Acute respiratory distress syndrome leads to reduced ratio of ACE/ACE2 activities and is prevented by angiotensin‐(1–7) or an angiotensin II receptor antagonist

Abstract

Acute respiratory distress syndrome (ARDS) is a devastating clinical syndrome. Angiotensin-converting enzyme (ACE) and its effector peptide angiotensin (Ang) II have been implicated in the pathogenesis of ARDS. A counter-regulatory enzyme of ACE, ie ACE2 that degrades Ang II to Ang-(1-7), offers a promising novel treatment modality for this syndrome. As the involvement of ACE and ACE2 in ARDS is still unclear, this study investigated the role of these two enzymes in an animal model of ARDS. ARDS was induced in rats by intratracheal administration of LPS followed by mechanical ventilation. During ventilation, animals were treated with saline (placebo), losartan (Ang II receptor antagonist), or with a protease-resistant, cyclic form of Ang-(1-7) [cAng-(1-7)]. In bronchoalveolar lavage fluid (BALF) of ventilated LPS-exposed animals, ACE activity was enhanced, whereas ACE2 activity was reduced. This was matched by enhanced BALF levels of Ang II and reduced levels of Ang-(1-7). Therapeutic intervention with cAng-(1-7) attenuated the inflammatory mediator response, markedly decreased lung injury scores, and improved lung function, as evidenced by increased oxygenation. These data indicate that ARDS develops, in part, due to reduced pulmonary levels of Ang-(1-7) and that repletion of this peptide halts the development of ARDS.

The renin–angiotensin system, bone marrow and progenitor cells

“…Even more specific is the non-peptide analogue CGEN-856S [185] or the thioether-bridged Ang-(1-7) analogue called cyclic Ang-(1-7) [186,187], which are specific Mas receptor agonists. Infusion of cyclic Ang-(1-7) has shown promise in rat models as an intervention for acute respiratory syndrome or after myocardial infarction [188,189]. It will be of major interest to perform comparative studies on native Ang-(1-7) with these specific Mas receptor agonists and to unravel their effects on EPCs and other progenitor cells.…”

Agonists of MAS oncogene and angiotensin II type 2 receptors attenuate cardiopulmonary disease in rats with neonatal hyperoxia-induced lung injury

“…In addition, protective effects of MAS in cardiac disease are suggested by investigations in MAS-deficient mice that became hypertensive (4). In animal models of bleomycin or cigarette smoke-induced lung injury and neonatal rats with hyperoxia-induced fibrotic lung injury, beneficial effects can be obtained by blocking AT1 or ACE (7,26,28,49) or increasing expression of Ang-(1-7) or ACE-2 (23,29,33). Alternatively, the detrimental effects of AngII binding to AT1 may be counterbalanced by binding to AT2, resulting in reduced proliferation, inflammation, and fibrosis (20,34,44).…”

“…Binding of AngII to the AngII type 1 receptor (AT1) leads to vasoconstriction, proliferation, and fibrosis in multiple tissues, including the lung, whereas binding of Ang-(1-7) to the MAS oncogene receptor (MAS) counterbalances the detrimental biological actions of AngII, by inducing vasodilation and by inhibiting fibrinogenesis, thrombogenesis, hypertension, cardiac hypertrophy, and lung injury (9,20,24,31,33,40,43). In multiple adult rat models of cardiopulmonary disease Ang-(1-7) treatment protected against monocrotalin-induced PAH and RVH (33), bleomycin-induced pulmonary fibrosis (33), and LPS-induced respiratory distress (49). In addition, protective effects of MAS in cardiac disease are suggested by investigations in MAS-deficient mice that became hypertensive (4).…”

Pulmonary Circulation and Regulation of Fluid Balance

“…For example, ACE and angiotensin II have been found to serve a protective role in acute respiratory distress syndrome (ARDS), whereas ACE2, angiotensin II, and angiotensin I appear to mediate lung edema and injury associated with ARDS. 170,171 …”