角质细胞生长因子-2对脂多糖所致急性肺损伤的作用及机制研究
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摘要
角质细胞生长因子-2(KGF-2)是近年发现的专一作用于上皮细胞的生长因子,它对多种上皮细胞具有潜在的丝裂原活性,包括Ⅱ型肺泡上皮细胞。KGF-2在肺泡上皮细胞增生、分化、凋亡、损伤修复等过程中起重要作用。本文旨在探讨KGF-2提前气道内给药对内毒素所致大鼠急性肺损伤的作用及其机制。
本实验以LPS 5mg/kg体重气道内注入造成大鼠急性肺损伤模型。KGF-2以5mg/kg体重提前给药,分别在LPS刺激前1天、2天、3天、5天给药,探索KGF-2提前给药时间与肺损伤干预作用的关系。LPS气道内注入后24小时检测动脉血气分析、肺泡灌洗液(BALF)总蛋白浓度、BALF白细胞计数及分类计数、肺组织湿／干重比、肺组织病理。此外,检测BALF炎症因子水平、肺组织炎症因子表达水平、表面活性蛋白表达水平、肺泡Ⅱ型上皮细胞增殖情况等以探索其可能的作用机制。
实验结果显示,LPS致伤组动脉血氧分压较对照组显著降低,BALF总蛋白浓度、BALF白细胞总数及中性粒细胞数、肺组织湿／干重比、肺组织损伤评分均较对照组显著升高,肺组织病理提示炎症细胞浸润、肺组织实变、间质水肿等损伤表现显著。KGF-2提前1-5天给药对LPS所致肺损伤均有不同程度的减轻作用,但以提前2-3天给药保护作用最显著。LPS致伤组BALF中TNF-α及MIP-2水平、肺组织IL-1β和IL-6 mRNA表达水平较对照组显著升高,而KGF-2提前3天给药组BALF中TNF-α及MIP-2水平、肺组织IL-1β和IL-6 mRNA表达水平均较LPS致伤组显著降低。LPS刺激后肺泡表面活性蛋白A、表面活性蛋白B及表面活性蛋白C mRNA表达水平显著降低,而预先给予KGF-2可部分恢复SPA和SPC的合成水平。此外,KGF-2给药后肺泡Ⅱ型上皮细胞出现明显的增生情况。
本实验得出结论：KGF-2提前2-3天给药对LPS所致急性肺损伤有显著保护作用,其保护作用可能与KGF-2对LPS所致肺部炎症的调控作用,对肺泡表面活性蛋白合成的促进作用,以及对肺泡Ⅱ型上皮细胞增生的刺激作用这三方面机制有关。
Background:Keratinocyte growth factor-2(KGF-2)plays an essential role in survival,proliferation, and differentiation of distal-alveolar epithelial progenitor cells during lung development.We investigated the role of recombinant human KGF-2(rhKGF-2)in protecting against acute lung injury caused by lipopolysacchride (LPS) and its potential mechanisms.
Methods:LPS(5mg/kg) was administrated intratracheally to induce acute lung injury in rats.Single dose of rhKGF-2(5 mg/kg)was Intratracheally instilled 1,2,3, or 5 days before LPS challenge. Lung injury was measured by arterial blood gas analysis, lung wet-to-dry weight ratio, total protein, number of leukocytes and neutrophils in bronchoalveolar lavage fluid (BALF),and histological analysis.TNF-a and MIP-2 levels were measured in BALF.The mRNA expression level of IL-1βand IL-6 in lung tissue were analysed by quantitative PCR.Western blotting, quantitative PCR, and immunohistochemistry was done to assess expression of surfactant proteins and alveolar typeⅡepithelial cells proliferation.
Results:LPS instillation resulted in significantly decreased PaO2,and elevated lung wet-to-dry weight ratio, total protein, number of leukocytes and neutrophils in BALF, lung injury score.Pretreatment of rhKGF-2 resulted in a significant improvement in the above lung injury parameters, and pretreatment given 2 to 3 days before LPS challenge showed evident improvement in lung injury.LPS induced significant elevation of TNF-a and MIP-2 in BALF, and mRNA expression level of IL-1βand IL-6 in lung tissue, whereas pretreatment with rhKGF-2 markedly reduced the levels of TNF-a, MIP-2,IL-1βand IL-6. LPS instillation significantly inhibited the expression of surfactant protein A (SPA),surfactant protein B (SPB),and surfactant protein C(SPC)in lung tissue, while pretreatment of rhKGF-2 partially restored SPA and SPC expression. Furthermore,the improved lung injury was accompanied by increased proportion of alveolar typeⅡepithelial cells in lung parenchyma.
Conclusion:Topical administration of rhKGF-2 attenuates lung injury induced by LPS, suggesting that rhKGF-2 may be potent as a novel strategy to the treatment of acute lung injury.
本实验以LPS 5mg/kg体重气道内注入造成大鼠急性肺损伤模型。KGF-2以5mg/kg体重提前给药,分别在LPS刺激前1天、2天、3天、5天给药,探索KGF-2提前给药时间与肺损伤干预作用的关系。LPS气道内注入后24小时检测动脉血气分析、肺泡灌洗液(BALF)总蛋白浓度、BALF白细胞计数及分类计数、肺组织湿／干重比、肺组织病理。此外,检测BALF炎症因子水平、肺组织炎症因子表达水平、表面活性蛋白表达水平、肺泡Ⅱ型上皮细胞增殖情况等以探索其可能的作用机制。
实验结果显示,LPS致伤组动脉血氧分压较对照组显著降低,BALF总蛋白浓度、BALF白细胞总数及中性粒细胞数、肺组织湿／干重比、肺组织损伤评分均较对照组显著升高,肺组织病理提示炎症细胞浸润、肺组织实变、间质水肿等损伤表现显著。KGF-2提前1-5天给药对LPS所致肺损伤均有不同程度的减轻作用,但以提前2-3天给药保护作用最显著。LPS致伤组BALF中TNF-α及MIP-2水平、肺组织IL-1β和IL-6 mRNA表达水平较对照组显著升高,而KGF-2提前3天给药组BALF中TNF-α及MIP-2水平、肺组织IL-1β和IL-6 mRNA表达水平均较LPS致伤组显著降低。LPS刺激后肺泡表面活性蛋白A、表面活性蛋白B及表面活性蛋白C mRNA表达水平显著降低,而预先给予KGF-2可部分恢复SPA和SPC的合成水平。此外,KGF-2给药后肺泡Ⅱ型上皮细胞出现明显的增生情况。
本实验得出结论：KGF-2提前2-3天给药对LPS所致急性肺损伤有显著保护作用,其保护作用可能与KGF-2对LPS所致肺部炎症的调控作用,对肺泡表面活性蛋白合成的促进作用,以及对肺泡Ⅱ型上皮细胞增生的刺激作用这三方面机制有关。
Background:Keratinocyte growth factor-2(KGF-2)plays an essential role in survival,proliferation, and differentiation of distal-alveolar epithelial progenitor cells during lung development.We investigated the role of recombinant human KGF-2(rhKGF-2)in protecting against acute lung injury caused by lipopolysacchride (LPS) and its potential mechanisms.
Methods:LPS(5mg/kg) was administrated intratracheally to induce acute lung injury in rats.Single dose of rhKGF-2(5 mg/kg)was Intratracheally instilled 1,2,3, or 5 days before LPS challenge. Lung injury was measured by arterial blood gas analysis, lung wet-to-dry weight ratio, total protein, number of leukocytes and neutrophils in bronchoalveolar lavage fluid (BALF),and histological analysis.TNF-a and MIP-2 levels were measured in BALF.The mRNA expression level of IL-1βand IL-6 in lung tissue were analysed by quantitative PCR.Western blotting, quantitative PCR, and immunohistochemistry was done to assess expression of surfactant proteins and alveolar typeⅡepithelial cells proliferation.
Results:LPS instillation resulted in significantly decreased PaO2,and elevated lung wet-to-dry weight ratio, total protein, number of leukocytes and neutrophils in BALF, lung injury score.Pretreatment of rhKGF-2 resulted in a significant improvement in the above lung injury parameters, and pretreatment given 2 to 3 days before LPS challenge showed evident improvement in lung injury.LPS induced significant elevation of TNF-a and MIP-2 in BALF, and mRNA expression level of IL-1βand IL-6 in lung tissue, whereas pretreatment with rhKGF-2 markedly reduced the levels of TNF-a, MIP-2,IL-1βand IL-6. LPS instillation significantly inhibited the expression of surfactant protein A (SPA),surfactant protein B (SPB),and surfactant protein C(SPC)in lung tissue, while pretreatment of rhKGF-2 partially restored SPA and SPC expression. Furthermore,the improved lung injury was accompanied by increased proportion of alveolar typeⅡepithelial cells in lung parenchyma.
Conclusion:Topical administration of rhKGF-2 attenuates lung injury induced by LPS, suggesting that rhKGF-2 may be potent as a novel strategy to the treatment of acute lung injury.
引文
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