3 years ago

Acyloxyacyl hydrolase promotes the resolution of lipopolysaccharide-induced acute lung injury

Dapeng Yan, Ning Zhu, Zihui Tang, Mingfang Lu, Tianqing Chu, Wenhong Zhang, Weiying Mao, Han Han, Yiwei Chu, Jing Li, Wei Jiang, Benkun Zou, Jie Gu, Qian Yang, Rui He, Jing Qian, Guojun Qian, Wenjiao Zeng

by Benkun Zou, Wei Jiang, Han Han, Jing Li, Weiying Mao, Zihui Tang, Qian Yang, Guojun Qian, Jing Qian, Wenjiao Zeng, Jie Gu, Tianqing Chu, Ning Zhu, Wenhong Zhang, Dapeng Yan, Rui He, Yiwei Chu, Mingfang Lu

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.

Publisher URL: http://journals.plos.org/plosone/article

DOI: 10.1371/journal.ppat.1006436

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