In vivo suppression of immune complex-induced alveolitis by secretory leukoproteinase inhibitor and tissue inhibitor of metalloproteinases 2.
In vivo suppression of immune complex-induced alveolitis by secretory leukoproteinase inhibitor and tissue inhibitor of metalloproteinases 2.
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DOI：
10.1073/pnas.90.24.11523
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发表时间：
1993-12
影响因子：
11.1
通讯作者：
M. Mulligan;P. E. Desrochers;A. Chinnaiyan;D. Gibbs;J. Varani;K. Johnson;S. Weiss
中科院分区：
文献类型：
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作者：
M. Mulligan;P. E. Desrochers;A. Chinnaiyan;D. Gibbs;J. Varani;K. Johnson;S. Weiss
在炎症性肺部疾病中，肺树暴露于中性粒细胞衍生的丝氨酸蛋白酶和基质金属蛋白酶，但这些酶参与组织损伤的程度仍不清楚，基于抗蛋白酶的干预措施的治疗效用也不清楚。为了解决这些问题，研究了体内大鼠模型，其中免疫复合物的肺内沉积引发中性粒细胞介导的急性肺泡炎。体外研究表明，大鼠中性粒细胞可以释放中性粒细胞弹性蛋白酶和组织蛋白酶 G 以及中性粒细胞原明胶酶，随后被氯化氧化剂或丝氨酸蛋白酶激活。基于大鼠和人中性粒细胞蛋白酶之间存在的结构同源性，重组人分泌性白蛋白酶抑制剂可以在体外特异性调节大鼠中性粒细胞弹性蛋白酶和组织蛋白酶G活性，并且大鼠中性粒细胞明胶酶活性被证明对重组人组织金属蛋白酶抑制剂2的抑制敏感。当将任何一种重组抗蛋白酶滴入气管内时，通过增加的通透性或出血评估的体内肺损伤显着减少。此外，丝氨酸和基质金属蛋白酶抑制剂的共同给药几乎完全防止了肺损伤，同时仅适度减少中性粒细胞流入。这些数据支持中性粒细胞衍生的蛋白酶在体内急性肺损伤中的关键作用，并确定重组人分泌性白蛋白酶和重组人金属蛋白酶组织抑制剂2作为炎症性疾病状态的潜在有效干预措施。
The pulmonary tree is exposed to neutrophil-derived serine proteinases and matrix metalloproteinases in inflammatory lung diseases, but the degree to which these enzymes participate in tissue injury remains undefined, as does the therapeutic utility of antiproteinase-based interventions. To address these issues, an in vivo rat model was examined in which the intrapulmonary deposition of immune complexes initiates a neutrophil-mediated acute alveolitis. In vitro studies demonstrated that rat neutrophils can release neutrophil elastase and cathepsin G as well as a neutrophil progelatinase, which was subsequently activated by either chlorinated oxidants or serine proteinases. Based on structural homologies that exist between rat and human neutrophil proteinases, rat neutrophil elastase and cathepsin G activities could be specifically regulated in vitro by recombinant human secretory leukoproteinase inhibitor, and rat neutrophil gelatinase activity proved sensitive to inhibition by recombinant human tissue inhibitor of metalloproteinases 2. When either of the recombinant antiproteinases were instilled intratracheally, in vivo lung damage as assessed by increased permeability or hemorrhage was significantly reduced. Furthermore, the coadministration of the serine and matrix metalloproteinase inhibitors almost completely prevented pulmonary damage while effecting only a modest decrease in neutrophil influx. These data support a critical role for neutrophil-derived proteinases in acute lung damage in vivo and identify recombinant human secretory leukoproteinase and recombinant human tissue inhibitor of metalloproteinases 2 as potentially efficacious interventions in inflammatory disease states.