Pirfenidone ameliorates pulmonary arterial pressure and neointimal remodeling in experimental pulmonary arterial hypertension by suppressing NLRP3 inflammasome activation.

Autor: Mavrogiannis E; Department of Pediatric Cardiology, Center For Congenital Heart Diseases, Beatrix Children's Hospital, University Medical Center Groningen University of Groningen Groningen The Netherlands.; Department of Pediatrics, Beatrix Children's Hospital, University Medical Center Groningen University of Groningen Groningen The Netherlands., Hagdorn QAJ; Department of Pediatric Cardiology, Center For Congenital Heart Diseases, Beatrix Children's Hospital, University Medical Center Groningen University of Groningen Groningen The Netherlands., Bazioti V; Department of Pediatrics, Beatrix Children's Hospital, University Medical Center Groningen University of Groningen Groningen The Netherlands., Douwes JM; Department of Pediatric Cardiology, Center For Congenital Heart Diseases, Beatrix Children's Hospital, University Medical Center Groningen University of Groningen Groningen The Netherlands., Van Der Feen DE; Department of Pediatric Cardiology, Center For Congenital Heart Diseases, Beatrix Children's Hospital, University Medical Center Groningen University of Groningen Groningen The Netherlands., Oberdorf-Maass SU; Department of Experimental Cardiology, University Medical Center Groningen University of Groningen Groningen The Netherlands., Westerterp M; Department of Pediatrics, Beatrix Children's Hospital, University Medical Center Groningen University of Groningen Groningen The Netherlands., Berger RMF; Department of Pediatric Cardiology, Center For Congenital Heart Diseases, Beatrix Children's Hospital, University Medical Center Groningen University of Groningen Groningen The Netherlands.
Jazyk: angličtina
Zdroj: Pulmonary circulation [Pulm Circ] 2022 Jul 01; Vol. 12 (3), pp. e12101. Date of Electronic Publication: 2022 Jul 01 (Print Publication: 2022).
DOI: 10.1002/pul2.12101
Abstrakt: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by increased pulmonary arterial pressure, inflammation, and neointimal remodeling of pulmonary arterioles. Serum levels of interleukin (IL)-1β and IL-18 are elevated in PAH patients and may enhance proinflammatory neointimal remodeling. NLRP3 inflammasome activation induces cleavage of the cytokines IL-1β and IL-18, required for their secretion. Pirfenidone (PFD), an antifibrotic and anti-inflammatory drug, has been suggested to inhibit NLRP3 inflammasome activation. We hypothesized that PFD delays the progression of PAH by suppressing NLRP3 inflammasome activation. We assessed the effects of PFD treatment in a rat model for neointimal PAH induced by monocrotaline and aortocaval shunt using echocardiographic, hemodynamic, and vascular remodeling parameters. We measured inflammasome activation by NLRP3 immunostaining, Western blots for caspase-1, IL-1β, and IL-18 cleavage, and macrophage IL-1β secretion. PFD treatment ameliorated pulmonary arterial pressure, pulmonary vascular resistance, and pulmonary vascular remodeling in PAH rats. In PAH rats, immunostaining of NLRP3 in pulmonary arterioles and caspase-1, IL-1β, and IL-18 cleavage in lung homogenates were increased compared to controls, reflecting NLRP3 inflammasome activation in vivo. PFD decreased IL-1β and IL-18 cleavage, as well as macrophage IL-1β secretion in vitro. Our studies show that PFD ameliorates pulmonary hemodynamics and vascular remodeling in experimental PAH. Although PFD did not affect all NLRP3 inflammasome parameters, it decreased IL-1β and IL-18 cleavage, the products of NLRP3 inflammasome activation that are key to its downstream effects. Our findings thus suggest a therapeutic benefit of PFD in PAH via suppression of NLRP3 inflammasome activation.
(© 2022 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)
Databáze: MEDLINE
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