N-Acetylcysteine Inhibits RhoA and Promotes Apoptotic Cell Clearance during Intense Lung Inflammation
N-Acetylcysteine Inhibits RhoA and Promotes Apoptotic Cell Clearance during Intense Lung Inflammation
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DOI：
10.1164/rccm.200907-1061oc
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发表时间：
2010-02-15
影响因子：
24.7
通讯作者：
Kang, Jihee Lee
中科院分区：
文献类型：
--
作者：
Moon, Changsuk;Lee, Ye-Ji;Kang, Jihee Lee
基本原理：在各种炎性肺病中观察到的肺部炎症的消退取决于凋亡细胞的清除以防止永久性组织损伤或进行性疾病。氧化剂通过激活Rho信号转导抑制肺泡巨噬细胞对凋亡细胞的摄取。目的：我们假设抗氧化剂暴露会增加肺泡巨噬细胞通过抑制RhoA清除肺凋亡细胞的能力。抗氧化剂N-乙酰半胱氨酸（NAC）对肺免疫应答的影响在用LIPS、LPS + NAC、LPS + NAC治疗的小鼠中观察到，或盐水。凋亡细胞清除RhoA活性，并在肺部炎症反应的变化进行了分析，在体内或exvivo.Measures和主要结果：神经元的积累，凋亡，坏死，氧化剂的生产达到高峰后3天LPS治疗。NAC可增强LPS处理后3天肺泡巨噬细胞对凋亡细胞的清除，抑制RhoA活性。NAC抑制LPS诱导的促炎介质，促进转化生长因子-PI的产生，减少炎性细胞的积聚，并降低支气管肺泡灌洗液中蛋白质和乳酸脱氢酶的水平。在存在离体凋亡细胞的情况下，暴露于LIPS或LIPS + NAC的肺泡巨噬细胞具有降低的肿瘤坏死因子-α水平和增加的转化生长因子-β 1水平。Rho激酶抑制剂模拟NAC对凋亡细胞的清除和炎症反应的影响。结论：这些结果表明，NAC可以通过抑制RhoA活性和增强凋亡细胞的清除来加速LPS诱导的肺部炎症的消退。
Rationale: The resolution of pulmonary inflammation seen in various inflammatory lung conditions depends on the clearance of apoptotic cells to prevent permanent tissue damage or progressive disease. Uptake of apoptotic cells by alveolar macrophages is suppressed by oxidants through the activation of Rho signaling.Objectives: We hypothesized that antioxidant exposure would increase the ability of alveolar macrophages to clear pulmonary apo ptotic cells through the inhibition of RhoA.Methods: The effects of the antioxidant N-acetylcysteine (NAC) on the pulmonary immune response were seen in mice treated intratracheally with LIPS, LPS + NAC, or saline. Apoptotic cell clearance RhoA activity, and changes in the lung inflammatory responses were analyzed in vivo or ex vivo.Measurements and Main Results: Neutrophil accumulation, apoptosis, necrosis, and oxidant production peaked at 3 days post LPS treatment. NAC enhanced the clearance of apoptotic cells and inhibited RhoA activity in alveolar macrophages at 3 days post LPS treatment. NAC suppressed LPS-induced proinflammatory mediators, enhanced the production of transforming growth factor-PI, reduced the accumulation of inflammatory cells, and reduced levels of protein and lactate dehydrogenase in bronchoalveolar lavage fluid. In the presence of ex vivo apoptotic cells, alveolar macrophages exposed to LIPS or LIPS + NAC had reduced tumor necrosis factor-a levels and increased transforming growth factor-beta 1 levels. A Rho kinase inhibitor mimicked the effects of NAC on the clearance of apoptotic cells and the inflammatory responses.Conclusions: These results indicate that NAC can expedite the resolution of LPS-induced pulmonary inflammation through the inhibition of RhoA activity and the enhancement of apoptotic cell clearance.