Therapeutic effect of pirfenidone in the sugen/hypoxia rat model of severe pulmonary hypertension

Abstract

Heightened pulmonary artery smooth muscle cell (PA‐SMC) proliferation and migration and dynamic remodeling of the extracellular matrix are hallmark pathogenic features of pulmonary arterial hypertension (PAH). Pirfenidone (PFD) is an orally bioavailable pyridone derivative with antifibrotic, antiinflammatory, and antioxidative properties currently used in the treatment of idiopathic pulmonary fibrosis. We therefore evaluated the efficacy of curative treatments with PFD in the sugen/hypoxia (SuHx) rat model of severe pulmonary hypertension. Treatment with PFD (30 mg/kg per day by mouth 3 times a day for 3 wk) started 5 wk after sugen injection partially reversed established pulmonary hypertension, reducing total pulmonary vascular resistance and remodeling. Consistent with these observations, we found that continued PFD treatment decreases PA‐SMC proliferation and levels of extracellular matrix deposition in lungs and right ventricles in SuHx rats. Importantly, PFD attenuated the proproliferative and promigratory potentials of cultured PA‐SMCs from patients with idiopathic PAH and their capacity to produce extracellular matrix components. Finally, we found that PFD dose dependently enhanced forkhead box Ol protein levels and its nuclear translocation in cultured idiopathic PAH PA‐SMCs and in PFD‐treated SuHx rats. PFD appears to be a potential therapy for PAH worthy of investigation and evaluation for clinical use in conjunction with current PAH treatments.—Poble, P.‐B., Phan, C., Quatremare, T., Bordenave, J., Thuillet, R., Cumont, A., Huertas, A., Tu, L., Dorf muller, P., Humbert, M., Ghigna, M.‐R., Savale, L., Guignabert, C. Therapeutic effect of pirfenidone in the sugen/hypoxia rat model of severe pulmonary hypertension. FASEB J. 33,3670–3679 (2019). http://www.fasebj.org

Pressure overload induced right ventricular remodeling is not attenuated by the anti‐fibrotic agent pirfenidone

“…15 In the Sugen-hypoxia model of PH and RV failure, pirfenidone (30 mg/kg/day by mouth three times a day for three weeks) reduced RV fibrosis, but whether the reduction in RV fibrosis was secondary to the reduction in pulmonary vascular resistance also observed in the study or direct effects of pirfenidone on the RV could not be concluded. 22 Our results suggest that the reduction in RV fibrosis after pirfenidone treatment in the Sugen-hypoxia model may be explained primarily by the RV afterload reduction, as we did not observe any direct effects of pirfenidone treatment on RV fibrosis in our model of isolated RV failure. The lower absolute volume of fibrosis in the septum and the trend towards lower volume of LV fibrosis in the PTB rats after pirfenidone treatment observed in this study reflect lower volumes of the septum and LV in the PTB þ pirf rats compared with the non-treated PTB rats, as there was no difference in the volume fraction of fibrosis between the groups.…”

“…The study by Poble et al also demonstrated increased FoxO1 expression in lung tissue from both PAH patients and SuHx rats after pirfenidone treatment. 22 In this study, there was no effect of pirfenidone on RV FoxO1 expression, suggesting a different regulation of FoxO1 in the RV compared with the lungs.…”

“…17 The ability of pirfenidone to reduce myocardial fibrosis has been demonstrated in a number of studies, although only the left ventricle (LV) was evaluated. [18][19][20][21] In recent studies, treatment with pirfenidone reduced pulmonary vascular remodeling and RV fibrosis in the Sugen-hypoxia model of PH 22 and RV fibrosis in pulmonary artery banded mice. 23 A phase II study investigating safety and efficacy of pirfenidone in heart failure patients with preserved ejection fraction (EF), who often present with concomitant RV dysfunction, is ongoing (NCT02932566).…”

Idiopathic pulmonary fibrosis and pulmonary hypertension: Heracles meets the Hydra

“…A trial evaluating combination treatment with the vasodilator sildenafil in patients with IPF and risk of PH is currently underway, although there is little evidence of efficacy for pirfenidone in the treatment of human pulmonary vascular disease (Behr et al, 2018). The drug is associated, however, with protection against pulmonary vascular remodelling and cardiac fibrosis in the rat Sugen/hypoxia model, although there was no change reported in mean PA pressure (Poble et al, 2019). Intriguingly, the same investigators showed that in smooth muscle cells isolated from lungs of patients with idiopathic PAH, application of pirfenidone did result in positive regulatory transcriptional element changes consistent with protective factors again pulmonary vascular disease development.…”

Is Myocardial Fibrosis Impairing Right Heart Function?

“…In most clinical studies, myocardial fibrosis is quantified using late gadolinium enhancement, and histological proof of the validity of this concept is readily available (9). The list of drugs that concomitantly improve RV function and decrease fibrosis in experimental models is long and includes beta-adrenergic blockers (10), iloprost (11), p38 MAPK inhibition (12), pirfenidone (13), and nintedanib (14). In most of these studies, RV effects were partly mediated by a drug-induced decrease in pulmonary vascular resistance.…”