Neutral endopeptidase determines the severity of pancreatitis-associated lung injury
Neutral endopeptidase determines the severity of pancreatitis-associated lung injury
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DOI：
10.1016/j.jss.2005.03.010
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发表时间：
2005-09-01
影响因子：
2.2
通讯作者：
Kirkwood, KS
中科院分区：
文献类型：
--
作者：
Day, AL;Wick, E;Kirkwood, KS
背景。中性肽链内切酶 (NEP) 是一种细胞表面金属蛋白酶，可降解 P 物质、神经激肽 A 和缓激肽等促炎肽。抑制 NEP 会加剧实验性胰腺炎和相关的肺损伤。目前尚不清楚恶化的肺损伤是否是更严重的胰腺炎的间接结果，或者是否是肺部 NEP 抑制的直接影响。材料和方法。我们使用胰腺炎相关肺损伤 (PALI) 模型来检验以下假设：无论胰腺炎症的程度如何，NEP 的拮抗或基因缺失都会加剧 PALI 炎症和肺部损伤。结果。在 NEP(+/+) 小鼠中，腹腔注射猪胰弹性蛋白酶（弹性蛋白酶，0.085 U/g，t = 0 h 和 t = 1 h）与对照动物相比，4 h 时肺髓过氧化物酶 (MPO) 活性增加 7 倍，并出现明显的肺水肿、中性粒细胞浸润和出血。弹性蛋白酶诱导的肺损伤模式与在另一组由雨蛙蛋白诱导的 PALI 动物中观察到的情况相似，但与胰腺炎无关。与单独给予弹性蛋白酶的 NEP(+/+) 小鼠相比，用 NEP 拮抗剂磷酰胺 (10 mg/kg s.c.) 预处理的 NEP(-/-) 小鼠和 NEP(+/+) 小鼠的肺 MPO 显着升高，且肺组织学恶化。香草酸受体瞬时受体香草酸 I 或 P 物质受体 NK1-R 的拮抗作用对 NEP 缺陷小鼠中弹性蛋白酶介导的肺损伤没有影响。结论。 NEP 是一种胰腺弹性蛋白酶诱导的肺损伤的抑制剂，可能是通过降解促炎介质来实现的。 (c) 2005 Elsevier Inc. 保留所有权利。
Background. Neutral endopeptidase (NEP) is a cell-surface metalloprotease that degrades proinflammatory peptides such as substance P, neurokinin A, and bradykinin. Inhibition of NEP exacerbates both experimental pancreatitis and the associated lung injury. It is unclear if worsened lung injury is the indirect result of more severe pancreatitis or if it is a direct effect of NEP inhibition in the lung.Materials and methods. We used a model of pancreatitis-associated lung injury (PALI) to test the hypothesis that antagonism or genetic deletion of NEP augments PALI inflammation and pulmonary damage irregardless of the degree of pancreatitic inflammation.Results. In NEP(+/+) mice, intraperitoneal injection of porcine pancreatic elastase (elastase, 0.085 U/g at t = 0 h and t = 1 h) caused a 7-fold increase in lung myeloperoxidase (MPO) activity and marked pulmonary edema, neutrophil infiltration, and hemorrhage at 4 h as compared to control animals. The pattern of lung injury induced by elastase mimicked that observed among a separate group of animals with PALI induced by cerulein but was not associated with pancreatitis. Both NEP(-/-) mice and NEP(+/+) mice pretreated with the NEP antagonist phosphoramidon (10 mg/kg s.c.) had significant elevations of lung MPO and worsened lung histology compared to NEP(+/+) mice given elastase alone. Antagonism of either the vanilloid receptor transient receptor vanilloid I or the substance P receptor NK1-R had no effect on elastase-mediated lung injury in NEP-deficient mice.Conclusions. NEP is an inhibitor of pancreatic elastase-induced lung injury, presumably via degradation of proinflammatory mediators. (c) 2005 Elsevier Inc. All rights reserved.