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P ulmonary arterial hypertension (PAH) is a rare but devastating disease, which is defined as a mean pulmonary artery pressure of ≥25 mm Hg with a normal pulmonary capillary wedge pressure. It is characterized by remodeling of the muscular, precapillary vessels, leading to an increase in pulmonary vascular resistance. The associated strain exerted on the right heart ultimately results in right heart failure and premature death. 1,2 Autoimmunity has long been implicated in PAH 3 and, most recently, evidence has emerged implicating interferon (IFN). 4 IFN is central to the innate immune response to viral infection, and 3 types have been identified; type I IFN (IFNα and IFNβ) that signals through a heterodimeric receptor consisting of IFNAR1 and IFNAR2, type II IFN (IFNγ) that signals through IFNGR1 and IFNGR2, and type III IFN (IFNλ) the receptor for which comprises interleukin (IL)10RB and IL28RA. In This Issue, see p 587Clinical Track © 2013 American Heart Association, Inc. Rationale: Evidence is increasing of a link between interferon (IFN) and pulmonary arterial hypertension (PAH).Conditions with chronically elevated endogenous IFNs such as systemic sclerosis are strongly associated with PAH. Furthermore, therapeutic use of type I IFN is associated with PAH. This was recognized at the 2013 World Symposium on Pulmonary Hypertension where the urgent need for research into this was highlighted.Objective: To explore the role of type I IFN in PAH. Methods and Results: Cells were cultured using standard approaches. Cytokines were measured by ELISA.Gene and protein expression were measured using reverse transcriptase polymerase chain reaction, Western blotting, and immunohistochemistry. The role of type I IFN in PAH in vivo was determined using type I IFN receptor knockout (IFNAR1 −/− ) mice. Human lung cells responded to types I and II but not III IFN correlating with relevant receptor expression. Type I, II, and III IFN levels were elevated in serum of patients with systemic sclerosis associated PAH. Serum interferon γ inducible protein 10 (IP10; CXCL10) and endothelin 1 were raised and strongly correlated together. IP10 correlated positively with pulmonary hemodynamics and serum brain natriuretic peptide and negatively with 6-minute walk test and cardiac index. Endothelial cells grown out of the blood of PAH patients were more sensitive to the effects of type I IFN than cells from healthy donors. PAH lung demonstrated increased IFNAR1 protein levels. IFNAR1 −/− mice were protected from the effects of hypoxia on the right heart, vascular remodeling, and raised serum endothelin 1 levels. Conclusions: These data indicate that type I IFN, via an action of IFNAR1, mediates PAH. (Circ Res. 2014;114:677-688.)Key Words: chemokine CXCL10 ■ endothelin-1 ■ IFNAR1 subunit, interferon alpha-beta receptor ■ inflammation ■ interferon type I ■ pulmonary arterial hypertension ■ scleroderma, systemic Original received July 18, 2013; revision received December 11, 2013; accepted December 13, 2013. In November 2013, the averag...