Acyloxyacyl hydrolase promotes the resolution of lipopolysaccharide-induced acute lung injury.
Acyloxyacyl hydrolase promotes the resolution of lipopolysaccharide-induced acute lung injury.
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酰氧酰基水解酶促进脂多糖诱导的急性肺损伤的缓解
DOI：
10.1371/journal.ppat.1006436
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发表时间：
2017-06
期刊：
影响因子：
6.7
通讯作者：
Lu M
中科院分区：
文献类型：
--
作者：
Zou B;Jiang W;Han H;Li J;Mao W;Tang Z;Yang Q;Qian G;Qian J;Zeng W;Gu J;Chu T;Zhu N;Zhang W;Yan D;He R;Chu Y;Lu M
肺部感染是急性肺损伤（ALI）最常见的危险因素。由微生物相关分子模式（MAMP）分子诱导的天然免疫应答对于肺防御是必需的，但可导致组织损伤。关于MAMP分子如何在肺中降解或MAMP降解/失活如何帮助预防或改善产生ALI的有害炎症的知之甚少。酰氧酰基水解酶（AOAH）是一种使革兰氏阴性细菌内毒素（脂多糖或LPS）失活的宿主脂肪酶。我们在此报道，肺泡巨噬细胞在暴露于LPS后增加AOAH表达，并且Aoah+/+小鼠比Aoah-/-小鼠从鼻滴注LPS或肺炎克雷伯氏菌诱导的ALI中恢复得更快。Aoah-/-小鼠肺具有更长的白细胞浸润，更大的促炎和抗炎细胞因子表达，以及更持久的肺泡屏障损伤。我们还描述了Aoah-/-肺泡中的持续生物活性LPS可以直接刺激肺泡巨噬细胞和间接刺激上皮细胞产生趋化因子的证据，该趋化因子将中性粒细胞募集到肺中并可能阻止其清除。与在LPS暴露的Aoah-/-腹膜巨噬细胞中观察到的延长的耐受性不同，缺乏AOAH的肺泡巨噬细胞维持或增加了它们对生物活性LPS和持续炎症的反应。AOAH灭活LPS是一种以前未被认识到的促进革兰氏阴性细菌感染诱导的肺部炎症/损伤消退的机制。
Pulmonary infection is the most common risk factor for acute lung injury (ALI). Innate immune responses induced by Microbe-Associated Molecular Pattern (MAMP) molecules are essential for lung defense but can lead to tissue injury. Little is known about how MAMP molecules are degraded in the lung or how MAMP degradation/inactivation helps prevent or ameliorate the harmful inflammation that produces ALI. Acyloxyacyl hydrolase (AOAH) is a host lipase that inactivates Gram-negative bacterial endotoxin (lipopolysaccharide, or LPS). We report here that alveolar macrophages increase AOAH expression upon exposure to LPS and that Aoah+/+ mice recover more rapidly than do Aoah-/- mice from ALI induced by nasally instilled LPS or Klebsiella pneumoniae. Aoah-/- mouse lungs had more prolonged leukocyte infiltration, greater pro- and anti-inflammatory cytokine expression, and longer-lasting alveolar barrier damage. We also describe evidence that the persistently bioactive LPS in Aoah-/- alveoli can stimulate alveolar macrophages directly and epithelial cells indirectly to produce chemoattractants that recruit neutrophils to the lung and may prevent their clearance. Distinct from the prolonged tolerance observed in LPS-exposed Aoah-/- peritoneal macrophages, alveolar macrophages that lacked AOAH maintained or increased their responses to bioactive LPS and sustained inflammation. Inactivation of LPS by AOAH is a previously unappreciated mechanism for promoting resolution of pulmonary inflammation/injury induced by Gram-negative bacterial infection.