Abstract 202: The Role of Neutrophil Extracellular Traps in the Pathogenesis of Pulmonary Hypertension.

Abstract

Rationale: Inflammation contributes to vasoconstriction and remodeling in pulmonary hypertension (PH), but the mechanisms are not fully understood. Recent data link neutrophil extracellular traps (NETs) and NET components with endothelial dysfunction, thrombosis, and lung injury. NETs, produced as a result of neutrophil cell death induced by inflammation or cytotoxic stress, comprise chromatin fibers associated with a number of proteins including myeloperoxidase and neutrophil elastase. We hypothesized that NETs contribute to pulmonary vascular remodeling in pulmonary hypertension. The aim of the present study was to measure NET markers in plasma of PH patients and to analyze their effects on human pulmonary artery endothelial cell (HPAEC) function in vitro. Methods and Results: Patients with prevalent chronic thromboembolic pulmonary hypertension (CTEPH) (n=26) and idiopathic pulmonary arterial hypertension (IPAH) (n=52) show increased plasma levels of NET components including myeloperoxidase, neutrophil elastase and circulating DNA, compared with plasma from sex- and age-matched healthy volunteers (n=24). Endarterectomy specimens from CTEPH patients show accumulation of NET-forming peptidylarginine deiminase 4+ (PAD4+) neutrophils. PAD4+ neutrophils are also abundant in and around plexiform lesions in IPAH lungs, compared to corresponding uninvolved regions of lung tissues from cancer patients. Incubation of NETs with HPAECs in vitro activates the transcription factor nuclear factor-kB and increases expression of pro-inflammatory cytokines and leukocyte-binding adhesion molecules. NETs also increase endothelial angiogenesis in vitro and induce plateletet aggregation, possibly due to increased expression and surface deposition of von Willebrand factor and P-selectin. Conclusion: CTEPH and IPAH patients show elevated NET markers in plasma and increased numbers of NET-forming neutrophils in the remodelled lung. NETs induce endothelial dysfunction in vitro and are likely to contribute to vascular remodelling in vivo. Inhibition of NET components or NET formation in vivo may represent a new therapeutic approach in the treatment of PH.