Angiotensin-(1-7) improves oxygenation, while reducing cellular infiltrate and fibrosis in experimental Acute Respiratory Distress Syndrome

Abstract

BackgroundThe renin-angiotensin system (RAS) plays a role in the pathogenesis of ARDS, Angiotensin II (Ang-II) contributing to the pathogenesis of inflammation and fibrogenesis. Angiotensin-(1-7) (Ang-(1-7)) may antagonize the effects of Ang-II. This study was aimed at evaluating the potential for Ang-(1-7) to reduce injury, inflammation and fibrosis in an experimental model of ARDS in the acute and late phases.MethodsMale Sprague Dawley rats underwent an instillation of 0.1 M hydrochloric acid (HCl, 2.5 ml/kg) into the right bronchus. In an acute ARDS study, acid-injured rats were subjected to high stretch mechanical ventilation (18 ml/kg) for 5 h and randomized to receive an intravenous infusion of either vehicle (saline), Ang-(1-7) at low dose(0.27 μg/kg/h) (ALD), or high dose (60 μg/kg/h) (AHD) starting simultaneously with injury or 2 h afterwards. Arterial blood gas analysis and bronchoalveolar lavage (BAL) were performed to assess the injury. For the late ARDS study, after HCl instillation rats were randomized to either vehicle or high dose Ang-(1-7) (300 μg/kg/day) infused by mini osmotic pumps for two weeks, and lung hydroxyproline content measured.ResultsIn the acute ARDS study, Ang-(1-7) led to a significant improvement in oxygenation (PaO2/FiO2 : vehicle 359 ± 86; ALD 436 ± 72; AHD 44 442 ± 56; ANOVA p = 0.007) and reduced white blood cells counts (vehicle 4,519 ± 2,234; ALD 2,496 ± 621; AHD 2,744 ± 119/mm3; ANOVA p = 0.004). Only treatment with high dose Ang-(1-7) reduced inflammatory cell numbers in BAL (vehicle 127 ± 34; AHD 96 ± 34/ μl; p = 0.033). Interestingly also delayed administration of Ang-(1-7) was effective in reducing injury. In later ARDS, Ang-(1-7) decreased hydroxyproline content (649 ± 202 and 1,117 ± 297 μg/lung; p < 0.05).ConclusionsAngiotensin-(1-7), decreased the severity of acute lung injury and inflammation induced by combined acid aspiration and high stretch ventilation. Furthermore, continuous infusion of Ang-(1-7) reduced lung fibrosis 2 weeks following acid aspiration injury. These results call for further research on Ang-(1-7) as possible therapy for ARDS.

Therapeutic time window for angiotensin‐(1–7) in acute lung injury

“…In this model of ALI, all tested TWs for Ang‐(1–7) showed some form of therapeutic benefit, in that they alleviated OA‐induced increases in permeability, inflammatory markers or haemodynamic alterations. This finding is in line with prior work in which we and others have recently demonstrated the therapeutic potential of Ang‐(1–7) for the treatment of experimental ALI (Klein et al , ; Li et al , ; Zambelli et al , ). Of the four different time windows tested, the best protection in terms of lung vascular barrier function, inflammatory and haemodynamic parameters was provided by a continuous infusion of Ang‐(1–7) starting at the time of injury and continuing until the end of the experimental period (TW2).…”

“…However, metabolism of AngII by ACE2 concomitantly leads to the generation of Ang‐(1–7), which counteracts many of the effects of the AngII‐AT 1 receptor axis by signalling through its own receptor, Mas. In previous work, we and others have provided experimental proof‐of‐principle demonstrating not only that exogenous Ang‐(1–7) exerts similar or even more pronounced protective effects as recombinant ACE2 or pharmacological blockade of AT 1 receptors respectively (Klein et al , ; Li et al , ; Zambelli et al , ), but also that the protective effect of AT 1 receptor blockade is largely attributable to an enhanced signalling via the Ang‐(1–7)/Mas axis (Klein et al , ). The cellular mechanisms underlying the protective effects of Ang‐(1–7) in ALI are still incompletely understood but are likely to involve endothelial barrier‐stabilizing effects via cGMP‐dependent and cAMP‐dependent pathways, given that inhibition of NO synthase by L‐NAME inhibited the barrier‐protective effect of Ang‐(1–7) in lung microvascular endothelial cells challenged by thrombin (Klein et al , ) and that Ang‐(1–7) increased intracellular cAMP levels (Liu et al , ), which can attenuate endothelial leak (Moore et al , ) and reduce inflammatory cell infiltration (Derian et al , ).…”

“…Furthermore, we recently reported proof of principle for a highly effective therapeutic effect of Ang‐(1–7) in different preclinical models of ALI/ARDS including the model of oleic acid (OA)‐induced ALI in rats, and models of overventilation‐induced and acid instillation‐induced lung injury in mice (Klein et al , ). Meanwhile, these beneficial effects have been successfully reproduced by others, demonstrating the validity and reproducibility of this therapeutic effect in different models and laboratories respectively (Li et al , ; Zambelli et al , ). As the heptapeptide Ang‐(1–7) has already been approved by the Food and Drug http://www.oxforddictionaries.com/us/definition/english/administration#administration__11 for use in a series of clinical trials (Balingit et al , ; Pham et al , ), testing of this peptide as a therapeutic strategy for the treatment of ARDS is becoming a realistic and promising scenario.…”

Classic and Nonclassic Renin-Angiotensin Systems in the Critically Ill

“…74,86,87 Ang (1-7) infusion in murine experimental ARDS decreased the proinflammatory response, improved lung injury scores and lung function, and decreased cellular infiltrate in piglets with acid aspiration. 74,82 These beneficial effects are mediated by downregulation of the intracellular proinflammatory NFkB cascade and increased NO synthesis. 51 A randomized controlled trial of recombinant human ACE2 in humans with ARDS showed it decreased Ang II levels and proinflammatory mediators, and augmented plasmatic surfactant protein D, with no hemodynamic side effects.…”

“…73 In sheer contrast, activation of the Ang (1-7)/ACE2 axis inhibits ROS production, downregulates proinflammatory cytokine secretion, and has immunomodulatory tissue-protective features (see Box 2). 60,62,66,74…”