Abstract 19577: Diminazene Aceturate Inhibits Apoptotic Cell Death to Protect from Pulmonary Fibrosis and Associated Pulmonary Hypertension

Abstract

INTRODUCTION: Studies have demonstrated that Angiotensin-converting enzyme2 (ACE2) plays a protective role against lung fibrosis. In this study, we evaluated the pharmacological actions of a recently identified synthetic activator of ACE2, Diminazene aceturate (DIZE) in the bleomycin model of pulmonary fibrosis (PF). METHODS: PF was induced by a single intratracheal instillation of bleomycin (Bleo, 5U/Kg) in 8 weeks old male Sprague-Dawley rats. Rats were randomized into three groups; Control, Bleo and Bleo+DIZE. DIZE treatment (15mg/Kg, sc) was commenced at the same time as bleomycin administration. After 2-weeks of bleomycin instillation, rats were instrumented to measure right ventricular systolic pressure (RVSP), followed by heart and lung excision to examine cardio-pulmonary remodeling and apoptosis. RESULTS: Bleomycin administration resulted in significant elevation of right ventricular systolic pressure (RVSP; Control: 26+1mmHg; Bleo: 41+2mmHg), signifying development of pulmonary hypertension. In addition, these animals exhibited maladaptive cardiac remodeling in terms of increased myocardial fibrosis (%Fibrosis; Control: 6+0.23; Bleo: 17+0.3) and right ventricular hypertrophy (RVH; Control: 0.26+0.007; Bleo: 0.40+0.03). Co-administration of DIZE significantly attenuated all these parameters (RVSP; 32+0.5mmHg; RVH; 0.30+0.01 and %Fibrosis; 7.2+0.6). A higher Ashcroft score was observed in bleomycin-challenged animals, signifying development of PF, which was prevented by DIZE treatment (Control: 1.2+0.09; Bleo: 6.5+0.06; Bleo+DIZE: 2.8+0.03). The protective effects of DIZE were associated with favorable modulation of the pulmonary renin angiotensin system and decreased pro-inflammatory cytokines. Furthermore, lung sections of bleomycin administered animals showed increased TUNEL staining for apoptosis, which was prevented by DIZE treatment (TUNEL positive index; Con: 0.03+0.005; Bleo: 0.2+0.04; Bleo+DIZE: 0.07+0.003). CONCLUSION: Our studies show that DIZE, an ACE2 activator attenuates bleomycin-induced lung fibrosis and associated cardio-pulmonary pathology, indicating a therapeutic potential of this drug in PF therapy .