Lymphatic Endothelial Senescence Is Associated with Drainage Failure Despite Vessel Expansion in Pulmonary Fibrosis.

Pulmonary fibrosis is characterized by progressive architectural distortion and extracellular matrix accumulation that resists endogenous repair. Lymphatic vessels are essential for interstitial clearance and immune cell trafficking, yet their roles in fibrotic persistence remain unclear. Through analysis of publicly available single-cell transcriptomic datasets from coal workers' pneumoconiosis lungs and a precision-cut lung slice fibrogenesis model, we identified consistent CDKN1A upregulation and enrichment of a senescence program in fibrotic lymphatic endothelial cells (LECs). Regulatory network inference uncovered a shared 15-transcription-factor module, seven members of which harbored predicted CDKN1A binding sites and exhibited stimulus-dependent induction in human LECs challenged with silica or transforming growth factor (TGF)-β1. Silica exposure in vivo elicited an increase in lymphatic vessel density yet induced LEC senescence and severely compromised drainage function, highlighting a divergence between vascular morphology and transport competence. Prophylactic AAV-mediated vascular endothelial growth factor (VEGF)-C156S delivery restored lymphatic transport, reduced the LEC senescence burden, and attenuated pathological remodeling in the non-resolving silica model. By contrast, VEGF receptor 3 (VEGFR3) blockade during the resolution phase of bleomycin injury exacerbated LEC senescence and arrested spontaneous fibrosis regression. Transcriptomic profiling and in vitro migration assays revealed that fibrotic LECs downregulated signals required for macrophage egress. Accordingly, lymphatic functional status inversely correlated with intrapulmonary macrophage accumulation. Collectively, these data link senescence-associated LEC reprogramming to defective drainage and sustained immune entrapment in fibrotic lungs. Bidirectional modulation of lymphatic function establishes drainage competence as a critical determinant of disease trajectory, positioning lymphatic-directed approaches as promising therapeutic strategies for fibrotic lung disease.