Evidence for the Involvement of Type I Interferon in Pulmonary Arterial Hypertension
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.
- pulmonary hypertension
- pulmonary circulation
- vascular remodeling
- Received July 18, 2013.
- Revision received December 11, 2013.
- Accepted December 13, 2013.