Alleviation of cigarette smoke-induced cellular senescence in BALB/c mice by the Lipoxin A4 receptor agonist BML-111 is associated with mitophagy.

Abstract

Cigarette smoke (CS) significantly accelerates age-associated pulmonary pathologies by promoting cellular senescence. BML-111, a synthetic lipoxin A4 analog, exhibits therapeutic potential in inflammatory diseases owing to its antioxidant and anti-inflammatory properties, yet its impact on CS-induced senescence remains undefined. This study investigated the effect and mechanism of BML-111 on CS-induced cellular senescence using a BALB/c mouse model and the murine alveolar macrophage cell line MH-S. Our findings indicate that BML-111 attenuated CS-induced histopathological damage and senescence markers in murine lungs, while substantially suppressing cigarette smoke extract-triggered senescence in MH-S cells. In addition, BML-111 inhibited mitochondrial damage, and promoted autophagosome formation and mitophagy-related protein expression in both in vivo and in vitro models. Crucially, the mitophagy inhibitor Mdivi-1 abrogated BML-111's effects on cellular senescence, mitochondrial damage restoration, and mitophagy. Taken together, BML-111 may mitigate CS-induced cellular senescence in the lung by promoting processes associated with mitophagy initiation, highlighting its potential as a therapeutic strategy against CS-associated lung pathologies.