Administration of a specific inhibitor of neutrophil elastase attenuates pulmonary fibrosis after acute lung injury in mice
Administration of a specific inhibitor of neutrophil elastase attenuates pulmonary fibrosis after acute lung injury in mice
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DOI：
10.3109/01902148.2011.633306
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发表时间：
2012-02-01
影响因子：
1.7
通讯作者：
Yamaya, Mutsuo
中科院分区：
文献类型：
--
作者：
Fujino, Naoya;Kubo, Hiroshi;Yamaya, Mutsuo
中性粒细胞弹性蛋白酶的过量产生与急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）的发病机制有关。然而，中性粒细胞弹性酶在ALI/ARDS后的修复过程中的作用尚不清楚。本研究旨在探讨中性粒细胞弹性蛋白酶对小鼠急性肺损伤后组织修复过程的影响。对C57BL/6小鼠进行亚致死照射，然后鼻内注射脂多糖（LPS），建立肺修复受损模型。作者在每日给予中性粒细胞弹性酶抑制剂的照射和/或lps诱导的损伤后7天评估组织病理学、肺力学和肺总胶原含量。同时观察支气管肺泡灌洗液（BALF）中炎症细胞的数量。此外，我们还研究了活化的转化生长因子(TGF)- β 1在BALF中的浓度和phospho-SMAD2/3的表达。辐照和lps处理的小鼠在损伤后发生肺纤维化。中性粒细胞弹性酶抑制剂显著降低肺实质胶原沉积，改善损伤肺的静态肺顺应性。中性粒细胞弹性酶抑制剂的施用也减少了中性粒细胞在BALF中的积累、tgf - β 1的激活和磷酸化smad2 /3的表达。作者认为，抑制中性粒细胞弹性蛋白酶可防止急性损伤后肺纤维化的发生。此外，这些数据表明，这种中性粒细胞弹性酶抑制剂对ALI/ARDS的纤维增殖期具有治疗潜力。
Excess production of neutrophil elastase contributes to the pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). However, the role of neutrophil elastase in the repair process following ALI/ARDS is not well understood. The objective of this study was to evaluate the effect of neutrophil elastase on the process of tissue repair after acute lung injury in mice. C57BL/6 mice were exposed to sublethal irradiation followed by intranasal instillation of lipopolysaccharide (LPS) to generate a model of impaired lung repair. The authors assessed the histopathology, lung mechanics, and total lung collagen content 7 days after irradiation and/or LPS-induced injury with daily administration of a neutrophil elastase inhibitor. The number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) was also evaluated. In addition, the concentration of activated transforming growth factor (TGF)-beta 1 in the BALF and the expression of phospho-SMAD2/3 were investigated. Irradiated and LPS-treated mice developed pulmonary fibrosis after injury. The neutrophil elastase inhibitor significantly decreased the collagen deposition in lung parenchyma and improved the static lung compliance of injured lungs. Administration of the neutrophil elastase inhibitor also decreased the accumulation of neutrophils in the BALF, TGF-beta 1 activation, and expression of phospho-SMAD2/3. The authors conclude that inhibiting neutrophil elastase protects against the development of lung fibrosis after acute injury. In addition, these data suggest that this neutrophil elastase inhibitor has therapeutic potential for the fibroproliferative phase of ALI/ARDS.