Oxidized mtDNA Contributes to Pulmonary Inflammation and Fibrosis in Bleomycin-Induced Lung Injury

Abstract

Pulmonary fibrosis is a chronic and progressive interstitial lung disease with limited treatment options aside from lung transplantation. Bleomycin (BLM)-induced lung injury is the most commonly used experimental model to mimic the key pathological features of human pulmonary fibrosis, which include an early inflammatory phase and a later fibrotic phase. Neutrophil infiltration and M2 macrophage activation are key events in these stages, respectively. However, the molecular mechanisms by which BLM triggers pulmonary inflammation and fibrosis remain incompletely understood. In this study, we found that BLM treatment induced ROS-mediated oxidative damage in the lungs, leading to an inflammatory microenvironment and the release of oxidized mitochondrial DNA (oxid-mtDNA). Oxid-mtDNA was shown to contribute to the early inflammatory response by promoting neutrophil recruitment and enhancing macrophage polarization, which subsequently drove tissue remodeling and fibrosis. Notably, direct injection of oxid-mtDNA into the lungs recapitulated the fibrotic features observed in the BLM model. Furthermore, studies using STING- and NLRP3-deficient mice demonstrated that loss of either pathway significantly attenuated BLM-induced inflammation and fibrosis, implicating their involvement downstream of oxid-mtDNA signaling. Collectively, our findings identify oxid-mtDNA as a critical mediator linking oxidative injury to immune activation and fibrotic remodeling in the lung, offering new insights into pulmonary fibrosis pathogenesis and potential therapeutic targets.

Keywords

bleomycin / inflammation / macrophage polarization / oxidized mitochondrial DNA / pulmonary fibrosis

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