The neutrophil serine protease inhibitor serpinb1 preserves lung defense functions in Pseudomonas aeruginosa infection.
The neutrophil serine protease inhibitor serpinb1 preserves lung defense functions in Pseudomonas aeruginosa infection.
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DOI：
10.1084/jem.20070494
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发表时间：
2007-08-06
期刊：
影响因子：
--
通讯作者：
Remold-O'Donnell E
中科院分区：
文献类型：
--
作者：
Benarafa C;Priebe GP;Remold-O'Donnell E
中性粒细胞丝氨酸蛋白酶（NSP;弹性蛋白酶、组织蛋白酶G和蛋白酶-3）直接杀死入侵的微生物。然而，肺中过量的NSP在炎性肺病的病理学中起着核心作用。我们发现，serpinb 1，一个有效的抑制剂的三个NSP，保护细胞和分子组件负责宿主防御铜绿假单胞菌。在感染时，野生型（WT）和serpinb 1缺陷小鼠产生类似的早期反应，包括细胞因子和趋化因子的大量产生，中性粒细胞的募集和细菌的初始遏制。然而，serpinb 1 −/−小鼠的死亡率相对于WT小鼠显著增加，这与迟发性细菌清除失败有关。我们发现，serpinb 1缺陷的中性粒细胞招募到肺部有一个内在的缺陷，伴随着释放中性粒细胞蛋白酶活性，持续的炎症细胞因子的生产，和蛋白水解的聚集蛋白表面活性蛋白-D（SP-D）的生存。重组SERPINB 1与铜绿假单胞菌接种物共同给药使serpinb 1 −/−小鼠的细菌清除率正常化。因此，通过serpinb 1调节肺先天免疫是非冗余的，并且需要保护两个关键组分，中性粒细胞和SP-D，在宿主对感染的反应期间免受NSP损伤。
Neutrophil serine proteases (NSPs; elastase, cathepsin G, and proteinase-3) directly kill invading microbes. However, excess NSPs in the lungs play a central role in the pathology of inflammatory pulmonary disease. We show that serpinb1, an efficient inhibitor of the three NSPs, preserves cell and molecular components responsible for host defense against Pseudomonas aeruginosa. On infection, wild-type (WT) and serpinb1-deficient mice mount similar early responses, including robust production of cytokines and chemokines, recruitment of neutrophils, and initial containment of bacteria. However, serpinb1−/− mice have considerably increased mortality relative to WT mice in association with late-onset failed bacterial clearance. We found that serpinb1-deficient neutrophils recruited to the lungs have an intrinsic defect in survival accompanied by release of neutrophil protease activity, sustained inflammatory cytokine production, and proteolysis of the collectin surfactant protein–D (SP-D). Coadministration of recombinant SERPINB1 with the P. aeruginosa inoculum normalized bacterial clearance in serpinb1−/− mice. Thus, regulation of pulmonary innate immunity by serpinb1 is nonredundant and is required to protect two key components, the neutrophil and SP-D, from NSP damage during the host response to infection.
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