Background/Purpose: Pulmonary arterial hypertension (PAH) is a serious complication of systemic autoimmune diseases, resulting in substantial morbidity and mortality. In PAH patients, pulmonary lymphatics expand however their role in the pathogenesis of PAH is not understood. Emerging evidence suggests that impaired lymphatic function promotes formation of tertiary lymphoid follicles leading to autoantibody production in mice. We hypothesized that although pulmonary lymphatics expand in PAH, they exhibit features of dysfunctional immune regulation contributing to formation of tertiary lymphoid follicles.

Methods: We performed immunohistochemical staining and fluorescence microscopy to assess alterations in pulmonary lymphatics in our chronic pulmonary inflammation mouse model of PAH. To evaluate whether similar changes occur in humans, we analyzed publicly available single-cell RNA sequencing data from Saygin et al., 2020 (GEO Accession Number: GSE169471) to identify lymphatic endothelial cells and compare gene expression profiles between healthy controls and PAH patients.

Results: In our mouse model, we observed marked expansion of lymphatic vessels within regions of localized inflammation, particularly surrounding pulmonary arteries and airways within bronchovascular bundles, as well as around pulmonary veins. Lymphatic expansion was noted at 2 weeks and persisted for at least 8 weeks after exposure.Analysis of human single-cell RNA sequencing data revealed upregulation of key lymphangiogenic genes ( FLT4, PDPN, and TIE2) in PAH lymphatic endothelial cells. Despite this pro-lymphangiogenic signature, we found downregulation of chemokines essential for leukocyte trafficking (CCL21, CCL2, CXCL1–3), suggesting impaired lymphatic-mediated egress of neutrophils, macrophages and T cells, as well as dendritic cells that may contribute to persistent pulmonary inflammation and tertiary lymphoid follicles observed in PAH.

Conclusion: Our findings demonstrate that although pulmonary lymphatic vessels expand in both our mouse model of PAH and in patients with PAH, their gene expression profile suggests impaired immune cell clearance that may contribute to chronic inflammation and tertiary lymphoid follicle formation in PAH. These results highlight the pulmonary lymphatics may be a future therapeutic target for treatment of PAH.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pathologic-lymphangiogenesis-in-mouse-model-and-patients-with-pulmonary-arterial-hypertension/