Lenti‐viral mediated overexpression of ACE2 or Angiotensin‐(1‐7) prevents bleomycin‐induced pulmonary fibrosis

An activated pulmonary renin angiotensin system (RAS), comprising of ACE‐AngII‐AT1R has been implicated in the pathogenesis of idiopathic pulmonary fibrosis. The recent discovery of a counter‐regulatory arm of the RAS (ACE2‐Ang‐(1‐7)‐Mas), has led us to examine the role of this vasoprotective axis on pulmonary fibrosis with the use of lentiviral vector mediated gene transfer. Lentiviral particles carrying either the ACE2 or Ang‐(1‐7) fusion protein were administered intratracheally into the lungs of 5 weeks old male Sprague‐Dawley rats. Pulmonary fibrosis was induced by intratracheal administration of bleomycin (2.5mg/kg), following 2 weeks of gene transfer. Systemic blood pressure, body weights, right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) were examined after two weeks of bleomycin administration. Bleomycin administration resulted in significant reduction in body weights, elevated RVSP, RVH and increased fibrotic lesions in the lungs. All these pathophysiological parameters were prevented in lenti‐ACE2 or lenti‐Ang‐(1‐7) treated rats. No significant change in the systemic blood pressure was observed among the different study groups. Collectively, these observations demonstrate that ACE2 or Ang‐(1‐7) gene transfer shifts the balance of the RAS from the vasoconstrictive‐proliferative axis (ACE‐AngII‐AT1R), towards vasoprotective axis (ACE2‐Ang‐(1‐7)‐Mas), resulting in attenuation of bleomycin‐induced pulmonary fibrosis.