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 (IFNα), 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 IFNα attenuated the development of PH and reversed established PH as assessed by measuring right ventricular systolic pressure and right ventricular hypertrophy. The effect of IFNα was dependent on the type I interferon receptor (IFNAR) since mice lacking a subunit of the IFNAR were not protected by IFNα. Morphometric analysis of pulmonary aterioles from hypoxic mice or SUH rats showed that IFNα inhibited pulmonary vascular remodeling in both models and that IFNα reversed remodeling in SUH rats with established disease. Immunohistochemical staining revealed that IFNα decreased the number of PCNA and Tunel positive cells in the wall of pulmonary arterioles. In vitro, IFNα 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 IFNα reverses established experimental PH and provide a rationale for further exploration of the use of IFNα and other immunotherpies in PH.
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America; University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Eileen M
EM
Bauer
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Han
H
Zheng
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America; University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Michael T
MT
Lotze
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America; Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Philip M
PM
Bauer
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000473:pathology; D000860:Hypoxia / Q000150:complications*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D066253:Vascular Remodeling / Q000187:drug effects; D017725:Ventricular Pressure / Q000502:physiology
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D053633:Receptor, Interferon alpha-beta