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.
Highlights
Acute lung injury (ALI) and its most severe form, namely, acute respiratory distress syndrome (ARDS), are devastating clinical conditions for critically ill patients
We firstly found that zymosan upregulates Heme oxygenase-1 (HO-1) mRNA and protein expressions in the lung tissues and alveolar epithelial cells (AECs)-II of WT mice compared with the control group (Figure 1A–1C)
ISO enhanced zymosan-induced increase in HO-1 activity in the lung and type II AECs (AECs-II) of WT mice (Figure 1D). These results demonstrated that ISO improves the expression and activity of HO-1 in zymosan-stimulated mouse lung and AECs-II
Summary
Acute lung injury (ALI) and its most severe form, namely, acute respiratory distress syndrome (ARDS), are devastating clinical conditions for critically ill patients. ALI/ARDS is mainly characterized by increased inflammation, hypercoagulation, hypofibrinolysis, and vascular and epithelial permeability [1]. ALI/ARDS occurs in approximately 79 per 100, 000 patients annually in the United States and has a mortality of up to 30%–40%. Despite the great improvement in ALI/ARDS, there are limited therapeutic interventions [4]. Identifying the novel pathological mechanisms of ALI/ARDS and developing specific pharmacological treatments are necessary and urgent. Various types of cells participate in the pathology of ALI/ARDS, and alveolar epithelial cells (AECs) disruption increased lung epithelial permeability [5]. The biological functions of AECs-II and the underlying mechanisms in ALI remain unknown
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