Remote ischemic conditioning mitigates diesel exhaust-induced pulmonary fibrosis by alleviating pulmonary inflammation and fibrogenesis

Remote ischemic conditioning (RIC), a promising non-pharmacological strategy, mitigates ischemia-reperfusion injury in multiple conditions. However, its potential as a therapeutic strategy in pulmonary fibrosis (PF), which is associated with poor survival outcomes and limited pharmacotherapies, remains unexplored. Thus, the present study aimed to explore the therapeutic utility of RIC in a diesel exhaust (DE)-induced mouse model recapitulating PF pathology. The effects of RIC were comprehensively assessed by measuring physiological and molecular endpoints, including weight, heart rate variability (HRV), lung histopathology, circulating plasma biomarkers, bronchoalveolar lavage fluid cytokine profiles, and indices of pulmonary mitochondrial health in age-matched mice allocated to nine study groups. DE-induced PF groups receiving RIC showed marked improvements in body weight, HRV, and lung mitochondrial function, along with substantial attenuation of histopathological damage and significant reductions in inflammatory and fibrotic markers. These effects were comparable to those observed in the pharmacotherapy group receiving pirfenidone, suggesting that RIC may have the potential to mitigate DE-induced pulmonary fibrotic damage. Further, the observations were supported by bulk transcriptome sequencing and analysis of lung tissue from eight experimental groups, which revealed downregulation of PF markers in RIC-receiving groups, highlighting RIC’s efficacy in attenuating PF features. Additionally, potential PF-relevant markers, including Calhm6 , Hrc , Dnase1l3 , Pla2g2d , Stab2 and Timd4 , were identified across these groups that may be linked to therapeutic benefits conferred by RIC.