C21, a nonpeptide angiotensin II type 2 receptor agonist attenuates lung fibrosis and associated cardiac dysfunction

Abstract

Pulmonary fibrosis (PF) is a fatal disease characterized by scarring of the lung tissue. A dysregulated renin angiotensin system (RAS) has been implicated in the pathology of PF. Recent reports suggest a beneficial role for the angiotensin type II receptor (AT2R) in cardiopulmonary disorders; however, the effects of AT2R in PF have not been studied. We have taken advantage of a recently identified AT2R agonist, Compound 21 (C21), to evaluate its actions in the bleomycin (BLM) model of PF. PF was induced by a single intra-tracheal instillation of 2.5mg/kg of BLM. Following BLM administration, a subset of animals was treated with C21 (0.03mg/kg, ip, daily) for 2 weeks (prevention protocol). In a subsequent study, C21 was administered after three days of BLM injection (reversal protocol). For both prevention and reversal protocols, hemodynamic parameters were measured, and tissues collected after 15 days of BLM injection. BLM caused significant increase in right ventricular systolic pressure (RVSP) and induced maladaptive cardiac remodeling. However, C21 treatment considerably reduced BLM-induced elevation in RVSP (Con: 29+1; BLM: 47+2; BLM+C21(P): 37+2; BLM+C21(R): 41+3 mmHg), attenuated ventricular hypertrophy (Con: 0.28+0.01; BLM: 0.41+0.01; BLM+C21(P): 0.35+0.01; BLM+C21(R): 0.37+0.02) and improved right heart function in both prevention (P) and reversal (R) protocols. Histopathological assessment of hematoxylin and eosin stained lung sections also showed decreased collagen accumulation in the C21 treated group. Collectively, our results suggest that the AT2R agonist, C21 exerts potent antifibrotic effects and may hold promise for patients with PF.