Structural and molecular alterations in lung lymphatic endothelial cells induced by cigarette smoking: insights and emerging hypotheses for vaping.

Abstract

Pulmonary lymphatics play multiple essential roles in lung homeostasis through interstitial fluid removal, traffic of immune cells, and antigen presentation. This highly branching vascular bed comprises initial capillaries, pre-collecting vessels, and collecting lymphatics, and it is lined by characteristic lymphatic endothelial cells (LECs). These cells are distinct from blood endothelial cells in their structure, molecular markers (e.g., PROX1, LYVE-1, VEGFR-3), and responsiveness to inflammatory and mechanical stimuli. In health, LECs preserve barrier integrity, promote immune surveillance, and support unidirectional lymph flow. However, during pulmonary inflammation or injury, LECs may undergo phenotypic changes that impair function and promote local coagulation. This review consolidates current knowledge on pulmonary lymphatic vessel structure and function and LEC biology, with a focus on their involvement in inflammation and coagulation pathways. We examine how cigarette smoke disrupts LEC homeostasis, leading to endothelial injury, procoagulant factor upregulation [e.g., tissue factor, plasminogen activator inhibitor-1 (PAI-1)], and fibrin-rich thrombosis in lung lymphatics. Although vaping induces oxidative stress and vascular inflammation, its effects on the pulmonary lymphatic system have not been clearly explained. Based on pathological features shared with smoking, we propose potential mechanisms by which e-cigarette aerosols may contribute to lymphatic endothelial dysfunction and altered coagulation in lungs. Given the increasing prevalence of vaping, further research using in vitro, in vivo, and human studies is needed to elucidate how inhaled toxicants alter LEC function and to identify novel targets for preserving lymphatic health in lung disease.