吸烟对重型颅脑损伤伴发肺损伤的影响及穿心莲内酯在吸烟诱发肺损伤中的保护机制研究
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摘要
第一部分：吸烟对重型颅脑损伤伴发急性肺损伤的影响
目的：
探讨吸烟对重型颅脑损伤伴发急性肺损伤的影响。
方法：
选择162例我院于2010年1月至2011年12月收治的重型颅脑损伤患者,其中男性139例,女性23例,年龄18～72岁,平均年龄(44.86±13.51)岁。其中交通事故伤85例,高空坠落伤30例,跌倒伤28例,暴力伤8例,其他11例。根据是否吸烟分为吸烟组(74例)和非吸烟组(88例)。
于入院后第5天依据急性肺损伤诊断标准判断重型颅脑损伤患者是否患有急性肺损伤,比较吸烟组与非吸烟组急性肺损伤发病率。于入院后第0、5天检测重型颅脑损伤患者肺功能。肺容量指标：呼吸频率(Breathing frequency,BF)、肺活量(Vital capacity, VC);肺通气量指标：用力呼气一秒量(Forced expiratory volume in the first second,FEV1)、用力呼气肺活量(Forced expiratory vital capacity,FVC)、最大分钟通气量(Most minute ventilation,MMV);小气道指标：最高呼气流速(Peak expiratory flow,PEF)。于入院后第0、5天采集肺泡灌洗液,按照试剂盒说明书检测肺泡灌洗液上清液中的肿瘤坏死因子-α (Tumor necrosis factor-alpha,TNF-a),白介素-8(interleukin-8,IL-8)和丙二醛(Malondialdehyde MDA)水平及超氧化物歧化酶(Superoxide Dismutase, SOD)活性。
结果：
1.吸烟组中有26例重型颅脑损伤患者伴发急性肺损伤,发病率达到35.14%,而非吸烟组中仅有16例伴发急性肺损伤,发病率为18.18%,两组差异具有统计学意义(P=0.019)。
2.入院后第0天,吸烟组的BF, VC、 FEV1、 FVC、 MMV、 PEF均低于非吸烟组,其中,两组的MMV、PEF的差异具有统计学意义(P<0.05)。入院后第5天与入院后第0天比较,两组患者的肺功能均呈下降趋势,吸烟组的下降趋势较非吸烟组更为明显。
3.入院后第0天,吸烟组的TNF-α. IL-8、MDA水平均高于非吸烟组,差异具有统计学意义(P<0.05)；吸烟组的SOD活性低于非吸烟组。入院后第5天与入院后第0天比较,两组患者的TNF-α. IL-8、 MDA水平均呈上升趋势,吸烟组的上升趋势较非吸烟组更为明显；两组患者的SOD活性呈下降趋势,吸烟组的下降趋势较非吸烟组更为明显。入院后第5天,两组的4个指标具有显著性差异(P<0.05)。
结论：
与非吸烟组相比较,吸烟组的重型颅脑损伤患者的基础肺功能和SOD活性较低,fNF-α. IL-8和MDA水平较高；伤后肺功能和SOD活性降低以及TNF-α、IL-8和MDA水平升高更为明显,急性肺损伤发病率更高,可能与吸烟和颅脑损伤协同促进炎症反应和氧化应激相关。
第二部分：穿心莲内酯在被动吸烟诱发肺损伤中的保护作用
目的：
本部分研究穿心莲内酯对吸烟诱导的小鼠肺部急性炎症反应的作用。
方法：
本研究所用实验动物为32只清洁级成年雄性C57BL/6小鼠(6-8周龄),体重为18-20g。将实验小鼠随机分为4组(每组8只),分别为：正常对照组(C)、烟草烟雾暴露组(CS)、用溶质DMSO处理的烟草烟雾暴露组(CS+DMSO)和穿心莲内酯处理的烟草烟雾暴露组(CS+A)。穿心莲内酯是在烟草烟雾暴露前1h通过腹腔内注射途径给予,剂量为1mg/kg体重。将模型组小鼠置于被动吸烟箱中,每天被动吸烟9支,连续4天。对照组小鼠置于相同的实验条件下只是不接受被动吸烟处理。小鼠于实验第5天经腹腔注射过量戊巴比妥钠处死。收集支气管肺泡灌洗液(Bronchoalveolar lavage fluid, BALF),并作肺部组织学分析。对BALF中细胞进行计数,并经Wright-Giemsa染色进行细胞分类记数。ELSIA法分析BALF中肿瘤坏死因子-α (Tumor necrosis factor-alpha,TNF-a),白介素-6(Interleukin-6,IL-6),巨噬细胞炎症蛋白-2(Macrophage inflammatory protein-2, MIP-2),白介素10(interleukin-10,IL-10),LPS诱导CXC趋化因子(LPS-induced CXC chemokine, LIX),干扰素γ (interferon-γ,IFN-γ)的水平。并对肺组织髓过氧化物酶(myeloperoxidase, MPO)活性进行测定。体外研究中,肺上皮细胞A549细胞作为细胞模型。用DNA片段化法分析穿心莲内酯对烟草烟雾诱导的A549细胞凋亡的影响,并用Western blot法分析穿心莲内酯对烟草烟雾介导的凋亡相关蛋白的表达的影响。
结果：
HE染色显示,被动吸烟组小鼠肺部毛细血管充血,肺泡出血；肺泡壁稍增厚；肺泡腔内充满大量单核／巨噬细胞,多形核白细胞等炎症细胞,以及大量渗出液。DMSO处理对吸烟诱导的肺部急性炎症反应没有明显影响。而穿心莲内酯处理组小鼠肺泡炎症轻,肺泡腔中炎症细胞及渗出液较少。穿心莲内酯能够抑制吸烟诱导的肺部炎症反应还表现为：穿心莲内酯能够显著抑制吸烟诱导的小鼠BALF中总细胞,单核／巨噬细胞,中性粒细胞以及淋巴细胞的数目的增加,减少吸烟介导的小鼠BALF中肿瘤坏死因子-a,白介素-6和巨噬细胞炎症蛋白-2的分泌,以及降低吸烟诱发的肺部髓过氧化物酶的活性。体外结果显示,烟草烟雾处理能够促进A549细胞的凋亡,而穿心莲内酯能够显著抑制烟草烟雾诱导的A549细胞的凋亡。
结论：
穿心莲内酯能够抑制吸烟诱导的小鼠肺部的急性损伤；能够保护烟雾烟草介导的肺上皮细胞A549细胞的凋亡。
第三部分：穿心莲内酯在被动吸烟诱发肺损伤中作用机制目的：
深入揭示穿心莲内酯影响吸烟诱导肺损伤的相关分子机制,重点探讨血红素加氧酶.1(Heme oxygenase-1, HO-1)通路对该药物发挥保护作用的贡献。
方法：
在体外研究中肺上皮细胞A549细胞作为细胞模型。利用RT-PCR和Westernblot法研究烟草烟雾和穿心莲内酯对A549细胞中HO-1mRNA和蛋白表达的影响。本研究所用实验动物为32只清洁级成年雄性C57BL/6小鼠(6-8周龄),体重为18-20g。将实验小鼠随机分为4组(每组8只),分别为：正常对照组(C)、烟雾暴露组(CS)、穿心莲内酯处理组(A)和穿心莲内酯+ZnPP组(A+Z)。穿心莲内酯是在烟雾暴露前1h通过腹腔内注射途径给予,剂量为1mg/kg体重。ZnPP为一种很强的HO抑制剂,本文应用其阻断HO-1通路。ZnPP在穿心莲内酯注射之前1h通过腹腔注射方式给予,剂量为10pμmol/kg体重。对照组小鼠通过腹腔注射给予等量的生理盐水。将模型组小鼠置于被动吸烟箱中,每天被动吸烟9支,连续4天。对照组小鼠置于相同的实验条件下只是不接受被动吸烟处理。小鼠于实验第5天经腹腔注射过量戊巴比妥钠处死。收集支气管肺泡灌洗液(Bronchoalveolar lavage fluid, BALF),并作肺部组织学分析。PCR和Westernblot用来检测小鼠肺组织中HO-1RNA和蛋白质的表达情况,并对肺组织HO-1酶活性进行测定。对BALF中细胞进行计数,并经Wright-Giemsa染色进行细胞分类记数。用BCA蛋白浓度测定试剂盒测定BALF总蛋白浓度。ELSIA法分析BALF中瘤坏死因子-α (Tumor necrosis factor-alpha,TNF-a),白介素-6(Interleukin-6, IL-6)和巨噬细胞炎症蛋白-2(Macrophage inflammatory protein-2,MIP-2)的水平。对肺组织和BALF中的MDA水平进行测定。并对BALF中LDH的活性以及肺组织中超氧化物歧化酶(Superoxide Dismutase, SOD),谷胱甘肽过氧化物酶(Glutathione peroxidase, GSH-Px),过氧化氢酶(Catalase, CAT)和髓过氧化物酶(myeloperoxidase, MPO)活性进行测定。Western blot法检测穿心莲内酯对信号传导及转录活化子3(signal transducer and activator of transcription3, STAT3)通路活化的影响。
结果：
烟草烟雾处理和穿心莲内酯预处理显著增加HO-1mRNA和蛋白表达。而且这种诱导作用呈剂量依赖关系,这提示HO-1在烟草烟雾诱导细胞损伤过程中可能具有保护作用。HE染色显示,被动吸烟组小鼠肺部毛细血管充血,肺泡出血；肺泡壁稍增厚；肺泡腔内充满大量单核/巨噬细胞,多形核白细胞等炎症细胞,以及大量渗出液。DMSO处理对吸烟诱导的肺部急性炎症反应没有明显影响。而穿心莲内酯处理组小鼠肺泡炎症轻,肺泡腔中炎症细胞及渗出液较少,表明穿心莲内酯能够抑制吸烟诱导的肺部炎症反应。而用ZnPP阻断HO-1通路后,穿心莲内酯的保护作用被逆转。这说明穿心莲内酯对吸烟诱导肺部炎症的抑制作用依赖于HO-1通路活化。另外,穿心莲内酯能够抑制吸烟诱导的肺部炎症反应还表现为：穿心莲内酯能够显著抑制吸烟诱导的小鼠BALF中总细胞,单核/巨噬细胞,中性粒细胞以及淋巴细胞的数目的增加,减少吸烟介导的的小鼠BALF总蛋白浓度,肿瘤坏死因子-a,白介素-6和巨噬细胞炎症蛋白-2的分泌,减少吸烟诱导的肺组织和BALF中的MDA水平。以及降低吸烟诱发肺组织中超氧化物歧化酶,谷胱甘肽过氧化物酶,过氧化氢酶和髓过氧化物酶的活性和BALF中LDH的活性。而穿心莲内酯介导的这些保护吸烟诱导肺部炎症反应的作用均随着ZnPP抑制HO-1信号通路而被逆转,提示HO-1在穿心莲内酯对被动吸烟诱导的肺氧化应激、炎症及损伤的保护效应中起着重要的作用。穿心莲内酯处理显著提高吸烟小鼠肺组织中STAT3磷酸化水平,而对总STAT3蛋白影响不明显,这表明穿心莲内酯可促进肺组织STAT3通路活化。穿心莲内酯对STAT3通路的活化作用能够被ZnPP抑制,这提示STAT3可能位于HO-1通路下游。
结论：
穿心莲内酯可诱导肺组织HO-1表达及活性增加。HO-1表达上调介导穿心莲内酯对被动吸烟诱导肺氧化应激、炎症及损伤的保护效应。HO-1在被动吸烟诱导肺损伤中的抗炎、抗氧化活性与激活STAT3通路有关。
Part1:The Effect of Smoking on Acute Lung Injury after Severe Craniocerebral Injury
Objective:
To investigate the effect of smoking on acute lung injury after severe craniocerebral injury.
Methods:
Select162severe craniocerebral injury patients admitted to our hospital from January2010to December2011, male139cases and female23cases, aged18to72years old, the average age was (44.86±13.51) years. Traffic accident injury85cases, high-altitude fall injury30cases, mucker injury28cases, violence hurt8cases, the other11cases. Patients were divided into smoking group (74cases) and non-smoking group (88cases) basing on the status of smoking.
Judging whether severe craniocerebral injury patients were associated with acute lung injury on the5day after admission and comparing the acute lung injury incidence rates between smoking group and non-smoking group. Measurement of the lung function in patients with severe craniocerebral injury was performed on day0and day5after admission. Lung capacity indicators:breathing frequency (BF), vital capacity (VC); pulmonary ventilation indicators:forced expiratory volume in one second (FEV1), forced expiratory vital capacity (FVC), maximum minute ventilation (MMV); small airways indicators:peak expiratory flow rate (PEF). Collecting bronchoalveolar lavage fluid on day0and day5after admission, and detecting the TNF-a, IL-8and MDA levels and SOD activity in broncho alveolar lavage fluid supernatant in accordance with the the kit instructions.
Results:
1.26severe craniocerebral injury patients were associated with acute lung injury and the incidence rate reached35.14%in the smoking group, while only16cases were associated with acute lung injury and the incidence rate was18.18%, the difference between the two groups was statistically significant(P=0.019).
2. On the0day after admission, the BF, VC, FEV1, FVC, MMV, PEF in smoking goup were lower than the non-smoking group, and the differences of MMV, PEF between two groups were statistically significant(P=0.019). On the5day after admission comparing with on the0day after admission, the lung functions of patients in two groups both showed a downward trend, and the downward trend in smoking group was more obvious than the non-smoking group.
3. On the0day after admission, the TNF-a, IL-8, MDA levels in smoking group were higher than the non-smoking group and the difference between was statistically significant(P<0.05); the SOD activity in smoking group was lower than the non-smoking group. On the5day after admission comparing with on the0day after admission, the TNF-a, IL-8, MDA levels of patients in two groups both showed a upward trend, and the upward trend in smoking group was more obvious than the non-smoking group; the SOD activity of patients in two groups showed a downward trend, and the downward trend in smoking group was more obvious than the non-smoking group. The four indicators between two groups had significant differences (P<0.05).
Conclusions:
Compared with the non-smoking group, the basic lung function and SOD activity of severe craniocerebral injury were lower and TNF-a, IL-8and MDA levels were higher; the decrease of lung function and SOD activity and increase of TNF-a, IL-8and MDA levels were more significant, the incidence rate of acute lung injury was higher in the smoking group after injury, which may be related to smoking and craniocerebral injury cooperatively promoting inflammatory response and oxidative stres
Part2:The effects of andrographolide on passive cigarette smoke-induced acute lung injury
Objective:
To investigate the effects of andrographolide on cigarette smoke-induced acute lung inflammation.
Methods:
32C57/BL/6mice (18-20g) were6-8weeks old. Mice were randomly divided into4groups (8mice for each group):control group (C), cigarette smoke-exposed group (CS), DMSO and CS-treated group (CS+DMSO), andrographolide and CS-treated group (CS+A). Andrographolide was given by intraperitoneal injection at a dose of1mg/kg body weight,1h before CS exposure. Animals were placed in an inhalation chamber and exposed to9cigarettes daily for4consecutive days for CS-exposed groups.Control mice were placed in the same condition but not exposed to cigarette smoke. On the fifth day, mice were killed with an overdose of intraperitoneal sodium pentobarbital. Bronchoalveolar lavage fluid (BALF) was collected. Histologial analysis of mouse lungs was performed. Total cell count in BALF was determined by a hemocytometer. Differential cell counts were performed with Wright-Giemsa method. ELISA assay was used to analyze the production of tumor necrosis factor-alpha (TNF-α), interleukine-6(IL-6), macrophage inflammatory protein-2(MIP-2), interleukine-10(IL-10), LPS-induced CXC chemokine (LIX), and interferon-gamma (IFN-γ) in BALF. The pulmonary myeloperoxidase (MPO) activity was measured. Lung epithemial cell line A549cells were used as an in-vitro cell mdoel. DNA fragmentation assay was done to analyze the effect of andrographolide on cigarette smoke extract-induced apoptosis of A549cells. Western blot analysis was used to analyze the expression of apoptosis-associated factors in CS-exposed mice.
Results:
Mice in response to CS exposure had pulmonary lesions with interstitial edema and large areas of marked intravascular, interstitial, and intra-alveolar inflammatory cell infiltration Pretreatment with DMSO had no effects on CS-induced acute lung inflammation. However, the influx of inflammatory cells and edema in the lungs of CS-exposed mice was alleviated by the administration of andrographolide. Andrographolide inhibited CS-enhanced BALF cellularity, such as total cells, macrophages, neutrophils, and lymphocytes, suppressed CS-induced production of BALF TNF-a, IL-6and MIP-2, and also decreased the lung MPO activity. In vitro study showed that the treatment with cigarette smoke extract significantly enhaned the apoptosis of A549cells and increased the expresson of cleaved caspase-3and cleaved poly (ADP-ribose) polymerase, all which were markedly decreased by andrographolide.
Conclusion:
Andrographolide inhibits CS-induced acute lung inflammation and protects against CSE-mediated apoptosis of A549cells.
Part3:The mechanisms for andrographolide-mediated protective effects against passive cigarette smoke-induced lung injury
Objective:
To investigate the molecular mechanisms underlying andrographolide-mediated protective effects against cigarette smoke-induced acute lung injury, especially the involvement of heme oxygenase-1(HO-1) signaling patheay.
Methods:
In the present study, lung epithemial cell line A549cells were used as an in-vitro cell mdoel. RT-PCR and Western blot analysis were employed to analyze the effects of cigarette smoke and andrographolide on HO-1expression at both mRNA and protein levels.32C57/BL/6mice (18-20g) were6-8weeks old. Mice were randomly divided into4groups (8mice for each group):control group (C), cigarette smoke exposure group (CS), andrographolide treatment together with CS exposure group (A), and A+Z group, with zinc protoporphyrin IX (ZnPP) administration before andrographolide treatment and CS exposure. Andrographolide was given by intraperitoneal injection at a dose of1mg/kg body weight,1h before CS exposure. ZnPP, a potent heme oxygenase inhibitor, was administered intraperitoneally at a dose of10μmol/kg body weight,1h before andrographolide administration. Animals were placed in an inhalation chamber and exposed to9cigarettes daily for4consecutive days for CS-exposed groups.Control mice were placed in the same condition but not exposed to cigarette smoke. On the fifth day, mice were killed with an overdose of intraperitoneal sodium pentobarbital. Bronchoalveolar lavage fluid (BALF) was collected. Histologial analysis of mouse lungs was performed. RT-PCR and Western blot analysis were performed to analyze the expression of HO-1in the lung tissues. Pulmonary HO-1activity was also analyzed. Total cell count in BALF was determined by a hemocytometer. Differential cell counts were performed with Wright-Giemsa method. The total protein in BALF was measured by the BCA method. ELISA assay was used to analyze the production of tumor necrosis factor-alpha (TNF-a), interleukine-6(IL-6), macrophage inflammatory protein-2(MIP-2). The levels of MDA in the lung tissues and BALF were measured. The activity of LDH in BALF and the lung tissues and the activities of Superoxide Dismutase (SOD), Glutathione peroxidase (GSH-Px), Catalase (CAT), myeloperoxidase (MPO) were detected in mouse lung tissues.Western blot analysis was performed to analyze the effects of andrographolide on STAT3signaling pathway.
Results:
Both CS and andrographolide increased the expression of HO-1at both mRNA and protein levels in a dose-dependent manner, indicating that HO-1might exhibit protecitive effect against CS-induced lung injury. Mice in response to CS exposure had pulmonary lesions with interstitial edema and large areas of marked intravascular, interstitial, and intra-alveolar inflammatory cell infiltration. The influx of inflammatory cells and edema in the lungs of CS-exposed mice was alleviated by the administration of andrographolide. Interestingly, ZnPP pretreatment markedly abolished the protective effects of andrographolide on CS-induced lung injury. Pretreatment with andrographolide markedly attenuated lung inflammation in CS-exposed mice, coupled with reduced numbers of total cells, neutrophils, and macrophages, total protein level in bronchial alveolar lavage fluid (BALF), decreased production of cytokine/chemokine (TNF-a, IL-6, and MIP-2) into BALF, less MDA in the lung tissues and BALF, and lowered activities of LDH (in both BALF and the lung tissues), SOD, GSH-Px, CAT, and MPO in lung tissues. Notably, these histological and biochemical changes induced by andrographolide were blocked by prior administration of ZnPP. Moreover, andrographolide-induced phosphorylation of signal transducer and activator of transcription3was attenuated by ZnPP treatment in CS-exposed animals.
Conclusion:
Our data collectively demonstrate that andrographolide confers protection against CS-induced lung inflammation, partially through activation of HO-1and STAT3.
目的：
探讨吸烟对重型颅脑损伤伴发急性肺损伤的影响。
方法：
选择162例我院于2010年1月至2011年12月收治的重型颅脑损伤患者,其中男性139例,女性23例,年龄18～72岁,平均年龄(44.86±13.51)岁。其中交通事故伤85例,高空坠落伤30例,跌倒伤28例,暴力伤8例,其他11例。根据是否吸烟分为吸烟组(74例)和非吸烟组(88例)。
于入院后第5天依据急性肺损伤诊断标准判断重型颅脑损伤患者是否患有急性肺损伤,比较吸烟组与非吸烟组急性肺损伤发病率。于入院后第0、5天检测重型颅脑损伤患者肺功能。肺容量指标：呼吸频率(Breathing frequency,BF)、肺活量(Vital capacity, VC);肺通气量指标：用力呼气一秒量(Forced expiratory volume in the first second,FEV1)、用力呼气肺活量(Forced expiratory vital capacity,FVC)、最大分钟通气量(Most minute ventilation,MMV);小气道指标：最高呼气流速(Peak expiratory flow,PEF)。于入院后第0、5天采集肺泡灌洗液,按照试剂盒说明书检测肺泡灌洗液上清液中的肿瘤坏死因子-α (Tumor necrosis factor-alpha,TNF-a),白介素-8(interleukin-8,IL-8)和丙二醛(Malondialdehyde MDA)水平及超氧化物歧化酶(Superoxide Dismutase, SOD)活性。
结果：
1.吸烟组中有26例重型颅脑损伤患者伴发急性肺损伤,发病率达到35.14%,而非吸烟组中仅有16例伴发急性肺损伤,发病率为18.18%,两组差异具有统计学意义(P=0.019)。
2.入院后第0天,吸烟组的BF, VC、 FEV1、 FVC、 MMV、 PEF均低于非吸烟组,其中,两组的MMV、PEF的差异具有统计学意义(P<0.05)。入院后第5天与入院后第0天比较,两组患者的肺功能均呈下降趋势,吸烟组的下降趋势较非吸烟组更为明显。
3.入院后第0天,吸烟组的TNF-α. IL-8、MDA水平均高于非吸烟组,差异具有统计学意义(P<0.05)；吸烟组的SOD活性低于非吸烟组。入院后第5天与入院后第0天比较,两组患者的TNF-α. IL-8、 MDA水平均呈上升趋势,吸烟组的上升趋势较非吸烟组更为明显；两组患者的SOD活性呈下降趋势,吸烟组的下降趋势较非吸烟组更为明显。入院后第5天,两组的4个指标具有显著性差异(P<0.05)。
结论：
与非吸烟组相比较,吸烟组的重型颅脑损伤患者的基础肺功能和SOD活性较低,fNF-α. IL-8和MDA水平较高；伤后肺功能和SOD活性降低以及TNF-α、IL-8和MDA水平升高更为明显,急性肺损伤发病率更高,可能与吸烟和颅脑损伤协同促进炎症反应和氧化应激相关。
第二部分：穿心莲内酯在被动吸烟诱发肺损伤中的保护作用
目的：
本部分研究穿心莲内酯对吸烟诱导的小鼠肺部急性炎症反应的作用。
方法：
本研究所用实验动物为32只清洁级成年雄性C57BL/6小鼠(6-8周龄),体重为18-20g。将实验小鼠随机分为4组(每组8只),分别为：正常对照组(C)、烟草烟雾暴露组(CS)、用溶质DMSO处理的烟草烟雾暴露组(CS+DMSO)和穿心莲内酯处理的烟草烟雾暴露组(CS+A)。穿心莲内酯是在烟草烟雾暴露前1h通过腹腔内注射途径给予,剂量为1mg/kg体重。将模型组小鼠置于被动吸烟箱中,每天被动吸烟9支,连续4天。对照组小鼠置于相同的实验条件下只是不接受被动吸烟处理。小鼠于实验第5天经腹腔注射过量戊巴比妥钠处死。收集支气管肺泡灌洗液(Bronchoalveolar lavage fluid, BALF),并作肺部组织学分析。对BALF中细胞进行计数,并经Wright-Giemsa染色进行细胞分类记数。ELSIA法分析BALF中肿瘤坏死因子-α (Tumor necrosis factor-alpha,TNF-a),白介素-6(Interleukin-6,IL-6),巨噬细胞炎症蛋白-2(Macrophage inflammatory protein-2, MIP-2),白介素10(interleukin-10,IL-10),LPS诱导CXC趋化因子(LPS-induced CXC chemokine, LIX),干扰素γ (interferon-γ,IFN-γ)的水平。并对肺组织髓过氧化物酶(myeloperoxidase, MPO)活性进行测定。体外研究中,肺上皮细胞A549细胞作为细胞模型。用DNA片段化法分析穿心莲内酯对烟草烟雾诱导的A549细胞凋亡的影响,并用Western blot法分析穿心莲内酯对烟草烟雾介导的凋亡相关蛋白的表达的影响。
结果：
HE染色显示,被动吸烟组小鼠肺部毛细血管充血,肺泡出血；肺泡壁稍增厚；肺泡腔内充满大量单核／巨噬细胞,多形核白细胞等炎症细胞,以及大量渗出液。DMSO处理对吸烟诱导的肺部急性炎症反应没有明显影响。而穿心莲内酯处理组小鼠肺泡炎症轻,肺泡腔中炎症细胞及渗出液较少。穿心莲内酯能够抑制吸烟诱导的肺部炎症反应还表现为：穿心莲内酯能够显著抑制吸烟诱导的小鼠BALF中总细胞,单核／巨噬细胞,中性粒细胞以及淋巴细胞的数目的增加,减少吸烟介导的小鼠BALF中肿瘤坏死因子-a,白介素-6和巨噬细胞炎症蛋白-2的分泌,以及降低吸烟诱发的肺部髓过氧化物酶的活性。体外结果显示,烟草烟雾处理能够促进A549细胞的凋亡,而穿心莲内酯能够显著抑制烟草烟雾诱导的A549细胞的凋亡。
结论：
穿心莲内酯能够抑制吸烟诱导的小鼠肺部的急性损伤；能够保护烟雾烟草介导的肺上皮细胞A549细胞的凋亡。
第三部分：穿心莲内酯在被动吸烟诱发肺损伤中作用机制目的：
深入揭示穿心莲内酯影响吸烟诱导肺损伤的相关分子机制,重点探讨血红素加氧酶.1(Heme oxygenase-1, HO-1)通路对该药物发挥保护作用的贡献。
方法：
在体外研究中肺上皮细胞A549细胞作为细胞模型。利用RT-PCR和Westernblot法研究烟草烟雾和穿心莲内酯对A549细胞中HO-1mRNA和蛋白表达的影响。本研究所用实验动物为32只清洁级成年雄性C57BL/6小鼠(6-8周龄),体重为18-20g。将实验小鼠随机分为4组(每组8只),分别为：正常对照组(C)、烟雾暴露组(CS)、穿心莲内酯处理组(A)和穿心莲内酯+ZnPP组(A+Z)。穿心莲内酯是在烟雾暴露前1h通过腹腔内注射途径给予,剂量为1mg/kg体重。ZnPP为一种很强的HO抑制剂,本文应用其阻断HO-1通路。ZnPP在穿心莲内酯注射之前1h通过腹腔注射方式给予,剂量为10pμmol/kg体重。对照组小鼠通过腹腔注射给予等量的生理盐水。将模型组小鼠置于被动吸烟箱中,每天被动吸烟9支,连续4天。对照组小鼠置于相同的实验条件下只是不接受被动吸烟处理。小鼠于实验第5天经腹腔注射过量戊巴比妥钠处死。收集支气管肺泡灌洗液(Bronchoalveolar lavage fluid, BALF),并作肺部组织学分析。PCR和Westernblot用来检测小鼠肺组织中HO-1RNA和蛋白质的表达情况,并对肺组织HO-1酶活性进行测定。对BALF中细胞进行计数,并经Wright-Giemsa染色进行细胞分类记数。用BCA蛋白浓度测定试剂盒测定BALF总蛋白浓度。ELSIA法分析BALF中瘤坏死因子-α (Tumor necrosis factor-alpha,TNF-a),白介素-6(Interleukin-6, IL-6)和巨噬细胞炎症蛋白-2(Macrophage inflammatory protein-2,MIP-2)的水平。对肺组织和BALF中的MDA水平进行测定。并对BALF中LDH的活性以及肺组织中超氧化物歧化酶(Superoxide Dismutase, SOD),谷胱甘肽过氧化物酶(Glutathione peroxidase, GSH-Px),过氧化氢酶(Catalase, CAT)和髓过氧化物酶(myeloperoxidase, MPO)活性进行测定。Western blot法检测穿心莲内酯对信号传导及转录活化子3(signal transducer and activator of transcription3, STAT3)通路活化的影响。
结果：
烟草烟雾处理和穿心莲内酯预处理显著增加HO-1mRNA和蛋白表达。而且这种诱导作用呈剂量依赖关系,这提示HO-1在烟草烟雾诱导细胞损伤过程中可能具有保护作用。HE染色显示,被动吸烟组小鼠肺部毛细血管充血,肺泡出血；肺泡壁稍增厚；肺泡腔内充满大量单核/巨噬细胞,多形核白细胞等炎症细胞,以及大量渗出液。DMSO处理对吸烟诱导的肺部急性炎症反应没有明显影响。而穿心莲内酯处理组小鼠肺泡炎症轻,肺泡腔中炎症细胞及渗出液较少,表明穿心莲内酯能够抑制吸烟诱导的肺部炎症反应。而用ZnPP阻断HO-1通路后,穿心莲内酯的保护作用被逆转。这说明穿心莲内酯对吸烟诱导肺部炎症的抑制作用依赖于HO-1通路活化。另外,穿心莲内酯能够抑制吸烟诱导的肺部炎症反应还表现为：穿心莲内酯能够显著抑制吸烟诱导的小鼠BALF中总细胞,单核/巨噬细胞,中性粒细胞以及淋巴细胞的数目的增加,减少吸烟介导的的小鼠BALF总蛋白浓度,肿瘤坏死因子-a,白介素-6和巨噬细胞炎症蛋白-2的分泌,减少吸烟诱导的肺组织和BALF中的MDA水平。以及降低吸烟诱发肺组织中超氧化物歧化酶,谷胱甘肽过氧化物酶,过氧化氢酶和髓过氧化物酶的活性和BALF中LDH的活性。而穿心莲内酯介导的这些保护吸烟诱导肺部炎症反应的作用均随着ZnPP抑制HO-1信号通路而被逆转,提示HO-1在穿心莲内酯对被动吸烟诱导的肺氧化应激、炎症及损伤的保护效应中起着重要的作用。穿心莲内酯处理显著提高吸烟小鼠肺组织中STAT3磷酸化水平,而对总STAT3蛋白影响不明显,这表明穿心莲内酯可促进肺组织STAT3通路活化。穿心莲内酯对STAT3通路的活化作用能够被ZnPP抑制,这提示STAT3可能位于HO-1通路下游。
结论：
穿心莲内酯可诱导肺组织HO-1表达及活性增加。HO-1表达上调介导穿心莲内酯对被动吸烟诱导肺氧化应激、炎症及损伤的保护效应。HO-1在被动吸烟诱导肺损伤中的抗炎、抗氧化活性与激活STAT3通路有关。
Part1:The Effect of Smoking on Acute Lung Injury after Severe Craniocerebral Injury
Objective:
To investigate the effect of smoking on acute lung injury after severe craniocerebral injury.
Methods:
Select162severe craniocerebral injury patients admitted to our hospital from January2010to December2011, male139cases and female23cases, aged18to72years old, the average age was (44.86±13.51) years. Traffic accident injury85cases, high-altitude fall injury30cases, mucker injury28cases, violence hurt8cases, the other11cases. Patients were divided into smoking group (74cases) and non-smoking group (88cases) basing on the status of smoking.
Judging whether severe craniocerebral injury patients were associated with acute lung injury on the5day after admission and comparing the acute lung injury incidence rates between smoking group and non-smoking group. Measurement of the lung function in patients with severe craniocerebral injury was performed on day0and day5after admission. Lung capacity indicators:breathing frequency (BF), vital capacity (VC); pulmonary ventilation indicators:forced expiratory volume in one second (FEV1), forced expiratory vital capacity (FVC), maximum minute ventilation (MMV); small airways indicators:peak expiratory flow rate (PEF). Collecting bronchoalveolar lavage fluid on day0and day5after admission, and detecting the TNF-a, IL-8and MDA levels and SOD activity in broncho alveolar lavage fluid supernatant in accordance with the the kit instructions.
Results:
1.26severe craniocerebral injury patients were associated with acute lung injury and the incidence rate reached35.14%in the smoking group, while only16cases were associated with acute lung injury and the incidence rate was18.18%, the difference between the two groups was statistically significant(P=0.019).
2. On the0day after admission, the BF, VC, FEV1, FVC, MMV, PEF in smoking goup were lower than the non-smoking group, and the differences of MMV, PEF between two groups were statistically significant(P=0.019). On the5day after admission comparing with on the0day after admission, the lung functions of patients in two groups both showed a downward trend, and the downward trend in smoking group was more obvious than the non-smoking group.
3. On the0day after admission, the TNF-a, IL-8, MDA levels in smoking group were higher than the non-smoking group and the difference between was statistically significant(P<0.05); the SOD activity in smoking group was lower than the non-smoking group. On the5day after admission comparing with on the0day after admission, the TNF-a, IL-8, MDA levels of patients in two groups both showed a upward trend, and the upward trend in smoking group was more obvious than the non-smoking group; the SOD activity of patients in two groups showed a downward trend, and the downward trend in smoking group was more obvious than the non-smoking group. The four indicators between two groups had significant differences (P<0.05).
Conclusions:
Compared with the non-smoking group, the basic lung function and SOD activity of severe craniocerebral injury were lower and TNF-a, IL-8and MDA levels were higher; the decrease of lung function and SOD activity and increase of TNF-a, IL-8and MDA levels were more significant, the incidence rate of acute lung injury was higher in the smoking group after injury, which may be related to smoking and craniocerebral injury cooperatively promoting inflammatory response and oxidative stres
Part2:The effects of andrographolide on passive cigarette smoke-induced acute lung injury
Objective:
To investigate the effects of andrographolide on cigarette smoke-induced acute lung inflammation.
Methods:
32C57/BL/6mice (18-20g) were6-8weeks old. Mice were randomly divided into4groups (8mice for each group):control group (C), cigarette smoke-exposed group (CS), DMSO and CS-treated group (CS+DMSO), andrographolide and CS-treated group (CS+A). Andrographolide was given by intraperitoneal injection at a dose of1mg/kg body weight,1h before CS exposure. Animals were placed in an inhalation chamber and exposed to9cigarettes daily for4consecutive days for CS-exposed groups.Control mice were placed in the same condition but not exposed to cigarette smoke. On the fifth day, mice were killed with an overdose of intraperitoneal sodium pentobarbital. Bronchoalveolar lavage fluid (BALF) was collected. Histologial analysis of mouse lungs was performed. Total cell count in BALF was determined by a hemocytometer. Differential cell counts were performed with Wright-Giemsa method. ELISA assay was used to analyze the production of tumor necrosis factor-alpha (TNF-α), interleukine-6(IL-6), macrophage inflammatory protein-2(MIP-2), interleukine-10(IL-10), LPS-induced CXC chemokine (LIX), and interferon-gamma (IFN-γ) in BALF. The pulmonary myeloperoxidase (MPO) activity was measured. Lung epithemial cell line A549cells were used as an in-vitro cell mdoel. DNA fragmentation assay was done to analyze the effect of andrographolide on cigarette smoke extract-induced apoptosis of A549cells. Western blot analysis was used to analyze the expression of apoptosis-associated factors in CS-exposed mice.
Results:
Mice in response to CS exposure had pulmonary lesions with interstitial edema and large areas of marked intravascular, interstitial, and intra-alveolar inflammatory cell infiltration Pretreatment with DMSO had no effects on CS-induced acute lung inflammation. However, the influx of inflammatory cells and edema in the lungs of CS-exposed mice was alleviated by the administration of andrographolide. Andrographolide inhibited CS-enhanced BALF cellularity, such as total cells, macrophages, neutrophils, and lymphocytes, suppressed CS-induced production of BALF TNF-a, IL-6and MIP-2, and also decreased the lung MPO activity. In vitro study showed that the treatment with cigarette smoke extract significantly enhaned the apoptosis of A549cells and increased the expresson of cleaved caspase-3and cleaved poly (ADP-ribose) polymerase, all which were markedly decreased by andrographolide.
Conclusion:
Andrographolide inhibits CS-induced acute lung inflammation and protects against CSE-mediated apoptosis of A549cells.
Part3:The mechanisms for andrographolide-mediated protective effects against passive cigarette smoke-induced lung injury
Objective:
To investigate the molecular mechanisms underlying andrographolide-mediated protective effects against cigarette smoke-induced acute lung injury, especially the involvement of heme oxygenase-1(HO-1) signaling patheay.
Methods:
In the present study, lung epithemial cell line A549cells were used as an in-vitro cell mdoel. RT-PCR and Western blot analysis were employed to analyze the effects of cigarette smoke and andrographolide on HO-1expression at both mRNA and protein levels.32C57/BL/6mice (18-20g) were6-8weeks old. Mice were randomly divided into4groups (8mice for each group):control group (C), cigarette smoke exposure group (CS), andrographolide treatment together with CS exposure group (A), and A+Z group, with zinc protoporphyrin IX (ZnPP) administration before andrographolide treatment and CS exposure. Andrographolide was given by intraperitoneal injection at a dose of1mg/kg body weight,1h before CS exposure. ZnPP, a potent heme oxygenase inhibitor, was administered intraperitoneally at a dose of10μmol/kg body weight,1h before andrographolide administration. Animals were placed in an inhalation chamber and exposed to9cigarettes daily for4consecutive days for CS-exposed groups.Control mice were placed in the same condition but not exposed to cigarette smoke. On the fifth day, mice were killed with an overdose of intraperitoneal sodium pentobarbital. Bronchoalveolar lavage fluid (BALF) was collected. Histologial analysis of mouse lungs was performed. RT-PCR and Western blot analysis were performed to analyze the expression of HO-1in the lung tissues. Pulmonary HO-1activity was also analyzed. Total cell count in BALF was determined by a hemocytometer. Differential cell counts were performed with Wright-Giemsa method. The total protein in BALF was measured by the BCA method. ELISA assay was used to analyze the production of tumor necrosis factor-alpha (TNF-a), interleukine-6(IL-6), macrophage inflammatory protein-2(MIP-2). The levels of MDA in the lung tissues and BALF were measured. The activity of LDH in BALF and the lung tissues and the activities of Superoxide Dismutase (SOD), Glutathione peroxidase (GSH-Px), Catalase (CAT), myeloperoxidase (MPO) were detected in mouse lung tissues.Western blot analysis was performed to analyze the effects of andrographolide on STAT3signaling pathway.
Results:
Both CS and andrographolide increased the expression of HO-1at both mRNA and protein levels in a dose-dependent manner, indicating that HO-1might exhibit protecitive effect against CS-induced lung injury. Mice in response to CS exposure had pulmonary lesions with interstitial edema and large areas of marked intravascular, interstitial, and intra-alveolar inflammatory cell infiltration. The influx of inflammatory cells and edema in the lungs of CS-exposed mice was alleviated by the administration of andrographolide. Interestingly, ZnPP pretreatment markedly abolished the protective effects of andrographolide on CS-induced lung injury. Pretreatment with andrographolide markedly attenuated lung inflammation in CS-exposed mice, coupled with reduced numbers of total cells, neutrophils, and macrophages, total protein level in bronchial alveolar lavage fluid (BALF), decreased production of cytokine/chemokine (TNF-a, IL-6, and MIP-2) into BALF, less MDA in the lung tissues and BALF, and lowered activities of LDH (in both BALF and the lung tissues), SOD, GSH-Px, CAT, and MPO in lung tissues. Notably, these histological and biochemical changes induced by andrographolide were blocked by prior administration of ZnPP. Moreover, andrographolide-induced phosphorylation of signal transducer and activator of transcription3was attenuated by ZnPP treatment in CS-exposed animals.
Conclusion:
Our data collectively demonstrate that andrographolide confers protection against CS-induced lung inflammation, partially through activation of HO-1and STAT3.
引文
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