Tissue Factor Driven Coagulation and Inflammation in Lung Injury: Insights From In Vitro and In Vivo Models

Lung injury and fibrosis involve a complex interplay between inflammation and coagulation, with tissue factor (TF/CF-III/Thromboplastin/CD142) acting as a crucial mediator. Despite its known role in initiating the extrinsic coagulation cascade, TF's contribution to fibrin deposition in lung injury remains underexplored. This study examines the dysregulation of the extrinsic coagulation cascade and its pathological implications in lung injury, contributing to the progression of pulmonary fibrosis (PF). Utilizing bleomycin (BLM), transforming growth factor-β (TGF-β), and TF models, we systematically investigate coagulation-driven inflammatory responses in lung pathology. By integrating in vitro (A549 and Beas2b epithelial cell models) and in vivo (C57BL/6 murine models) approaches, this study elucidates TF-mediated molecular mechanisms driving inflammation, fibrin deposition, endothelial dysfunction, and fibrotic remodeling. Protein-protein interaction (PPI) network analysis highlights functional associations between coagulation factors (CFs) and inflammatory mediators, reinforcing their involvement in lung homeostasis. Also, gene enrichment analysis identifies key biological processes, including coagulation, fibrinolysis, and immune activation, emphasizing their role in disease progression. In A549 and Beas2b epithelial cells, CF-III, CF-VII, and CF-X expression increased significantly, with A549 cells exhibiting a heightened pro-coagulant response. Elevated IL-6, TNF-α, and IL-1β levels suggest an inflammatory amplification tied to TF activation. Immunofluorescence analysis demonstrates marked TF upregulation and TNF-α activation, reinforcing the interplay between coagulation pathways and inflammatory cytokine signaling. Histological assessments (H&E, and Masson Trichrome [MT] staining) in murine lung tissues confirm fibrotic and inflammatory changes, reinforcing TF's pathogenic role. Our findings establish TF as a key molecular driver of thrombo-inflammatory lung injury, providing potential therapeutic targets to mitigate fibrosis and improve patient outcomes.