Key result
Diminazene aceturate reduces RVSP by ~22% and limits myocardial fibrosis in bleomycin-induced pulmonary hypertension.
Why the study?
There are no approved anti-fibrotic agents that directly target the mechanism of fibrosis in fibroproliferative diseases of the heart and lungs.
Does Diminazene aceturate attenuate bleomycin-induced lung fibrosis and associated cardiac remodeling in a rodent model?
RCT
randomized
Does Diminazene aceturate attenuate bleomycin-induced lung fibrosis and associated cardiac remodeling in a rodent model?
Absolute Event Rate: 32% vs 41%
p-value: p=<0.05
In a rodent model of pulmonary fibrosis, the ACE2 activator Diminazene aceturate attenuated lung fibrosis, pulmonary hypertension, and associated maladaptive cardiac remodeling.
DIZE antifibrotic effects in rodent PF remain preclinical; leaves open human translation and clinical trials.
Introduction: Fibroproliferative diseases of the heart & lungs are a leading cause of morbidity and mortality. Currently there are no approved anti-fibrotic agents that directly target the mechanism of fibrosis. Pre-clinical studies have demonstrated protective role of Angiotensin-converting enzyme2 (ACE2) in tissue fibrosis and apoptosis. Hypothesis: ACE2 activation by a small molecule, Diminazene aceturate (DIZE) exerts antifibrotic actions in a rodent model of pulmonary fibrosis (PF). Methods: PF was induced by intratracheal instillation of bleomycin (5U/Kg) in 8 week old male SD rats. Rats were randomized into three groups: control, bleomycin and bleomycin+DIZE. DIZE (15 mg/Kg, sc) was administered along with bleomycin. After 14 days, rats were instrumented to measure right ventricular systolic pressure (RVSP), followed by heart and lung excision to examine cardiopulmonary remodeling and apoptosis. Results: Bleomycin resulted in a 57% elevation of RVSP (control: 26+1mmHg; bleomycin: 41+2mmHg; p<0.05), signifying development of pulmonary hypertension. In addition, these animals exhibited maladaptive cardiac remodeling in terms of increased myocardial fibrosis (%Fibrosis: control: 6+0.23; bleomycin: 17+0.3; p<0.05) and right ventricular hypertrophy (RVH: control: 0.26+0.007; bleomycin: 0.40+0.03; p<0.05). Co-administration of DIZE significantly attenuated all these parameters (RVSP; 32+0.5mmHg(? by 22%); RVH; 0.30+0.01(? by 25%) and %Fibrosis; 7.2+0.6(? by 58%)). A higher Ashcroft score was observed in the bleomycin group signifying development of PF, which was decreased by DIZE treatment (control: 1.2+0.09; bleomycin: 6.5+0.06; bleomycin+DIZE: 2.8+0.03; p<0.05). The protective effects of DIZE were associated with favorable modulation of the pulmonary renin angiotensin system and decreased pro-inflammatory cytokines. Increased TUNEL staining for apoptosis was observed in the lung sections of bleomycin group, which was reduced by DIZE (TUNEL positive index; control: 0.03+0.005; bleomycin:0.2+0.04; bleomycin+DIZE: 0.07+0.003; p<0.05). Conclusions: DIZE, an ACE2 activator attenuates bleomycin-induced lung fibrosis and associated cardiac remodeling, indicating its therapeutic potential as an anti-fibrotic agent.
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Gupta et al. (2012) conducted an RCT in pulmonary fibrosis. Diminazene aceturate (DIZE) vs. bleomycin was evaluated on right ventricular systolic pressure (RVSP) (p=<0.05). Diminazene aceturate significantly attenuated bleomycin-induced elevation of right ventricular systolic pressure (32 vs 41 mmHg, p<0.05) and myocardial fibrosis in a rat model.
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