Circ Res. 2013 Dec 13. [Epub ahead of print]

Evidence for the Involvement of Type I Interferon in Pulmonary Arterial Hypertension.

George PM, Oliver E, Dorfmüller P, Dubois OD, Reed DM, Kirkby NS, Mohamed NA, Perros F, Antigny F, Fadel E, Schreiber BE, Holmes A, Southwood M, Hagan G, Wort SJ, Bartlett N, Morrell NW, Coghlan G, Humbert M, Zhao L, Mitchell JA.

National Heart and Lung Institute, Imperial College London.

Abstract

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 (SSc) are strongly associated with PAH. Furthermore, therapeutic use of type I IFN is associated with PAH. This was recognised 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 RT-PCR, Western blotting and immunohistochemistry. The role of type I IFN in PAH in vivo was determined using type I IFN receptor knock out (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 SSc-PAH patients. Serum IP10 and ET-1 were raised and strongly correlated together. IP10 correlated positively with pulmonary haemodynamics 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 remodelling and raised serum ET-1 levels.

CONCLUSIONS: These data indicate that type I IFN, via an action of IFNAR1, mediates PAH.

PMID:24334027