Interleukin-33 in pulmonary arterial hypertension: a role in disease pathogenesis? (1090.4)

Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance that leads to right ventricular failure. PAH can be a primary disease (idiopathic, IPAH) or secondary to conditions such as connective tissue disease. Interleukin‐33 (IL‐33), which is the ligand for the ST2 receptor, is a cytokine that acts as an alarmin. Since PAH is associated with the infiltration of inflammatory cells and increased cytokines, we aimed to investigate the role of IL‐33 in PAH. Using an IL‐33 ELISA we found that IL‐33 is increased in the serum of PAH patients, in particular IPAH [1798 +/‐846 pg/ml (n=6) vs. 24 +/‐ 13 pg/ml (n=6), p<0.01], compared to control subjects. We found that the mRNA expression of IL‐33 is increased ~8‐fold in peripheral blood mononuclear cells isolated from PAH‐patients and PAH‐animal models compared to control; Il‐33 is up‐regulated in the lung of animal models of PAH. Injury of pulmonary artery endothelial cells (PAEC) released IL‐33, thus implying that the increased circulating IL‐33 with PAH may occur if the membrane integrity of PAEC is compromised. Administration of IL‐33 (500 ng/day intracheally for four days) induced pulmonary arterial remodeling in WT and IL‐33 KO mice, but not ST2 KO mice. Our data demonstrate that IL‐33 is increased in PAH, which via ST2‐dependent signaling, contributes to remodeling of the PA and hence the pathophysiology of the disease. Grant Funding Source : Supported by NIH