血管活性肠肽对巨噬细胞和成纤维细胞在肺损伤修复中的作用探讨
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摘要
血管活性肠肽(vasoactive intestinal peptides,VIP)是肺内重要的感觉神经肽,主要由非肾上腺素能非胆碱能神经纤维释放,其阳性神经纤维及受体广泛分布于肺内。VIP除扩张血管外,还具有舒张气道平滑肌、抑制肺泡巨噬细胞吞噬和T淋巴细胞增殖、减少肺炎性介质释放、促进气道上皮的损伤修复、清除氧自由基和抗细胞凋亡等生物学作用,其在机体内的多种效应日益受到重视。
在急性肺损伤(acute lung injury,ALI)中,肺巨噬细胞作为炎性细胞发挥着重要作用,能分泌炎性介质肿瘤坏死因子-α(tumornecrosis factor-alpha,TNF-α)和转化生长因子-β(transforminggrowth factor-beta,TGF-β)。TNF-α可能作为始动因素参与了ALI的发生、发展,既可加重ALI的炎症反应,促进成纤维细胞的增殖和胶原的沉积,又可进一步激活巨噬细胞释放氧自由基引起恶性循环;TGF-β可通过诱导纤维母细胞增生、成纤维细胞表型改变、胶原纤维及细胞外基质合成增加等多种机制参与肺的重塑。作为肺内重要的神经肽,VIP具有抗肺损伤的重要作用,可能是切断ALI启动的关键因素之一。因此,探讨VlP在调整神经肽-炎症反应网络回复到生理状态中的作用具有重要意义。
目的:研究VIP对巨噬细胞和成纤维细胞在肺损伤修复的作用。
方法:(1)VIP对巨噬细胞(RAW264.7)株损伤修复的影响:以巨噬细胞为研究对象,观察脂多糖(lipopolysaccharide,LPS)诱导的巨噬细胞的MDA和SOD含量变化,反映肺氧化和抗氧化损伤的程度:采用RT-PCR和Western-blot法检测TNF-α和TGF-βmRNA及其蛋白的表达。(2)VIP对肺成纤维细胞(NIH3T3)株损伤修复的影响:以肺成纤维细胞为研究对象,采用MTT法测定其增殖活性;免疫细胞化学方法检测α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)的表达;羟脯氨酸(hydroxyproline,HYP)试剂盒和RT-PCR法检测Ⅲ型胶原蛋白与mRNA的表达。
结果:
1.VIP对巨噬细胞损伤修复的影响
(1)黄嘌呤氧化酶法和硫代巴比妥酸法测定SOD活力和MDA含量的结果显示:LPS刺激后巨噬细胞SOD活性减弱,MDA生成增多,表明巨噬细胞氧化损伤加重;而VIP可明显减轻此效应(P＜0.01),应用VIP受体拮抗剂则可阻断VIP的抗氧化损伤效应。
(2)RT-PCR和Western-blot检测结果显示:LPS刺激后巨噬细胞生成炎性因子TNF—αmRNA及其蛋白的表达上调,VIP预处理组则可逆转该上调作用(P＜0.01),应用VIP受体拮抗剂后,炎性因子表达与单独应用LPS组无明显差异(P＞0.05)。TGF-βmRNA及其蛋白表达无明显变化。
2.VIP对肺成纤维细胞损伤修复的影响
(1)MTT法显示LPS刺激后,肺成纤维细胞增殖活性明显加强,VIP预处理可抑制其增殖活性(P＜0.01),应用VIP受体拮抗剂可使抑制作用消失。
(2)LPS刺激可使肺成纤维细胞发生表型改变,生成以α-SMA为典型特征的肌成纤维细胞。免疫细胞化学检测结果表明,LPS刺激24h后,肺成纤维细胞胞浆内出现棕黄色细颗粒状物(α-SMA),而对照组无明显变化,表明成纤维细胞已向肌成纤维细胞转化。VIP可明显抑制肺成纤维细胞的表型改变,而其受体拮抗剂则可逆转该效应。
(3)羟脯氨酸试剂盒和RT-PCR法检测结果显示,LPS刺激后,肺成纤维细胞Ⅲ型胶原蛋白和mRNA的表达与对照组相比均增强(P＜0.05),VIP可显著减弱肺成纤维细胞Ⅲ型胶原蛋白和mRNA的表达,而VIP受体拮抗剂则可逆转VIP的效应。
结论:
1.LPS刺激后巨噬细胞氧化损伤加重,TNF-α分泌增多。
2.LPS刺激后成纤维细胞增殖活动、胶原合成明显加强,向肌成纤维细胞转化。
3.VIP可逆转LPS刺激后的上述效应,提示VIP可能参与切断急性肺损伤的启动,促进损肺伤修复。
Background: Vasoactive intestinal peptide (VIP) is one of the most important sensory neuropeptides, which comes mainly from non-adrenergic and non-cholinergic nerve fibers. The positive immunoreactivity fibers and receptors of VIP widely distribute in pulmonary. VIP has played a vital role in organism's physiological processes such as relaxing airway smooth muscle, inhibiting phagocytosis of alveolar macrophage and cell proliferation of T lympholeukocyte, reducing the release of inflammation media, enhancing the wound repairing of airway epithelium, eliminating oxygen-derived free radicals and antagonizing cell apoptosis in lung and evidences have being accumulated that its mechanisms are involved in various biological effects.
Macrophage played important role in acute lung injury (ALI). It can secrete inflammation mediators such as tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-β) etc. TNF-αtook part in the genesis and development of ALI as initiating agent. It can aggravate inflammatory reaction, promote the proliferation of the lung fibroblast and facilitate the deposition of collagen and activate the macrophage to release oxygen free radical. TGF-βparticipated in pulmonary remodeling through inducing the proliferation and phenotypic alternation of fibroblast, encouraging the synthesis of collagen fibers and extracellular matrix (ECM). As an important neuropeptide in lung, there were no reports published about the effects of VIP on lung injury after stimulus by lipopolysaccharide (LPS). Therefore, it is significant to adjust the network of neuropeptide- inflammatory reaction back to physiology condition.
Objective: The present study was designed to investigate the effects and mechanisms of VIP on wound repair in ALI.
Methods: (1) The influence of VIP on wound repair of macrophage: the oxidative damage of macrophage was observed by xanthine oxidase and thio-barbituric acid methods; the mRNA and protein expression of TNF-αand TGF-βwere measured by RT-PCR and Western-blot. (2) The influence of VIP on wound repair of lung fibroblast: the proliferation of lung fibroblast was determined by MTT; a-SMA expression of lung fibroblast was observed by immunohistochemistry; the protein and mRNA expression of III collagen were determined by hydroxyproline content and RT-PCR.
Results:
1. The influence of VIP on wound repair of macrophage
(1) The activity of SOD was decreased while the generation of MDA was increased by SOD and MDA kits, which indicating that LPS could aggravate the oxidative damage. VIP can protect RAW264.7 from oxidative damage (P<0.01) while the VIP receptor antagonist blocked the protective effects of VIP.
(2) The protein and mRNA expression of TNF-αwere up-regulated by RT-PCR and Western-blot. VIP pretreated could reverse the effects (P<0.01). There was no significant difference compared with LPS group by using VIP receptor antagonist. There was no change about the expression of TGF-β.
2. The influence of VIP on wound repair of lung fibroblast
(1) When compared with control group, the proliferation of lung fibroblast treated with LPS was strengthened obviously by using MTT. Pretreated with VIP could repress the proliferation activity while VIP receptor antagonist could block the effects evoked by VIP.
(2) The lung fibroblast will have a-SMA for its phenotypic alternation treated with LPS. The immunocytochemistry detected that there was buffy fine grain in the intracytoplasm of lung fibroblast which indicating that fibroblast transformed to myofibroblast. Pretreated with VIP could inhibit obviously the phenotypic alternation (P<0.05). VIP receptor antagonist could eliminate the effects.
(3) The hydroxyproline kit and RT-PCR showed that the protein and mRNA expression of III collagen protein in lung fibroblast enhanced with LPS stimulus compared with control group. VIP could attenuate the expression above while VIP receptor antagonist had the opposite effects.
Conclusions:
(1) After stimulated with LPS, the oxidative damage of RAW264.7 was aggravated and the production of inflammatory factors was increase.
(2) After stimulated with LPS, the proliferation activity and collagen synthesis of lung fibroblast were augmented, the phenotype of the lung fibroblast was changed to myofibroblast.
(3) Pretreated with VIP could reverse the changes above, indicating that it may participate in cutting down the priming of ALI and enhance the lung wound repair.
在急性肺损伤(acute lung injury,ALI)中,肺巨噬细胞作为炎性细胞发挥着重要作用,能分泌炎性介质肿瘤坏死因子-α(tumornecrosis factor-alpha,TNF-α)和转化生长因子-β(transforminggrowth factor-beta,TGF-β)。TNF-α可能作为始动因素参与了ALI的发生、发展,既可加重ALI的炎症反应,促进成纤维细胞的增殖和胶原的沉积,又可进一步激活巨噬细胞释放氧自由基引起恶性循环;TGF-β可通过诱导纤维母细胞增生、成纤维细胞表型改变、胶原纤维及细胞外基质合成增加等多种机制参与肺的重塑。作为肺内重要的神经肽,VIP具有抗肺损伤的重要作用,可能是切断ALI启动的关键因素之一。因此,探讨VlP在调整神经肽-炎症反应网络回复到生理状态中的作用具有重要意义。
目的:研究VIP对巨噬细胞和成纤维细胞在肺损伤修复的作用。
方法:(1)VIP对巨噬细胞(RAW264.7)株损伤修复的影响:以巨噬细胞为研究对象,观察脂多糖(lipopolysaccharide,LPS)诱导的巨噬细胞的MDA和SOD含量变化,反映肺氧化和抗氧化损伤的程度:采用RT-PCR和Western-blot法检测TNF-α和TGF-βmRNA及其蛋白的表达。(2)VIP对肺成纤维细胞(NIH3T3)株损伤修复的影响:以肺成纤维细胞为研究对象,采用MTT法测定其增殖活性;免疫细胞化学方法检测α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)的表达;羟脯氨酸(hydroxyproline,HYP)试剂盒和RT-PCR法检测Ⅲ型胶原蛋白与mRNA的表达。
结果:
1.VIP对巨噬细胞损伤修复的影响
(1)黄嘌呤氧化酶法和硫代巴比妥酸法测定SOD活力和MDA含量的结果显示:LPS刺激后巨噬细胞SOD活性减弱,MDA生成增多,表明巨噬细胞氧化损伤加重;而VIP可明显减轻此效应(P＜0.01),应用VIP受体拮抗剂则可阻断VIP的抗氧化损伤效应。
(2)RT-PCR和Western-blot检测结果显示:LPS刺激后巨噬细胞生成炎性因子TNF—αmRNA及其蛋白的表达上调,VIP预处理组则可逆转该上调作用(P＜0.01),应用VIP受体拮抗剂后,炎性因子表达与单独应用LPS组无明显差异(P＞0.05)。TGF-βmRNA及其蛋白表达无明显变化。
2.VIP对肺成纤维细胞损伤修复的影响
(1)MTT法显示LPS刺激后,肺成纤维细胞增殖活性明显加强,VIP预处理可抑制其增殖活性(P＜0.01),应用VIP受体拮抗剂可使抑制作用消失。
(2)LPS刺激可使肺成纤维细胞发生表型改变,生成以α-SMA为典型特征的肌成纤维细胞。免疫细胞化学检测结果表明,LPS刺激24h后,肺成纤维细胞胞浆内出现棕黄色细颗粒状物(α-SMA),而对照组无明显变化,表明成纤维细胞已向肌成纤维细胞转化。VIP可明显抑制肺成纤维细胞的表型改变,而其受体拮抗剂则可逆转该效应。
(3)羟脯氨酸试剂盒和RT-PCR法检测结果显示,LPS刺激后,肺成纤维细胞Ⅲ型胶原蛋白和mRNA的表达与对照组相比均增强(P＜0.05),VIP可显著减弱肺成纤维细胞Ⅲ型胶原蛋白和mRNA的表达,而VIP受体拮抗剂则可逆转VIP的效应。
结论:
1.LPS刺激后巨噬细胞氧化损伤加重,TNF-α分泌增多。
2.LPS刺激后成纤维细胞增殖活动、胶原合成明显加强,向肌成纤维细胞转化。
3.VIP可逆转LPS刺激后的上述效应,提示VIP可能参与切断急性肺损伤的启动,促进损肺伤修复。
Background: Vasoactive intestinal peptide (VIP) is one of the most important sensory neuropeptides, which comes mainly from non-adrenergic and non-cholinergic nerve fibers. The positive immunoreactivity fibers and receptors of VIP widely distribute in pulmonary. VIP has played a vital role in organism's physiological processes such as relaxing airway smooth muscle, inhibiting phagocytosis of alveolar macrophage and cell proliferation of T lympholeukocyte, reducing the release of inflammation media, enhancing the wound repairing of airway epithelium, eliminating oxygen-derived free radicals and antagonizing cell apoptosis in lung and evidences have being accumulated that its mechanisms are involved in various biological effects.
Macrophage played important role in acute lung injury (ALI). It can secrete inflammation mediators such as tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-β) etc. TNF-αtook part in the genesis and development of ALI as initiating agent. It can aggravate inflammatory reaction, promote the proliferation of the lung fibroblast and facilitate the deposition of collagen and activate the macrophage to release oxygen free radical. TGF-βparticipated in pulmonary remodeling through inducing the proliferation and phenotypic alternation of fibroblast, encouraging the synthesis of collagen fibers and extracellular matrix (ECM). As an important neuropeptide in lung, there were no reports published about the effects of VIP on lung injury after stimulus by lipopolysaccharide (LPS). Therefore, it is significant to adjust the network of neuropeptide- inflammatory reaction back to physiology condition.
Objective: The present study was designed to investigate the effects and mechanisms of VIP on wound repair in ALI.
Methods: (1) The influence of VIP on wound repair of macrophage: the oxidative damage of macrophage was observed by xanthine oxidase and thio-barbituric acid methods; the mRNA and protein expression of TNF-αand TGF-βwere measured by RT-PCR and Western-blot. (2) The influence of VIP on wound repair of lung fibroblast: the proliferation of lung fibroblast was determined by MTT; a-SMA expression of lung fibroblast was observed by immunohistochemistry; the protein and mRNA expression of III collagen were determined by hydroxyproline content and RT-PCR.
Results:
1. The influence of VIP on wound repair of macrophage
(1) The activity of SOD was decreased while the generation of MDA was increased by SOD and MDA kits, which indicating that LPS could aggravate the oxidative damage. VIP can protect RAW264.7 from oxidative damage (P<0.01) while the VIP receptor antagonist blocked the protective effects of VIP.
(2) The protein and mRNA expression of TNF-αwere up-regulated by RT-PCR and Western-blot. VIP pretreated could reverse the effects (P<0.01). There was no significant difference compared with LPS group by using VIP receptor antagonist. There was no change about the expression of TGF-β.
2. The influence of VIP on wound repair of lung fibroblast
(1) When compared with control group, the proliferation of lung fibroblast treated with LPS was strengthened obviously by using MTT. Pretreated with VIP could repress the proliferation activity while VIP receptor antagonist could block the effects evoked by VIP.
(2) The lung fibroblast will have a-SMA for its phenotypic alternation treated with LPS. The immunocytochemistry detected that there was buffy fine grain in the intracytoplasm of lung fibroblast which indicating that fibroblast transformed to myofibroblast. Pretreated with VIP could inhibit obviously the phenotypic alternation (P<0.05). VIP receptor antagonist could eliminate the effects.
(3) The hydroxyproline kit and RT-PCR showed that the protein and mRNA expression of III collagen protein in lung fibroblast enhanced with LPS stimulus compared with control group. VIP could attenuate the expression above while VIP receptor antagonist had the opposite effects.
Conclusions:
(1) After stimulated with LPS, the oxidative damage of RAW264.7 was aggravated and the production of inflammatory factors was increase.
(2) After stimulated with LPS, the proliferation activity and collagen synthesis of lung fibroblast were augmented, the phenotype of the lung fibroblast was changed to myofibroblast.
(3) Pretreated with VIP could reverse the changes above, indicating that it may participate in cutting down the priming of ALI and enhance the lung wound repair.
引文
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