Circulation research · 2013
Evidence for the involvement of type I interferon in pulmonary arterial hypertension.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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George Peter M, Oliver Eduardo, Dorfmuller Peter, Dubois Olivier D, Reed Daniel M, Kirkby Nicholas S, Mohamed Nura A, Perros Frederic, Antigny Fabrice, Fadel Elie, Schreiber Benjamin E, Holmes Alan M, Southwood Mark, Hagan Guy, Wort Stephen J, Bartlett Nathan, Morrell Nicholas W, Coghlan John G, Humbert Marc, Zhao Lan, Mitchell Jane A
Аннотация
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.
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.
Предметные рубрики MeSH
AnimalsCells, CulturedChemokine CXCL10Disease Models, AnimalEndothelial CellsEndothelin-1Familial Primary Pulmonary HypertensionHumansHypertension, PulmonaryInterferon-alphaInterferon-betaInterferon-gammaLungMaleMiceMice, Inbred C57BLMice, KnockoutOrgan Culture TechniquesReceptor, Interferon alpha-betaScleroderma, SystemicSignal Transduction