Epithelial HO-1/STAT3 affords the protection of subanesthetic isoflurane against zymosan-induced lung injury in mice

// Ling Wang 1, * , Ya-Li Zhao 2, * , Ning-Ning Liu 2, * , Xiao-Shan Zhu 2, * , Qin-Qin Liu 2 , Hai-Yu Mei 3 , Li-Feng Wang 4 , An-Gang Yang 5 , Chun-Fang Gao 2 and Jun-Tang Li 2, 4, 5 1 Department of Anesthesiology, 150th Central Hospital of PLA, Luoyang, Henan 471031, China 2 Centre of Inflammation and Cancer Research, 150th Central Hospital of PLA, Luoyang, Henan 471031, China 3 Department of Respiration, 150th Central Hospital of PLA, Luoyang, Henan 471031, China 4 State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi’an, Shaanxi 710032, China 5 State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi’an, Shaanxi 710032, China * These authors have contributed equally to this work Correspondence to: Jun-Tang Li, email: juntangli@163.com Chun-Fang Gao, email: gaocfsoul@163.com An-Gang Yang, email: agyang@fmmu.edu.cn Keywords: acute lung injury, isoflurane, epithelial cells, heme oxygenase-1, signal transducers and activators of transcription 3 Received: February 28, 2017      Accepted: June 04, 2017      Published: June 22, 2017 ABSTRACT Epithelial dysfunction is a key characteristic of acute lung injury (ALI). Isoflurane (ISO) confers lung protection via anti-inflammatory and anti-apoptotic properties. However, the specific role and potential mechanisms of subanesthetic ISO in lung epithelium protection during zymosan-induced ALI remain unclear. In this study, zymosan increased the expression and activity of beneficial heme oxygenase-1 (HO-1) and signal transducers and activators of transcription 3 (STAT3) in the lung and isolated type II alveolar epithelial cells (AECs-II) from wild-type (WT) mice, which was further enhanced by ISO treatment. ISO reduced the mortality, lung edema, histological changes and pulmonary cell apoptosis, and simultaneously decreased total cells, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels in bronchoalveolar lavage fluid in the zymosan-stimulated WT mice but not in HO-1-deficient mice. Moreover, ISO abated zymosan-augmented lactate dehydrogenase activity, TNF-α and IL-1β production, and apoptosis in WT AECs-II but not in HO-1- or STAT3-silenced cells. Mechanisticly, the epithelial protective effects of ISO on zymosan insult in vivo and in vitro were mediated by a positive feedback loop comprising STAT3 and HO-1. Pro-survival and anti-apoptosis by ISO was highly reliant on activated STAT3, involving in downstream Akt activation and reduced ratio of pro-apoptotic/anti-apoptotic molecules. Overall, HO-1/STAT3 signaling is in favor of lung epithelial protection of ISO in zymosan-challenged mice, suggesting ISO as a valuable therapeutic agent for ALI.