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Angiotensin-converting enzyme 2 protects from severe acute lung failure.

ABSTRACT: Acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury, is a devastating clinical syndrome with a high mortality rate (30-60%) (refs 1-3). Predisposing factors for ARDS are diverse and include sepsis, aspiration, pneumonias and infections with the severe acute respiratory syndrome (SARS) coronavirus. At present, there are no effective drugs for improving the clinical outcome of ARDS. Angiotensin-converting enzyme (ACE) and ACE2 are homologues with different key functions in the renin-angiotensin system. ACE cleaves angiotensin I to generate angiotensin II, whereas ACE2 inactivates angiotensin II and is a negative regulator of the system. ACE2 has also recently been identified as a potential SARS virus receptor and is expressed in lungs. Here we report that ACE2 and the angiotensin II type 2 receptor (AT2) protect mice from severe acute lung injury induced by acid aspiration or sepsis. However, other components of the renin-angiotensin system, including ACE, angiotensin II and the angiotensin II type 1a receptor (AT1a), promote disease pathogenesis, induce lung oedemas and impair lung function. We show that mice deficient for Ace show markedly improved disease, and also that recombinant ACE2 can protect mice from severe acute lung injury. Our data identify a critical function for ACE2 in acute lung injury, pointing to a possible therapy for a syndrome affecting millions of people worldwide every year.

SUBMITTER: Imai Y

PROVIDER: S-EPMC7094998 | biostudies-literature | 2005 Jul

REPOSITORIES: biostudies-literature

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Angiotensin-converting enzyme 2 protects from severe acute lung failure.

Imai Yumiko Y Kuba Keiji K Rao Shuan S Huan Yi Y Guo Feng F Guan Bin B Yang Peng P Sarao Renu R Wada Teiji T Leong-Poi Howard H Crackower Michael A MA Fukamizu Akiyoshi A Hui Chi-Chung CC Hein Lutz L Uhlig Stefan S Slutsky Arthur S AS Jiang Chengyu C Penninger Josef M JM

Nature 20050701 7047

Acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury, is a devastating clinical syndrome with a high mortality rate (30-60%) (refs 1-3). Predisposing factors for ARDS are diverse and include sepsis, aspiration, pneumonias and infections with the severe acute respiratory syndrome (SARS) coronavirus. At present, there are no effective drugs for improving the clinical outcome of ARDS. Angiotensin-converting enzyme (ACE) and ACE2 are homologues with different key fun ...[more]

PMID: 16001071

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Project description:BackgroundAcute lung injury (ALI) and its most severe manifestation of acute respiratory distress syndrome (ARDS) is a disease with a clinical mortality rate of up to 40% and is one of the most dangerous and common complications of severe coronavirus disease 2019 (COVID-19). Sivelestat (SIV) is the only licensed therapeutic medicine in the world for ALI/ARDS treatment. The angiotensin-converting enzyme 2 (ACE2)/angiotensin (Ang)-(1-7)/Mas receptor axis is critical in the prevention of ALI/ARDS. This study aims to investigate whether SIV alleviates lipopolysaccharides (LPS)-induced ALI by inhibiting the down-regulation of ACE2/Ang-(1-7)/Mas receptor axis expression.MethodsIn vivo, 90 male Sprague-Dawley rats were randomized into 5 groups. Then, we pretreated different groups of rats with dexamethasone (DEX) or SIV. Rats were sacrificed at three different time points (3, 6, and 12 hours) following LPS instillation. In vitro, RAW264.7 cells were divided into 11 groups. Different groups of cells were pretreated with DEX or SIV. And then added with LPS for 3, 6, and 12 hours. Next, we introduced A779, a potent Ang-(1-7) receptor antagonist, and DX600 as the ACE2 antagonist in different groups. Then the protein and messenger RNA (mRNA) expression levels of ACE2 in rat lung tissue and the expression levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and Ang-(1-7) in the rat serum and the cell culture supernatant were measured. And the data were statistically analyzed.ResultsIn vivo, the rats pretreated with SIV or DEX had significantly lower lung wet/dry (W/D) ratios and lung pathological alterations than those exposed to LPS only. Both in vivo and in vitro, we observed that SIV or DEX significantly attenuated the LPS-induced up-regulation of IL-6 and TNF-α levels, and the down-regulation of ACE2 and Ang-(1-7) levels. In vitro, the pretreatment of the RAW264.7 cells with DX600 and A779 significantly reduced and even abolished the protective effects of SIV.ConclusionsTherefore, it was concluded that SIV protected against LPS-induced ALI and decreased inflammatory cytokine release by up-regulating the ACE2/Ang-(1-7)/Mas receptor axis. Our results enrich the theoretical foundation for the clinical application of SIV and provide fresh ideas for the treatment of ALI/ARDS.

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Angiotensin-converting enzyme 2 protects from severe acute lung failure.

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Angiotensin-converting enzyme 2 protects from severe acute lung failure.

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