Attenuation of IgG immune complex-induced acute lung injury by silencing C5aR in lung epithelial cells
Attenuation of IgG immune complex-induced acute lung injury by silencing C5aR in lung epithelial cells
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DOI：
10.1096/fj.09-133694
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发表时间：
2009-11-01
期刊：
影响因子：
4.8
通讯作者：
Ward, Peter A.
中科院分区：
文献类型：
--
作者：
Sun, Lei;Guo, Ren-Feng;Ward, Peter A.
小鼠急性肺损伤(ALI)发生在远端气道中免疫球蛋白免疫复合物(IgGICs)沉积后，导致血管-呼吸道屏障的破坏，导致肺内水肿、出血和中性粒细胞[中性粒细胞]在肺泡室聚集，这些变化是补体(C5a)和C5a受体(C5aR)依赖的。在该ALI模型中，C5aR蛋白表达于上(支气管)和下(肺泡)呼吸道上皮细胞。用腺病毒载体(SiRNA)沉默肺中C5aR的mRNA。在此条件下，肺上皮细胞上的C5aR蛋白显著减少，白蛋白向肺内的渗漏大大减少，中性粒细胞的积聚减少，支气管肺泡灌洗液中的促炎介质水平降低。这些研究表明，支气管和肺泡上皮细胞C5aR表达上调，并在很大程度上促进了肺部的炎症和损伤。使用siRNA进入呼吸道可以避免全身性抑制C5aR，这可能会损害先天免疫。这种干预可能被用于ALI或急性呼吸窘迫综合征患者以及慢性阻塞性肺疾病和哮喘等上呼吸道炎症性疾病，在这些疾病中，有证据表明补体激活和PMN积聚。-Sun，L.，Guo，R.-F.，Gao，H.，Sarma，J.V.，Zetoune，F.S.，Ward，P.A.通过沉默肺上皮细胞中的C5aR来减轻免疫复合物引起的急性肺损伤。FASE B J.23,3808-3818(2009)。Www.fasebj.org
Acute lung injury (ALI) in mouse lung occurs after distal airway deposition of IgG immune complexes (IgGICs), resulting in a breakdown of the vascular-airway barrier, causing intrapulmonary edema, hemorrhage, and accumulation of neutrophils [polymorphonuclear leukocytes (PMNs)] in the alveolar compartment, these changes being complement (C5a) and C5a receptor (C5aR) dependent. In this ALI model, C5aR expression (protein) was found to occur on upper (bronchial) and lower (alveolar) airway epithelial cells. An adenovirus construct (siRNA) was used to silence mRNA for C5aR in the lung. Under such conditions, C5aR protein was markedly reduced on lung epithelial cells, resulting in much reduced leakage of albumin into the lung, diminished buildup of PMNs, and lower levels of proinflammatory mediators in bronchoalveolar lavage fluids. These studies indicate that bronchial and alveolar epithelial cell C5aR is up-regulated and greatly contributes to inflammation and injury in the lung. The use of siRNA administered into the airways avoids systemic suppression of C5aR, which might compromise innate immunity. It is possible that such an intervention might be employed in humans with ALI or acute respiratory distress syndrome as well as in upper-airway inflammatory diseases, such as chronic obstructive pulmonary disease and asthma, where there is evidence for complement activation and buildup of PMNs.-Sun, L., Guo, R.-F., Gao, H., Sarma, J. V., Zetoune, F. S., Ward, P. A. Attenuation of IgG immune complex-induced acute lung injury by silencing C5aR in lung epithelial cells. FASEB J. 23, 3808-3818 (2009). www.fasebj.org