthma and COPD. Pulm Pharmacol Ther. 2003;16(5):247-277.
29. Di Stefano A, Caramori G, Ricciardolo FL, Capelli A, Adcock IM, Donner CF. Cellular and molecular mechanisms in chronic obstructive pulmonary disease: an overview. Clin Exp Allergy. Aug 2004;34(8):1156-1167.
30. Di Stefano A, Capelli A, Lusuardi M, et al. Decreased T lymphocyte infiltration in bronchial biopsies of subjects with severe chronic obstructive pulmonary disease. Clin Exp Allergy. Jun 2001;31(6):893-902.
31. Hill AT, Campbell EJ, Hill SL, Bayley DL, Stockley RA. Association between airway bacterial load and markers of airway inflammation in patients with stable chronic bronchitis. Am J Med. Sep 2000;109(4):288-295.
32. Turato G, Zuin R, Miniati M, et al. Airway inflammation in severe chronic obstructive pulmonary disease: relationship with lung function and radiologic emphysema. Am J Respir Crit Care Med. Jul 1 2002;166(1):105-110.
33. Russell RE, Culpitt SV, DeMatos C, et al. Release and activity of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 by alveolar macrophages from patients with chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol. May 2002;26(5):602-609.
34. Russell RE, Thorley A, Culpitt SV, et al. Alveolar macrophage-mediated elastolysis: roles of matrix metalloproteinases, cysteine, and serine proteases. Am J Physiol Lung Cell Mol Physiol. Oct 2002;283(4):L867-873.
35. Saetta M, Mariani M, Panina-Bordignon P, et al. Increased expression of the chemokine receptor CXCR3 and its ligand CXCL10 in peripheral airways of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. May 15 2002;165(10):1404-1409.
36. Majo J, Ghezzo H, Cosio MG. Lymphocyte population and apoptosis in the lungs of smokers and their relation to emphysema. Eur Respir J. May 2001;17(5):946-953.
37. Grumelli S, Corry DB, Song LZ, et al. An immune basis for lung parenchymal destruction in chronic obstructive pulmonary disease and emphysema. PLoS Med. Oct 2004;1(1):e8.
38. Barnes PJ, Shapiro SD, Pauwels RA. Chronic obstructive pulmonary disease: molecular and cellular mechanisms. EurRespir J. Oct 2003;22(4):672-688.
39. Agusti AG. COPD, a multicomponent disease: implications for management. Respir Med. Jun 2005;99(6):670-682.
40. Wedzicha JA. The heterogeneity of chronic obstructive pulmonary disease. Thorax. Aug 2000;55(8):631-632.
41. Hurst JR, Perera WR, Wilkinson TM, Donaldson GC, Wedzicha JA. Systemic and upper and lower airway inflammation at exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. Jan 1 2006;173(1):71-78.
42. Garcia-Aymerich J, Tobias A, Anto JM, Sunyer J. Air pollution and mortality in a cohort of patients with chronic obstructive pulmonary disease: a time series analysis. J Epidemiol Community Health. Jan 2000;54(1):73-74.
43. Sunyer J, Schwartz J, Tobias A, Macfarlane D, Garcia J, Anto JM. Patients with chronic obstructive pulmonary disease are at increased risk of death associated with urban particle air pollution: a case-crossover analysis. Am J Epidemiol. Jan 1 2000;151(1):50-56.
44. Sethi S. Bacteria in exacerbations of chronic obstructive pulmonary disease: phenomenon or epiphenomenon? Proc Am Thorac Soc. 2004;1(2):109-114.
45. Wilkinson TM, Donaldson GC, Hurst JR, Seemungal TA, Wedzicha JA. Early therapy improves outcomes of exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. Jun 15 2004;169(12):1298-1303.
46. Johnston SL. Overview of virus-induced airway disease. Proc AmThorac Soc. 2005;2(2):150-156.
47. Parnham MJ. Immunomodulatory effects of antimicrobials in the therapy of respiratory tract infections. Curr Opin Infect Dis. Apr 2005;18(2):125-131.
48. Culic O, Erakovic V, Cepelak I, et al. Azithromycin modulates neutrophil function and circulating inflammatory mediators in healthy human subjects. Eur J Pharmacol. Aug 30 2002;450(3):277-289.
49. Tsai WC, Standiford TJ. Immunomodulatory effects of macrolides in the lung: lessons from in-vitro and in-vivo models. Curr Pharm Des. 2004;10(25):3081-3093.
50. Parnham MJ, Culic O, Erakovic V, et al. Modulation of neutrophil and inflammation markers in chronic obstructive pulmonary disease by short-term azithromycin treatment. Eur J Pharmacol. Jul 4 2005;517(1-2):132-143.
51. Callard R, George AJ, Stark J. Cytokines, chaos, and complexity. Immunity. Nov 1999;11(5):507-513.
52. Shinkai M, Lopez-Boado YS, Rubin BK. Clarithromycin has an immunomodulatory effect on ERK-mediated inflammation induced by Pseudomonas aeruginosa flagellin. J Antimicrob Chemother. Jun 2007;59(6):1096-1101.
53. Shinkai M, Foster GH, Rubin BK. Macrolide antibiotics modulate ERK phosphorylation and IL-8 and GM-CSF production by human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol. Jan 2006;290(1):L75-85.
54. Shinkai M, Tamaoki J, Kobayashi H, et al. Clarithromycin delaysprogression of bronchial epithelial cells from G1 phase to S phase and delays cell growth via extracellular signal-regulated protein kinase suppression. Antimicrob Agents Chemother. May 2006;50(5):1738-1744.
55. Kikuchi T, Hagiwara K, Honda Y, et al. Clarithromycin suppresses lipopolysaccharide-induced interleukin-8 production by human monocytes through AP-1 and NF-kappa B transcription factors. J Antimicrob Chemother. May 2002;49(5):745-755.
56. Takaki M, Ushikai M, Deguchi K, Nishimoto K, Matsune S, Kurono Y. The role of nuclear factor-kappa B in interleukin-8 expression by human adenoidal fibroblasts. Laryngoscope. Aug 2003;113(8):1378-1385.
57. Desaki M, Okazaki H, Sunazuka T, Omura S, Yamamoto K, Takizawa H. Molecular mechanisms of anti-inflammatory action of erythromycin in human bronchial epithelial cells: possible role in the signaling pathway that regulates nuclear factor-kappaB activation. Antimicrob Agents Chemother. May 2004;48(5):1581-1585.
58. Reato G, Cuffini AM, Tullio V, et al. Immunomodulating effect of antimicrobial agents on cytokine production by human polymorphonuclear neutrophils. Int J Antimicrob Agents. Feb 2004;23(2):150-154.
59. Ishizawa K, Suzuki T, Yamaya M, et al. Erythromycin increases bactericidal activity of surface liquid in human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol. Oct 2005;289(4):L565-573.
60. Khan AA, Slifer TR, Araujo FG, Remington JS. Effect of clarithromycin and azithromycin on production of cytokines by human monocytes. Int J Antimicrob Agents. Feb 1999;11(2):121-132.
61. Suzaki H, Asano K, Ohki S, Kanai K, Mizutani T, Hisamitsu T. Suppressive activity of a macrolide antibiotic, roxithromycin, on pro-inflammatory cytokine production in vitro and in vivo. Mediators Inflamm. 1999;8(4-5):199-204.
62. Yamasawa H, Oshikawa K, Ohno S, Sugiyama Y. Macrolides inhibit epithelial cell-mediated neutrophil survival by modulating granulocyte macrophage colony-stimulating factor release. Am J Respir Cell Mol Biol. Apr 2004;30(4):569-575.
63. Hashimoto N, Kawabe T, Hara T, et al. Effect of erythromycin on matrix metalloproteinase-9 and cell migration. J Lab Clin Med. Mar 2001;137(3):176-183.
64. Kanai K, Asano K, Hisamitsu T, Suzaki H. Suppression of matrix metalloproteinase production from nasal fibroblasts by macrolide antibiotics in vitro. Eur Respir J. May 2004;23(5):671-678.
65. Villagrasa V, Berto L, Cortijo J, Perpina M, Sanz C, Morcillo EJ. Effects of erythromycin on chemoattractant-activated human polymorphonuclear leukocytes. Gen Pharmacol. Oct 1997;29(4):605-609.
66. Tsai WC, Rodriguez ML, Young KS, et al. Azithromycin blocks neutrophil recruitment in Pseudomonas endobronchial infection. Am J Respir Crit Care Med. Dec 15 2004;170(12):1331-1339.
67. Inamura K, Ohta N, Fukase S, Kasajima N, Aoyagi M. The effects of erythromycin on human peripheral neutrophil apoptosis. Rhinology. Sep 2000;38(3):124-129.
68. Ogawa N, Sugawara Y, Fujiwara Y, Noma T. Roxithromycin promotes lymphocyte apoptosis in Dermatophagoides-sensitive asthma patients. Eur J Pharmacol. Aug 8 2003;474(2-3):273-281.
69. Kadota J, Mizunoe S, Kishi K, Tokimatsu I, Nagai H, Nasu M. Antibiotic-induced apoptosis in human activated peripheral lymphocytes. Int J Antimicrob Agents. Mar 2005;25(3):216-220.
70. Shimizu T, Shimizu S, Hattori R, Gabazza EC, Majima Y. In vivo and in vitro effects of macrolide antibiotics on mucus secretion in airway epithelial cells. Am J Respir Crit Care Med. Sep 1 2003;168(5):581-587.
71. Imamura Y, Yanagihara K, Mizuta Y, et al. Azithromycin inhibits MUC5AC production induced by the Pseudomonas aeruginosa autoinducer N-(3-Oxododecanoyl) homoserine lactone in NCI-H292 Cells. Antimicrob Agents Chemother. Sep 2004;48(9):3457-3461.
72. Yatsunami J, Hayashi S. Fourteen-membered ring macrolides as anti-angiogenic compounds. Anticancer Res. Nov-Dec 2001;21(6B):4253-4258.
73. Desaki M, Takizawa H, Ohtoshi T, et al. Erythromycin suppresses nuclear factor-kappaB and activator protein-1 activation in human bronchial epithelial cells. Biochem Biophys Res Commun. Jan 7 2000;267(1):124-128.
74. Wozniak DJ, Keyser R. Effects of subinhibitory concentrations of macrolide antibiotics on Pseudomonas aeruginosa. Chest. Feb2004;125(2 Suppl):62S-69S; quiz 69S.
75. Pechere JC. New perspectives on macrolide antibiotics. Int J Antimicrob Agents. 2001;18 Suppl 1:S93-97.
76. Baumann U, Fischer JJ, Gudowius P, et al. Buccal adherence of Pseudomonas aeruginosa in patients with cystic fibrosis under long-term therapy with azithromycin. Infection. Jan-Feb 2001;29(1):7-11.
77. Tsang KW, Ng P, Ho PL, et al. Effects of erythromycin on Pseudomonas aeruginosa adherence to collagen and morphology in vitro. Eur Respir J. Mar 2003;21(3):401-406.
78. Tateda K, Comte R, Pechere JC, Kohler T, Yamaguchi K, Van Delden C. Azithromycin inhibits quorum sensing in Pseudomonas aeruginosa. Antimicrob Agents Chemother. Jun 2001;45(6):1930-1933.
79. Nagata T, Mukae H, Kadota J, et al. Effect of erythromycin on chronic respiratory infection caused by Pseudomonas aeruginosa with biofilm formation in an experimental murine model. Antimicrob Agents Chemother. Jun 2004;48(6):2251-2259.
80. Gillis RJ, Iglewski BH. Azithromycin retards Pseudomonas aeruginosa biofilm formation. J Clin Microbiol. Dec 2004;42(12):5842-5845.
81. Wagner T, Soong G, Sokol S, Saiman L, Prince A. Effects of azithromycin on clinical isolates of Pseudomonas aeruginosa from cystic fibrosis patients. Chest. Aug 2005;128(2):912-919.
82. Rubin BK. Immunomodulatory properties of macrolides: overview and historical perspective. Am J Med. Nov 8 2004;117 Suppl9A:2S-4S.
83. Labro MT. Macrolide antibiotics: current and future uses. Expert Opin Pharmacother. Mar 2004;5(3):541-550.
84. Shinkai M, Rubin BK. Macrolides and airway inflammation in children. Paediatr Respir Rev. Sep 2005;6(3):227-235.
85. Henke MO, Shah SA, Rubin BK. The role of airway secretions in COPD--clinical applications. COPD. Sep 2005;2(3):377-390.
86. Johnston SL. Macrolide antibiotics and asthma treatment. J Allergy Clin Immunol. Jun 2006;117(6):1233-1236.
87. Giamarellos-Bourboulis EJ. Macrolides beyond the conventional antimicrobials: a class of potent immunomodulators. Int J Antimicrob Agents. Jan 2008;31(1):12-20.
88. Wilson R, Kubin R, Ballin I, et al. Five day moxifloxacin therapy compared with 7 day clarithromycin therapy for the treatment of acute exacerbations of chronic bronchitis. J Antimicrob Chemother. Oct 1999;44(4):501-513.
89. Wilson KG, Aaron SD, Vandemheen KL, et al. Evaluation of a decision aid for making choices about intubation and mechanical ventilation in chronic obstructive pulmonary disease. Patient Educ Couns. Apr 2005;57(1):88-95.
90. Suzuki T, Yanai M, Yamaya M, et al. Erythromycin and common cold in COPD. Chest. Sep 2001;120(3):730-733.
91. Gomez J, Banos V, Simarro E, et al. [Prospective, comparative study (1994-1998) of the influence of short-term prophylactic treatment with azithromycin on patients with advanced COPD]. Rev Esp Quimioter. Dec 2000;13(4):379-383.
92. Basyigit I, Yildiz F, Ozkara SK, Yildirim E, Boyaci H, Ilgazli A. The effect of clarithromycin on inflammatory markers in chronic obstructive pulmonary disease: preliminary data. Ann Pharmacother. Sep 2004;38(9):1400-1405.
93. Banerjee D, Khair OA, Honeybourne D. The effect of oral clarithromycin on health status and sputum bacteriology in stable COPD. Respir Med. Feb 2005;99(2):208-215.
94. Banerjee D, Honeybourne D, Khair OA. The effect of oral clarithromycin on bronchial airway inflammation in moderate-to-severe stable COPD: a randomized controlled trial. Treat Respir Med. 2004;3(1):59-65.
95. Banerjee D, Khair OA, Honeybourne D. Impact of sputum bacteria on airway inflammation and health status in clinical stable COPD. Eur Respir J. May 2004;23(5):685-691.
96. Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ, Wedzicha JA. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. Dec 1 2008;178(11):1139-1147.
97. Tagaya E, Tamaoki J, Kondo M, Nagai A. Effect of a short course of clarithromycin therapy on sputum production in patients with chronic airway hypersecretion. Chest. Jul 2002;122(1):213-218.