Critical role for integrin-β4 in the attenuation of murine acute lung injury by simvastatin
Critical role for integrin-β4 in the attenuation of murine acute lung injury by simvastatin
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DOI：
10.1152/ajplung.00361.2011
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发表时间：
2012-08-01
影响因子：
4.9
通讯作者：
Jacobson, Jeffrey R.
中科院分区：
文献类型：
--
作者：
Chen, Weiguo;Sammani, Saad;Jacobson, Jeffrey R.
引用本文：陈伟，Sammani S, Mitra S, Ma SF, Garcia JGN, Jacobson JR.整合素- β 4在辛伐他汀急性肺损伤中的作用。[J] .中国生物医学工程学报，2016,31(4):559 - 559。2012年6月8日首次发表；doi: 10.1152 / ajplung.00361.2011。他汀类药物是一类3-羟基-3-甲基戊二酰辅酶a -还原酶抑制剂，被认为具有多效性。我们之前报道了辛伐他汀在体内对lps诱导的小鼠急性肺损伤（ALI）的衰减，并在体外鉴定了辛伐他汀对内皮细胞（EC）信号传导、激活和屏障功能的相关影响。特别是，辛伐他汀诱导整合素- β 4的上调，从而通过MAPK信号的衰减抑制EC炎症反应。然而，整合素- β 4在辛伐他汀对小鼠ALI保护中的作用尚不清楚。我们最初证实辛伐他汀对人肺EC中整合素- β 4 mRNA表达的增加具有时间和剂量依赖性，在16 h时蛋白表达达到峰值。随后，免疫互反沉淀显示辛伐他汀对lps诱导的整合素- β 4酪氨酸磷酸化的衰减（5 μ M, 16 h）。LPS （500 ng/ml, 4 h）增加的EC炎症因子[IL-6、IL-8、单核细胞化学诱导蛋白(MCP)-1，调节激活正常T细胞表达和分泌（RANTES）]的表达也被辛伐他汀预处理（5 μ M, 16 h）显著减弱，但与整合素- β 4阻断抗体共处理可逆转这种作用。最后，尽管辛伐他汀（20mg /kg）对小鼠ALI具有显著的保护作用，如支气管肺泡灌洗液细胞计数、蛋白质、炎症因子（IL-6、IL-1 β、MCP-1、RANTES）减少、肺组织Evans蓝染白蛋白外渗和肺组织学变化，但这些作用被整合素- β 4阻断抗体（IV, 1mg /kg， LPS前2小时）逆转。这些发现支持整合素- β 4是辛伐他汀对ALI保护的重要介质，并暗示整合素- β 4信号传导是ALI患者的一个新的治疗靶点。
Chen W, Sammani S, Mitra S, Ma SF, Garcia JGN, Jacobson JR. Critical role for integrin-beta 4 in the attenuation of murine acute lung injury by simvastatin. Am J Physiol Lung Cell Mol Physiol 303: L279-L285, 2012. First published June 8, 2012; doi:10.1152/ajplung.00361.2011.-The statins are a class of 3-hydroxy-3-methylglutaryl-coenzyme A-reductase inhibitors that are recognized to have pleiotropic properties. We previously reported the attenuation of LPS-induced murine acute lung injury (ALI) by simvastatin in vivo and identified relevant effects of simvastatin on endothelial cell (EC) signaling, activation, and barrier function in vitro. In particular, simvastatin induces the upregulation of integrin-beta 4, which in turn inhibits EC inflammatory responses via attenuation of MAPK signaling. The role of integrin-beta 4 in murine ALI protection by simvastatin, however, is unknown. We initially confirmed a time-and dose-dependent effect of simvastatin on increased integrin-beta 4 mRNA expression in human lung EC with peak protein expression evident at 16 h. Subsequently, reciprocal immunoprecipitation demonstrated an attenuation of LPS-induced integrin-beta 4 tyrosine phosphorylation by simvastatin (5 mu M, 16 h). Increased expression of EC inflammatory cytokines [IL-6, IL-8, monocyte chemoattractant protein (MCP)-1, regulated on activation normal T cell expressed and secreted (RANTES)] by LPS (500 ng/ml, 4 h) was also significantly attenuated by simvastatin pretreatment (5 mu M, 16 h), but this effect was reversed by cotreatment with an integrin-beta 4-blocking antibody. Finally, although simvastatin (20 mg/kg) conferred significant protection in murine ALI as evidenced by decreased bronchoalveolar lavage fluid cell counts, protein, inflammatory cytokines (IL-6, IL-1 beta, MCP-1, RANTES), decreased Evans blue dye albumin extravasation in lung tissue, and changes on lung histology, these effects were reversed by the integrin-beta 4-blocking antibody (IV, 1 mg/kg, 2 h before LPS). These findings support integrin-beta 4 as an important mediator of ALI protection by simvastatin and implicate signaling by integrin-beta 4 as a novel therapeutic target in patients with ALI.