Editors' ChoicePulmonary Arterial Hypertension

Linking Autoimmunity and Pulmonary Arterial Hypertension

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Science Translational Medicine  08 Jan 2014:
Vol. 6, Issue 218, pp. 218ec8
DOI: 10.1126/scitranslmed.3008246

Several U.S. Food and Drug Administration–approved therapies are now available for the treatment of pulmonary arterial hypertension (PAH); nevertheless, patients with PAH continue to die from progression of their disease. Therefore, there is a pressing need to better understand the pathobiology of PAH and identify new therapeutic targets for this deadly condition.

Recent reports suggest an association between treatment with type I interferons (IFNs), a group that includes IFN-α and -β and the development of PAH. Moreover, the incidence of PAH is higher in conditions in which type I IFN is chronically elevated, including systemic sclerosis and human immunodeficiency virus infection. George et al. studied whether the activation of certain IFN pathways, such as IFN-induced protein 10 (IP 10) and endothelin-1, contributes to the development of PAH. In human pulmonary artery smooth muscle cells, IFN-α and IFN-γ, a type II IFN, induced the release of IP 10 and endothelin-1. IP 10 promotes inflammation and endothelial dysfunction, whereas endothelin-1 mainly acts as a vasoconstrictor and stimulant of vascular smooth muscle cell proliferation. Serum levels of IFN-α, IFN-γ, IP 10, and endothelin-1 were higher in patients with systemic sclerosis and PAH than in those without PAH. Similarly, the expression of IFN-α receptor (IFNAR1) was higher in the lungs of patients with systemic sclerosis and PAH as compared with those of controls. In addition, mice lacking functional IFNAR1 (IFNAR1−/−) were protected from the development of PAH and had no significant rise in serum endothelin-1 when exposed to chronic hypoxia.

The results of this study provide a link (type I IFN) that connects autoimmunity with the development of PAH, an association partially mediated by endothelin-1. Although treatment with endothelin receptor antagonists (bosentan, ambrisentan, and the newly released macitentan) is currently available, the present investigation suggests that targeting upstream targets in the IFN pathway might be more effective.

P. M. George et al., Evidence for the involvement of type i interferon in pulmonary arterial hypertension. Circ. Res., published online 13 December 2013 (10.1161/CIRCRESAHA.114.302221). [Abstract]

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