Zou Benkun, Jiang Wei, Han Han, Li Jing, Mao Weiying, Tang Zihui, Yang Qian, Qian Guojun, Qian Jing, Zeng Wenjiao, Gu Jie, Chu Tianqing, Zhu Ning, Zhang Wenhong, Yan Dapeng, He Rui, Chu Yiwei, Lu Mingfang
Department of Immunology, Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, and Shanghai Key Laboratory of Clinical Geriatric Medicine, Fudan University, Shanghai, China.
Shanghai Medical College, Fudan University, Shanghai, China.
PLoS Pathog. 2017 Jun 16;13(6):e1006436. doi: 10.1371/journal.ppat.1006436. eCollection 2017 Jun.
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.
肺部感染是急性肺损伤（ALI）最常见的危险因素。微生物相关分子模式（MAMP）分子诱导的固有免疫反应对肺部防御至关重要，但也可能导致组织损伤。关于MAMP分子在肺部如何降解，或者MAMP降解/失活如何帮助预防或减轻导致ALI的有害炎症，目前知之甚少。酰氧基酰基水解酶（AOAH）是一种宿主脂肪酶，可使革兰氏阴性菌内毒素（脂多糖，或LPS）失活。我们在此报告，肺泡巨噬细胞在接触LPS后会增加AOAH表达，并且与Aoah-/-小鼠相比，Aoah+/+小鼠从经鼻滴注LPS或肺炎克雷伯菌诱导的ALI中恢复得更快。Aoah-/-小鼠肺部的白细胞浸润持续时间更长，促炎和抗炎细胞因子表达更高，肺泡屏障损伤持续时间更长。我们还描述了证据表明，Aoah-/-肺泡中持续具有生物活性的LPS可直接刺激肺泡巨噬细胞，并间接刺激上皮细胞产生趋化因子，从而将中性粒细胞募集到肺部，并可能阻止它们的清除。与在接触LPS的Aoah-/-腹膜巨噬细胞中观察到的长期耐受不同，缺乏AOAH的肺泡巨噬细胞维持或增强了它们对生物活性LPS的反应并持续炎症。AOAH使LPS失活是一种以前未被认识的促进革兰氏阴性菌感染诱导的肺部炎症/损伤消退的机制。
