Recombinant Human Interferon Alpha 2b Prevents and Reverses Experimental Pulmonary Hypertension

Pulmonary hypertension (PH) is a progressive and fatal disease with no cure. Vascular remodeling in PH involves intraluminal growth of endothelial and smooth muscle cells, leading to obliterative vascular lesions. Cell growth in these lesions is quasi-neoplastic, with evidence of monoclonality, apoptosis resistance and cancer-like metabolic derangements. Herein we tested the effect of human interferon alpha 2b (IFN alpha), a pleiotropic cytokine and anti-cancer therapeutic, on the development and progression of PH in the rat SU5416/hypoxia (SUH) model and mouse hypoxia model of the disease. In both models IFN alpha attenuated the development of PH and reversed established PH as assessed by measuring right ventricular systolic pressure and right ventricular hypertrophy. The effect of IFN alpha was dependent on the type I interferon receptor (IFNAR) since mice lacking a subunit of the IFNAR were not protected by IFN alpha. Morphometric analysis of pulmonary aterioles from hypoxic mice or SUH rats showed that IFN alpha inhibited pulmonary vascular remodeling in both models and that IFN alpha reversed remodeling in SUH rats with established disease. Immunohistochemical staining revealed that IFN alpha decreased the number of PCNA and Tunel positive cells in the wall of pulmonary arterioles. In vitro, IFN alpha inhibited proliferation of human pulmonary artery smooth muscle cells and as well as human pulmonary artery endothelial cell proliferation and apoptosis. Together these findings demonstrate that IFN alpha reverses established experimental PH and provide a rationale for further exploration of the use of IFN alpha and other immunotherpies in PH.