Inhibition of neutrophil exocytosis ameliorates acute lung injury in rats.
Inhibition of neutrophil exocytosis ameliorates acute lung injury in rats.
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DOI：
10.1097/shk.0b013e318282c9a1
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发表时间：
2013-03
期刊：
影响因子：
--
通讯作者：
McLeish KR
中科院分区：
文献类型：
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作者：
Uriarte SM;Rane MJ;Merchant ML;Jin S;Lentsch AB;Ward RA;McLeish KR
中性粒细胞的胞吐作用参与了由感染或炎症诱导的急性肺损伤（ALI），这表明抑制体内中性粒细胞的胞吐作用可能是一种可行的治疗策略。本研究使用大鼠免疫复合物沉积模型来确定抑制中性粒细胞胞吐的细胞可渗透融合蛋白（TAT-SNAP-23）对ALI的影响。通过白蛋白渗漏、中性粒细胞浸润、肺组织学和支气管肺泡灌洗液（BALf）的蛋白质组学分析来评估通过静脉内施用TAT-SNAP-23抑制中性粒细胞胞吐作用对ALI的影响。施用TAT-SNAP-23而非TAT-对照显著降低了白蛋白渗漏、BALf中的总蛋白水平以及肺泡内水肿和出血。TAT-SNAP-23抑制嗜中性粒细胞胞吐的证据包括BALf嗜中性粒细胞质膜CD 18表达的减少和BALf中嗜中性粒细胞颗粒蛋白的减少。肺和/或BALf中类似程度的嗜中性粒细胞积累表明TAT-SNAP-23不改变血管内皮细胞功能。BALf的蛋白质组学分析揭示，在来自TAT-SNAP-23处理的动物的BALf中，补体和凝血途径的组分显著减少。我们的研究结果表明，管理的TAT融合蛋白，抑制中性粒细胞胞吐减少在体内的ALI。靶向中性粒细胞胞吐是改善ALI的潜在治疗策略。
Exocytosis of neutrophil granules contributes to acute lung injury (ALI) induced by infection or inflammation, suggesting that inhibition of neutrophil exocytosis in vivo could be a viable therapeutic strategy. This study was conducted to determine the effect of a cell-permeable fusion protein that inhibits neutrophil exocytosis (TAT-SNAP-23) on ALI using an immune complex deposition model in rats. The effect of inhibition of neutrophil exocytosis by intravenous administration of TAT-SNAP-23 on ALI was assessed by albumin leakage, neutrophil infiltration, lung histology, and proteomic analysis of bronchoalveolar lavage fluid (BALf). Administration of TAT-SNAP-23, but not TAT-Control, significantly reduced albumin leakage, total protein levels in the BALf, and intra-alveolar edema and hemorrhage. Evidence that TAT-SNAP-23 inhibits neutrophil exocytosis included a reduction in plasma membrane CD18 expression by BALf neutrophils and a decrease in neutrophil granule proteins in BALf. Similar degree of neutrophil accumulation in the lungs and/or BALf suggests that TAT-SNAP-23 did not alter vascular endothelial cell function. Proteomic analysis of BALf revealed that components of the complement and coagulation pathways were significantly reduced in BALf from TAT-SNAP-23-treated animals. Our results indicate that administration of a TAT-fusion protein that inhibits neutrophil exocytosis reduces in vivo ALI. Targeting neutrophil exocytosis is a potential therapeutic strategy to ameliorate ALI.