The Selective Angiotensin II Type 2 Receptor Agonist, Compound 21, Attenuates the Progression of Lung Fibrosis and Pulmonary Hypertension in an Experimental Model of Bleomycin-Induced Lung Injury

Abstract

Idiopathic Pulmonary Fibrosis (IPF) is a chronic lung disease characterized by scar formation and respiratory insufficiency, which progressively leads to death. Pulmonary hypertension (PH) is a common complication of IPF that negatively impacts clinical outcomes, and has been classified as Group III PH. Despite scientific advances, the dismal prognosis of IPF and associated PH remains unchanged, necessitating the search for novel therapeutic strategies. Accumulating evidence suggests that stimulation of the angiotensin II type 2 (AT2) receptor confers protection against a host of diseases. In this study, we investigated the therapeutic potential of Compound 21 (C21), a selective AT2 receptor agonist in the bleomycin model of lung injury. A single intra-tracheal administration of bleomycin (2.5 mg/kg) to 8-week old male Sprague Dawley rats resulted in lung fibrosis and PH. Two experimental protocols were followed: C21 was administered (0.03 mg/kg/day, ip) either immediately (prevention protocol, BCP) or after 3 days (treatment protocol, BCT) of bleomycin-instillation. Echocardiography, hemodynamic, and Fulton's index assessments were performed after 2 weeks of bleomycin-instillation. Lung tissue was processed for gene expression, hydroxyproline content (a marker of collagen deposition), and histological analysis. C21 treatment prevented as well as attenuated the progression of lung fibrosis, and accompanying PH. The beneficial effects of C21 were associated with decreased infiltration of macrophages in the lungs, reduced lung inflammation and diminished pulmonary collagen accumulation. Further, C21 treatment also improved pulmonary pressure, reduced muscularization of the pulmonary vessels and normalized cardiac function in both the experimental protocols. However, there were no major differences in any of the outcomes measured from the two experimental protocols. Collectively, our findings indicate that stimulation of the AT2 receptor by C21 attenuates bleomycin-induced lung injury and associated cardiopulmonary pathology, which needs to be further explored as a promising approach for the clinical treatment of IPF and Group III PH.

Renin-angiotensin-system, a potential pharmacological candidate, in acute respiratory distress syndrome during mechanical ventilation

“…In line with this, a study by Imai and colleagues showed that Agtr2-knockout mice had more severe pathology in response to acid aspiration induced lung injury than wild-type controls [34]. A number of beneficial actions of AT2R in lung injury have recently been demonstrated [52][53][54]. Bruce and colleagues found that treatment with C21, an AT2R non-peptide agonist, ameliorates pulmonary fibrosis and prevents right ventricular fibrosis in pulmonary hypertension, and these beneficial effects are abolished by co-administration of the AT2R antagonist, PD123319 [52].…”

“…Bruce and colleagues found that treatment with C21, an AT2R non-peptide agonist, ameliorates pulmonary fibrosis and prevents right ventricular fibrosis in pulmonary hypertension, and these beneficial effects are abolished by co-administration of the AT2R antagonist, PD123319 [52]. Furthermore, Rathinasabapathy and colleagues found that stimulation of the AT2R by C21 attenuates bleomycin-induced lung injury by alleviating lung inflammation and fibrosis [53]. A double-blind and placebo-controlled Phase IIa study has been approved by the European Union Clinical Trials Register with EudraCT Number: 2017-004923-63 and begun to evaluate the effect of C21 on fibrotic lung injury and the safety of C21.…”

Anti‐fibrotic mechanisms of angiotensin AT2‐receptor stimulation

“…The mortality associated with pulmonary hypertension is largely because of right ventricular failure. Interestingly, the studies by Bruce et al and Rathinasabapathy et al both also looked at right ventricular (RV) pathology resulting from pulmonary hypertension because of pulmonary fibrosis …”

Expression of a Human Caveolin-1 Mutation in Mice Drives Inflammatory and Metabolic Defect-Associated Pulmonary Arterial Hypertension

“…After euthanization, the left lobe of the lung was processed and paraffin-embedded, and immunohistochemical staining was performed as explained previously (23). CD45 (1:100), CD68 (1:100), and α-smooth muscle actin (1:200) antibodies were used for the assessment of macrophage and pulmonary vessel muscularization (24), and the images were analyzed as explained previously.…”