Pulmonary hypertension, defined by an mPAP of 25 mm Hg or more at rest, is a severe, progressive disease with no cure. In addition, PAH is characterized by an angioproliferative vasculopathy, mainly in the small pulmonary arteries, which results in progressive pulmonary vascular remodeling, increased pulmonary vascular resistance, and right ventricle dysfunction and failure. The proliferation, migration, and collagen synthesis of PASMCs play critical roles in pulmonary vascular remodeling.Current pharmacotherapies that are approved for PAH treatment are focused on vasodilators. These therapeutic approaches relieve the pulmonary vasoconstrictive component of the disease and provide symptomatic relief with some amelioration in the prognosis. However, there is no strong evidence supporting that these vasodilators have a direct antiproliferative effect on PAMSCs, and the underlying pathological pulmonary vessels and right ventricle remodeling still progress. Therefore, future medical intervention strategies must go beyond vasodilation, for the medicine targeting vascular remodeling processes in pulmonary vasculature to have great potential therapeutic value and a promising future.Both pirfenidone and nintedanib were approved for treatment IPF in 2014 by the FDA, ending an era without effective pharmacologic therapy for IPF. Based on the antifibrotic effect of pirfenidone and nintedanib in experimental pulmonary fibrosis and IPF patients, it was hypothesized that pirfenidone may inhibit collagen synthesis and the cell proliferation of PASMCs induced by growth factors in PH. Thus, the effects of pirfenidone and nintedanib on proliferation, migration, collagen synthesis, and inflammation in vitro were investigated. The efficacy of pirfenidone and nintedanib on hemodynamics and pulmonary vascular remodeling were also investigated in a PAH animal model. An in vitro cellular study showed that both pirfenidone and nintedanib inhibited proliferation, migration, inflammation, collagen synthesis, and collagen secretion that was induced by PDGF. The PDGF-induced phosphorylation of PDGFR&
beta;/PI3K/Akt signaling was also inhibited by these two compounds. Given the promising in vitro effects, an experimental PAH rat model (SuHx) induced by a Sugen5416 injection and three weeks of hypoxia exposure was employed to evaluate the efficacy of pirfenidone and nintedanib in vivo. Pirfenidone treatment decreased the elevated RVSP, improved impaired RV function, and inhibited RV hypertrophy in SuHx rats. The pulmonary vascular remodeling in SuHx rats was also ameliorated after treatment with pirfenidone. To explore the mechanism of action for pirfenidone on vascular remodeling, vascular cells proliferation, collagen deposition, and inflammation were investigated. Pirfenidone decreased vascular cells proliferation and collagen deposition, and suppressed inflammation by inhibiting phosphorylation of the PDGFR&
beta;/Akt pathway. However, nintedanib did not demonstrate therapeutic effects on vascular remodeling, RVSP, RV function, or hypertrophy in the SuHx model.In summary, this is the first paper to describe the successful therapeutic use of pirfenidone in a well-accepted animal model of PAH. Pirfenidone significantly attenuated PAH and the vascular remodeling, and effectively improved RV function and RV hypertrophy. Pirfenidone appears to exert inhibitory effects on multiple pathways that lead to the development of PAH, which includes the suppression of inflammation, proliferation, migration, and collagen deposition of PASMCs by acting on PDGF and the PI3K/Akt signaling cascade. The clinical development of pirfenidone as a new indication for PAH and PH due to lung disease through the improvement of vascular remodeling might be imminent. Nintedanib demonstrated potent inhibitory effects on cellular function in vitro, but did not show therapeutic effects in the SuHx rat model.
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