Critical Care Medicine

Adult Critical Care

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

Wösten-van Asperen RM, Lutter R, Specht PA, et al (Emma Children’s Hosp/Academic Med Centre, Amsterdam, The Netherlands; Academic Med Centre, Amsterdam, The Netherlands; Erasmus Med Centre, Rotterdam, The Netherlands; et al) J Pathol 225:618-627, 2011^§

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 (Figs 2 and 4).

Figure 2 Imbalance of the ACE/Ang II and ACE2/Ang 1–7 pathways in a rat model of ARDS. (a) BALF ACE activity, ACE2 activity and ACE2/ACE ratio, and BALF levels of Ang II and Ang-(1–7) and Ang-(1–7)/Ang II ratio in unexposed and LPS-exposed non-ventilated (spontaneously breathing) and mechanically ventilated (MV) animals. n = 6 per group. ^*p < 0.05 compared with control; ^**p < 0.0001 versus all other groups; ^†p < 0.0001 versus control; ^‡p < 0.0001 versus MV and control. (b) Western blot for ACE and ACE2 protein in equal volumes of BALF from unexposed and LPS-exposed mechanically ventilated animals. (c) Immunohistochemistry for ACE and ACE2 in lung tissue from unexposed and LPS-exposed mechanically ventilated animals. Diffuse staining was found on endothelial cells and also on epithelial cells (see inset) and infiltrating cells (macrophages, monocyte-like cells) in the alveolar walls. Representative images are shown. Original magnification 20×, inset 100×. (Reprinted from Wösten-van Asperen RM, Lutter R, Specht PA, et al. 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. J Pathol. 2011;225:618-627, with permission from Pathological Society of Great Britain and Ireland.)

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