促炎症消退介质脂氧素对内毒素性肺损伤的保护作用及机制
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摘要
第一部分脂氧素对脂多糖诱导小鼠巨噬细胞钙信号转导及活性氧产生的影响及机制
目的研究脂氧素对脂多糖诱导的小鼠RAW264.7巨噬细胞钙信号转导及活性氧产生的影响并探讨其可能机制。方法小鼠RAW264.7巨噬细胞,随机分为6组:①对照组;②单纯lipopolysaccharide(LPS)组:以终浓度2-10μg/ml LPS刺激巨噬细胞;③单纯Thapsigargin(钙池操纵的钙通道激活剂)组:以终浓度2μM Thapsigargin刺激巨噬细胞;④脂氧素+ LPS组:分别用终浓度为10-7、10-8或10-9M的脂氧素预处理,再以LPS(2-10μg/ml)刺激;⑤脂氧素+ Thapsigargin组:分别用终浓度为10-7、10-8或10-9M的脂氧素预处理,再以2μM Thapsigargin刺激;⑥2-Aminoethoxydiphenylborate(2-APB,钙池操纵的钙通道阻滞剂)+ Thapsigargin组:20μM 2-APB预处理,再以2μM Thapsigargin刺激。采用细胞内钙离子特异性荧光探针Fluo3-AM和活性氧特异性荧光探针DCFH-DA标记小鼠巨噬细胞。激光共聚焦显微镜动态观察脂多糖引起巨噬细胞胞内游离钙浓度变化,流式细胞仪测定巨噬细胞活性氧产生变化。结果脂多糖呈剂量依赖升高细胞内游离钙浓度和活性氧的产生,钙池操纵的钙通道激活剂Thapsigargin可完全抑制脂多糖引起的胞内钙超载。脂氧素呈剂量依赖抑制脂多糖引起的胞内游离钙浓度升高,脂氧素同时可抑制Thapsigargin激活钙池操纵的钙通道引起的钙内流。细胞外无钙液及脂氧素均可抑制脂多糖和Thapsigargin诱导的活性氧产生。结论脂多糖通过促进内钙释放而开放钙池操纵的钙通道,大量细胞外钙离子进入细胞使钙超载,活性氧大量产生,引起组织细胞损伤。脂氧素可能通过抑制钙池操纵的钙通道,使外钙内流减少,保持细胞钙稳态,减少活性氧的生成而起到抗炎促炎症消退作用。
第二部分脂氧素对脂多糖诱导小鼠巨噬细胞TNF-α转化酶的影响
目的研究脂氧素对脂多糖诱导的小鼠RAW264.7巨噬细胞TNF-α转化酶表达的影响。方法小鼠RAW264.7巨噬细胞,随机分为3组:①对照组;②单纯LPS组:以终浓度1- 2μg/ml LPS刺激巨噬细胞;③脂氧素+ LPS组:分别用终浓度为10-7、10-8或10-9 M的脂氧素预处理,再以LPS(1- 2μg/ml)刺激。孵育6小时和24小时后,收集细胞上清液,酶联免疫法测定上清液TNF-α浓度。提取细胞总mRNA, RT-PCR测定TNF-α转化酶和TNF-α基因表达,提取细胞总蛋白测定TNF-α转化酶蛋白表达,流式细胞仪检测膜型TNF-α蛋白表达。结果脂氧素抑制脂多糖诱导的RAW264.7小鼠巨噬细胞TNF-α基因和膜型TNF-α蛋白表达。脂氧素抑制脂多糖诱导的TNF-α转化酶蛋白表达但不影响其mRNA表达,并呈剂量依赖抑制脂多糖诱导的分泌型TNF-α产生。结论脂氧素通过干扰TNF-α转化酶蛋白质翻译过程,进而减少脂多糖诱导的RAW264.7巨噬细胞分泌型TNF-α的产生,这可能是脂氧素抗炎促炎症消退的重要作用机制之一。
第三部分脂氧素对内毒素性肺损伤小鼠的保护作用及机制
目的研究脂氧素对脂多糖诱导小鼠急性肺损伤的影响并探讨其可能机制。方法36只雄性C57BL/6小鼠,随机分为6组(n = 6):①对照组:小鼠雾化吸入0.9%生理盐水20 min,60 min后尾静脉注射10%乙醇5 ml/kg;②脂氧素组:小鼠雾化吸入0.9%生理盐水20 min,60 min后尾静脉注射脂氧素(0.1 mg/kg);③ZnPP组:小鼠雾化吸入0.9%生理盐水20 min,60 min后尾静脉注射Zinc protoporphyrin IX(血红素氧合酶-1抑制剂)25 mg/kg;④LPS组:小鼠雾化吸入LPS 20 min,60 min后尾静脉注射10%乙醇5 ml/kg;⑤脂氧素治疗组:以脂氧素0.1 mg/kg代替乙醇,其余处理同LPS组;⑥ZnPP+脂氧素治疗组:处理同脂氧素治疗组,但静脉注射脂氧素30 min前注射ZnPP 25 mg/kg。雾化吸入LPS或生理盐水后8 h处死动物。光镜下观察肺组织病理学变化,测定肺泡灌洗液白细胞、中性粒细胞计数和TNF-α含量及总蛋白浓度;测定肺组织髓过氧化物酶(MPO)活性、干湿重比值、丙二醛(MDA)活性和一氧化氮(NO)浓度;测定肺组织血红素氧合酶-1(HO-1)的蛋白表达和活性。结果与LPS组比较,脂氧素治疗组肺组织中性粒细胞浸润减少、肺水肿减轻,肺组织MPO活性、MDA活性、NO含量、TNF-α浓度均降低(P < 0.01),肺泡灌洗液总蛋白浓度降低(P < 0.01)。而HO-1的蛋白表达和活性明显升高,HO-1抑制剂ZnPP减弱脂氧素保护作用。结论脂氧素通过上调HO-1减轻内毒素诱导的小鼠急性肺损伤。
PartⅠThe effects of lipoxin on calcium signal transduction and production of reactive oxygen species in macrophages induced by LPS
Objective To investigate the effects of lipoxin on calcium signal transduction and production of reactive oxygen species in macrophages induced by lipopolysaccharide (LPS). Methods Macrophages were randomly assigned to one of the following six groups:①control group;②LPS group;③Thapsigargin group;④Lipoxin + LPS group;⑤Lipoxin + Thapsigargin group;⑥2-Aminoethoxydiphenylborate + Thapsigargin group. The intracellular [Ca~(2+)]_i was analyzed by confocal laser microscopy. The production of ROS was assayed by flow cytometry. Results Both LPS and Thapsigargin induced an increase in intracellular [Ca~(2+)]_i, either in the presence or absence of extracellular Ca~(2+) in murine macrophages. The Ca~(2+) signal was sustained in the presence of external Ca~(2+) and only initiated a mild and transient rise in the absence of external Ca~(2+). SOC channel inhibitor 2-APB completely suppressed the Ca~(2+) entry signal evoked by thapsigargin and suppressed approximately 93% of the Ca~(2+) entry signal evoked by LPS. The increase in intracellular [Ca~(2+)]_i was associated with increased ROS production which was completely abolished in the absence of extracellular Ca~(2+) or in the presence of SOC channel inhibitors 2-APB or lipoxin. Conclusions These findings indicate that the LPS-induced intracellular [Ca~(2+)]_i increase depends on the Ca~(2+) entry through SOC channels, and lipoxin inhibits Ca~(2+) influx and ROS production through SOC channels in murine macrophages induced by LPS
PartⅡThe effects of lipoxin on expression of TNF-αconverting enzyme in RAW264.7 macrophages induced by LPS
Objective To observe the effects of lipoxin on expression of TNF-αconverting enzyme in RAW264.7 macrophages induced by LPS. Methods RAW264.7 macrophages were cultured in vitro with 1-2ug/ml lipopolysaccharide in the absence or presence of lipoxin at different concentrations for 6 and 24 hours, then the supernatant was collected for measuring TNF-αby ELISA kit and the expressions of TNF-αand TNF-αconverting enzyme were measured by semi-quantitative RT-PCR. Western blotting was applied to detect the expression of TNF-αconverting enzyme. The expressions of membrane-bound TNF-αprotein were assessed by flow cytrometry. Results Lipoxin inhibited the gene and protein expression of TNF-α, lipoxin inhibited up-regulation of TACE protein expression but did not inhibit TNF-αconverting enzyme mRNA expression. Conclusions Lipoxin inhibits the release of TNF-αthrough inhibition the protein expression of TNF-αconverting enzyme in RAW264.7 macrophages.
PartⅢProtective effect of lipoxin on LPS-induced acute lung injury in mice
Objective To investigate whether lipoxin could attenuate LPS induced acute lung injury in mice. Methods All of the animals were randomly assigned to one of six groups (n = 6 per group). In the sham-vehicle group, mice were treated with 0.9% saline 60 mins after they were challenged with saline. The sham-ATL group was identical to the sham-vehicle group except that ATL (0.7 mg/kg, intravenously) was administered instead of vehicle. The sham-ZnPP group was identical to the sham-vehicle group except that Zinc protoporphyrin IX (ZnPP, 25 mg/kg intravenously) was administered instead of vehicle. In the LPS-vehicle group, mice were treated with vehicle 60 mins after they were challenged with LPS. The LPS-ATL group was identical to the LPS-vehicle group but received ATL (0.7 mg/kg, intravenously) instead of vehicle. The ZnPP-ATL-LPS group was identical to the LPS-ATL group, but ZnPP (25 mg/kg intravenously) was administered 30 mins before ATL. Results Inhalation of LPS increased inflammatory cell counts, TNF (Tumor Necrosis Factor)-αand protein concentration in BALF and also induced lung histological injury and edema. Post-treatment with ATL inhibited TNF-α, nitric oxide and malondialdehyde production, with the outcome of decreased pulmonary edema, lipid peroxidation and the infiltration of neutrophils in lung tissues. In addition, Western blot and immunohistochemical analysis revealed that ATL promoted the formation of HO-1 in the lung tissues. Heme oxygenase-1(HO-1) activity was also increased in the lung tissues after ATL stimulation. The beneficial effects of ATL were abolished by ZnPP. Conclusions This study demonstrates that post-treatment with ATL significantly reduces LPS-induced acute lung injury in mice. HO-1 plays an essential role in the anti-inflammatory and pro-resolution bioactions of lipoxin.
目的研究脂氧素对脂多糖诱导的小鼠RAW264.7巨噬细胞钙信号转导及活性氧产生的影响并探讨其可能机制。方法小鼠RAW264.7巨噬细胞,随机分为6组:①对照组;②单纯lipopolysaccharide(LPS)组:以终浓度2-10μg/ml LPS刺激巨噬细胞;③单纯Thapsigargin(钙池操纵的钙通道激活剂)组:以终浓度2μM Thapsigargin刺激巨噬细胞;④脂氧素+ LPS组:分别用终浓度为10-7、10-8或10-9M的脂氧素预处理,再以LPS(2-10μg/ml)刺激;⑤脂氧素+ Thapsigargin组:分别用终浓度为10-7、10-8或10-9M的脂氧素预处理,再以2μM Thapsigargin刺激;⑥2-Aminoethoxydiphenylborate(2-APB,钙池操纵的钙通道阻滞剂)+ Thapsigargin组:20μM 2-APB预处理,再以2μM Thapsigargin刺激。采用细胞内钙离子特异性荧光探针Fluo3-AM和活性氧特异性荧光探针DCFH-DA标记小鼠巨噬细胞。激光共聚焦显微镜动态观察脂多糖引起巨噬细胞胞内游离钙浓度变化,流式细胞仪测定巨噬细胞活性氧产生变化。结果脂多糖呈剂量依赖升高细胞内游离钙浓度和活性氧的产生,钙池操纵的钙通道激活剂Thapsigargin可完全抑制脂多糖引起的胞内钙超载。脂氧素呈剂量依赖抑制脂多糖引起的胞内游离钙浓度升高,脂氧素同时可抑制Thapsigargin激活钙池操纵的钙通道引起的钙内流。细胞外无钙液及脂氧素均可抑制脂多糖和Thapsigargin诱导的活性氧产生。结论脂多糖通过促进内钙释放而开放钙池操纵的钙通道,大量细胞外钙离子进入细胞使钙超载,活性氧大量产生,引起组织细胞损伤。脂氧素可能通过抑制钙池操纵的钙通道,使外钙内流减少,保持细胞钙稳态,减少活性氧的生成而起到抗炎促炎症消退作用。
第二部分脂氧素对脂多糖诱导小鼠巨噬细胞TNF-α转化酶的影响
目的研究脂氧素对脂多糖诱导的小鼠RAW264.7巨噬细胞TNF-α转化酶表达的影响。方法小鼠RAW264.7巨噬细胞,随机分为3组:①对照组;②单纯LPS组:以终浓度1- 2μg/ml LPS刺激巨噬细胞;③脂氧素+ LPS组:分别用终浓度为10-7、10-8或10-9 M的脂氧素预处理,再以LPS(1- 2μg/ml)刺激。孵育6小时和24小时后,收集细胞上清液,酶联免疫法测定上清液TNF-α浓度。提取细胞总mRNA, RT-PCR测定TNF-α转化酶和TNF-α基因表达,提取细胞总蛋白测定TNF-α转化酶蛋白表达,流式细胞仪检测膜型TNF-α蛋白表达。结果脂氧素抑制脂多糖诱导的RAW264.7小鼠巨噬细胞TNF-α基因和膜型TNF-α蛋白表达。脂氧素抑制脂多糖诱导的TNF-α转化酶蛋白表达但不影响其mRNA表达,并呈剂量依赖抑制脂多糖诱导的分泌型TNF-α产生。结论脂氧素通过干扰TNF-α转化酶蛋白质翻译过程,进而减少脂多糖诱导的RAW264.7巨噬细胞分泌型TNF-α的产生,这可能是脂氧素抗炎促炎症消退的重要作用机制之一。
第三部分脂氧素对内毒素性肺损伤小鼠的保护作用及机制
目的研究脂氧素对脂多糖诱导小鼠急性肺损伤的影响并探讨其可能机制。方法36只雄性C57BL/6小鼠,随机分为6组(n = 6):①对照组:小鼠雾化吸入0.9%生理盐水20 min,60 min后尾静脉注射10%乙醇5 ml/kg;②脂氧素组:小鼠雾化吸入0.9%生理盐水20 min,60 min后尾静脉注射脂氧素(0.1 mg/kg);③ZnPP组:小鼠雾化吸入0.9%生理盐水20 min,60 min后尾静脉注射Zinc protoporphyrin IX(血红素氧合酶-1抑制剂)25 mg/kg;④LPS组:小鼠雾化吸入LPS 20 min,60 min后尾静脉注射10%乙醇5 ml/kg;⑤脂氧素治疗组:以脂氧素0.1 mg/kg代替乙醇,其余处理同LPS组;⑥ZnPP+脂氧素治疗组:处理同脂氧素治疗组,但静脉注射脂氧素30 min前注射ZnPP 25 mg/kg。雾化吸入LPS或生理盐水后8 h处死动物。光镜下观察肺组织病理学变化,测定肺泡灌洗液白细胞、中性粒细胞计数和TNF-α含量及总蛋白浓度;测定肺组织髓过氧化物酶(MPO)活性、干湿重比值、丙二醛(MDA)活性和一氧化氮(NO)浓度;测定肺组织血红素氧合酶-1(HO-1)的蛋白表达和活性。结果与LPS组比较,脂氧素治疗组肺组织中性粒细胞浸润减少、肺水肿减轻,肺组织MPO活性、MDA活性、NO含量、TNF-α浓度均降低(P < 0.01),肺泡灌洗液总蛋白浓度降低(P < 0.01)。而HO-1的蛋白表达和活性明显升高,HO-1抑制剂ZnPP减弱脂氧素保护作用。结论脂氧素通过上调HO-1减轻内毒素诱导的小鼠急性肺损伤。
PartⅠThe effects of lipoxin on calcium signal transduction and production of reactive oxygen species in macrophages induced by LPS
Objective To investigate the effects of lipoxin on calcium signal transduction and production of reactive oxygen species in macrophages induced by lipopolysaccharide (LPS). Methods Macrophages were randomly assigned to one of the following six groups:①control group;②LPS group;③Thapsigargin group;④Lipoxin + LPS group;⑤Lipoxin + Thapsigargin group;⑥2-Aminoethoxydiphenylborate + Thapsigargin group. The intracellular [Ca~(2+)]_i was analyzed by confocal laser microscopy. The production of ROS was assayed by flow cytometry. Results Both LPS and Thapsigargin induced an increase in intracellular [Ca~(2+)]_i, either in the presence or absence of extracellular Ca~(2+) in murine macrophages. The Ca~(2+) signal was sustained in the presence of external Ca~(2+) and only initiated a mild and transient rise in the absence of external Ca~(2+). SOC channel inhibitor 2-APB completely suppressed the Ca~(2+) entry signal evoked by thapsigargin and suppressed approximately 93% of the Ca~(2+) entry signal evoked by LPS. The increase in intracellular [Ca~(2+)]_i was associated with increased ROS production which was completely abolished in the absence of extracellular Ca~(2+) or in the presence of SOC channel inhibitors 2-APB or lipoxin. Conclusions These findings indicate that the LPS-induced intracellular [Ca~(2+)]_i increase depends on the Ca~(2+) entry through SOC channels, and lipoxin inhibits Ca~(2+) influx and ROS production through SOC channels in murine macrophages induced by LPS
PartⅡThe effects of lipoxin on expression of TNF-αconverting enzyme in RAW264.7 macrophages induced by LPS
Objective To observe the effects of lipoxin on expression of TNF-αconverting enzyme in RAW264.7 macrophages induced by LPS. Methods RAW264.7 macrophages were cultured in vitro with 1-2ug/ml lipopolysaccharide in the absence or presence of lipoxin at different concentrations for 6 and 24 hours, then the supernatant was collected for measuring TNF-αby ELISA kit and the expressions of TNF-αand TNF-αconverting enzyme were measured by semi-quantitative RT-PCR. Western blotting was applied to detect the expression of TNF-αconverting enzyme. The expressions of membrane-bound TNF-αprotein were assessed by flow cytrometry. Results Lipoxin inhibited the gene and protein expression of TNF-α, lipoxin inhibited up-regulation of TACE protein expression but did not inhibit TNF-αconverting enzyme mRNA expression. Conclusions Lipoxin inhibits the release of TNF-αthrough inhibition the protein expression of TNF-αconverting enzyme in RAW264.7 macrophages.
PartⅢProtective effect of lipoxin on LPS-induced acute lung injury in mice
Objective To investigate whether lipoxin could attenuate LPS induced acute lung injury in mice. Methods All of the animals were randomly assigned to one of six groups (n = 6 per group). In the sham-vehicle group, mice were treated with 0.9% saline 60 mins after they were challenged with saline. The sham-ATL group was identical to the sham-vehicle group except that ATL (0.7 mg/kg, intravenously) was administered instead of vehicle. The sham-ZnPP group was identical to the sham-vehicle group except that Zinc protoporphyrin IX (ZnPP, 25 mg/kg intravenously) was administered instead of vehicle. In the LPS-vehicle group, mice were treated with vehicle 60 mins after they were challenged with LPS. The LPS-ATL group was identical to the LPS-vehicle group but received ATL (0.7 mg/kg, intravenously) instead of vehicle. The ZnPP-ATL-LPS group was identical to the LPS-ATL group, but ZnPP (25 mg/kg intravenously) was administered 30 mins before ATL. Results Inhalation of LPS increased inflammatory cell counts, TNF (Tumor Necrosis Factor)-αand protein concentration in BALF and also induced lung histological injury and edema. Post-treatment with ATL inhibited TNF-α, nitric oxide and malondialdehyde production, with the outcome of decreased pulmonary edema, lipid peroxidation and the infiltration of neutrophils in lung tissues. In addition, Western blot and immunohistochemical analysis revealed that ATL promoted the formation of HO-1 in the lung tissues. Heme oxygenase-1(HO-1) activity was also increased in the lung tissues after ATL stimulation. The beneficial effects of ATL were abolished by ZnPP. Conclusions This study demonstrates that post-treatment with ATL significantly reduces LPS-induced acute lung injury in mice. HO-1 plays an essential role in the anti-inflammatory and pro-resolution bioactions of lipoxin.
引文
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