Downregulation of HDAC6 mitigates lung ischemia/reperfusion injury depending on activation of Nrf2/HO-1 signaling pathway and inactivation of ERK/NF-κB signaling pathway

Introduction: Lung ischemia/reperfusion injury (LIRI) is a pathological process caused by the deficiency and subsequent reperfusion of oxygen and blood to the lung. Literature reports that the catalytic activity and expression of HDAC6 can be induced in response to IRI. HDAC6 inhibition confers protective effects against a series of IRI and also exerts pulmonary protection against various lung damage. The present study was formulated to investigate the functional role of HDAC6 inhibitor in LIRI and to probe into the intrinsic mechanisms underlying the protective role of HDAC6 inhibitor against LIRI. Methods: Lung epithelial cell line MLE-12 cells were subjected to H/R injury to construct in vitro cell culture model of LIRI. For functional experiments, MLE-12 cells were pre-treated with various concentrations of selective HDAC6 inhibitor ACY-1215 (1, 5, 10 mu M) to evaluate the biological role of HDAC6 in LIRI. For rescue experiments, MLE-12 cells were pre-treated with Nrf2 inhibitor ML385 (10 mu M) or ERK activator LM22B-10 (50 mu M) to discuss the molecular mechanisms. Results: It was verified that HDAC6 inhibition repressed H/R-induced apoptosis, oxidative stress, inflammation and mitochondrial dysfunction of MLE-12 cells. HDAC6 inhibition activated Nrf2/HO-1 signaling pathway and inactivated ERK/NF- kappa B signaling pathway in MLE-12 cells. The repressing effects of HDAC6 inhibition on H/Rinduced apoptosis, oxidative stress, inflammation and mitochondrial dysfunction of MLE-12 cells were partially abolished upon pre-treatment with Nrf2 inhibitor ML385 or ERK activator LM22B-10. Conclusion: HDAC6 inhibition may mitigate H/R-induced lung epithelial cell injury depending on activation of Nrf2/HO-1 signaling pathway and inactivation of ERK/NF- kappa B signaling pathway.