Tobacco smoking drives pro-fibrotic immune modulation and CD40L dysregulation in pulmonary fibrosis 3458

Abstract Description Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a median survival of less than five years. Tobacco smoking (TS) is a significant risk factor, driving disease onset and progression; however, accurate biomarkers and effective therapeutic targets for TS-driven IPF remain unavailable. To address this gap, we analyzed whole blood transcriptomics and immunophenotype profiles to identify peripheral immune differences between smokers and non-smokers with IPF. Gene ontology analysis revealed that TS enhanced immune cellular processes, including protein trafficking, cytoskeletal organization, cell-cell communication, and metabolism while suppressing interferon signaling, B-cell activity, and phagocytosis. Mass cytometry further revealed that TS-mediated suppression of CD40L expression in leukocytes correlated with pack-years of smoking, suggesting reduced T-cell activation and dampened pro-inflammatory macrophage responses. In mouse models of lung injury and fibrosis, TS exposure significantly promoted fibrosis progression, marked by increased alveolar infiltration of monocyte-derived and pro-repair macrophages but not interstitial macrophages. These findings highlight the pro-fibrotic role of TS in shaping immune microenvironments and identify CD40L as a potential TS-specific biomarker for IPF progression. Funding Sources Supported by NIH R01HL146802; UCOP TRDRP T32IR5347; DoD PRMRP W81XWH2110086 (#PR202411). Topic Categories Immune Mechanisms of Human Disease (HUM)