Oncotarget

Research Papers:

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

Ling Wang, Ya-Li Zhao, Ning-Ning Liu, Xiao-Shan Zhu, Qin-Qin Liu, Hai-Yu Mei, Li-Feng Wang, An-Gang Yang, Chun-Fang Gao and Jun-Tang Li _

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Oncotarget. 2017; 8:54889-54903. https://doi.org/10.18632/oncotarget.18605

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Abstract

Ling Wang1,*, Ya-Li Zhao2,*, Ning-Ning Liu2,*, Xiao-Shan Zhu2,*, Qin-Qin Liu2, Hai-Yu Mei3, Li-Feng Wang4, An-Gang Yang5, Chun-Fang Gao2 and Jun-Tang Li2,4,5

1Department of Anesthesiology, 150th Central Hospital of PLA, Luoyang, Henan 471031, China

2Centre of Inflammation and Cancer Research, 150th Central Hospital of PLA, Luoyang, Henan 471031, China

3Department of Respiration, 150th Central Hospital of PLA, Luoyang, Henan 471031, China

4State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi’an, Shaanxi 710032, China

5State 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: [email protected]

Chun-Fang Gao, email: [email protected]

An-Gang Yang, email: [email protected]

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.


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