ABSTRACT: 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-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, accompanied by bulk transcriptome sequencing of lung tissue of age-matched mice allocated to nine study groups. DE-induced PF groups receiving RIC showed marked improvements in weight, HRV, and lung mitochondrial function, substantial attenuation of histopathological damage, and significant decreases in inflammatory and fibrotic markers, indicating the potential of RIC to mitigate DE-induced fibrotic damage. Transcriptome analysis of lung tissue further supported these observations by revealing 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.
