Department of Medicine, University of Louisville, Louisville, KY, USA.
Shock. 2013 Mar;39(3):286-92. doi: 10.1097/SHK.0b013e318282c9a1.
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.
中性粒细胞颗粒的胞吐作用导致感染或炎症引起的急性肺损伤（ALI），这表明体内抑制中性粒细胞胞吐作用可能是一种可行的治疗策略。本研究旨在使用大鼠免疫复合物沉积模型确定抑制中性粒细胞胞吐作用的细胞通透性融合蛋白（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）的蛋白质组学分析评估静脉注射 TAT-SNAP-23 抑制中性粒细胞胞吐作用对 ALI 的影响。TAT-SNAP-23 的给药，而不是 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 抑制中性粒细胞胞吐作用的证据包括 BALF 中性粒细胞的质膜 CD18 表达减少和 BALF 中性粒细胞颗粒蛋白减少。肺和/或 BALF 中中性粒细胞的积聚程度相似表明 TAT-SNAP-23 未改变血管内皮细胞功能。BALF 的蛋白质组学分析显示，TAT-SNAP-23 处理动物的 BALF 中补体和凝血途径的成分显着减少。我们的结果表明，抑制中性粒细胞胞吐作用的 TAT 融合蛋白的给药可减少体内 ALI。靶向中性粒细胞胞吐作用是改善 ALI 的潜在治疗策略。
