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Angiotensin-converting enzyme 2 protects from severe acute lung failure

2005; Nature Portfolio; Volume: 436; Issue: 7047 Linguagem: Inglês

10.1038/nature03712

1476-4687

Yumiko Imai, Keiji Kuba, Shuan Rao, Yi Huan, Feng Guo, Bin Guan, Xiaozhong Peng, Renu Sarao, Teiji Wada, Howard Leong‐Poi, Michael A. Crackower, Akiyoshi Fukamizu, Chi-chung Hui, Lutz Hein, Stefan Uhlig, Arthur S. Slutsky, Chengyu Jiang, Josef Penninger,

Receptor Mechanisms and Signaling

The SARS (severe acute respiratory syndrome) epidemic of 2003 caused almost 800 deaths, many of them due to acute respiratory distress syndrome (ARDS) as a complication. There are no effective drugs available for treating ARDS, but new work in mice suggests that ACE2 (angiotensin-converting enzyme 2) might be an option. ACE2 can protect mice from lung injury in an ARDS-like syndrome, whereas other components of the renin–angiotensin system for controlling blood pressure and salt balance actually make the condition worse. ACE2 is expressed in the healthy lung but downregulated by lung injury and it was shown recently (Nature 426, 450–454; 2003) to be a receptor for the SARS coronavirus. 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 diverse1,3 and include sepsis, aspiration, pneumonias and infections with the severe acute respiratory syndrome (SARS) coronavirus4,5. At present, there are no effective drugs for improving the clinical outcome of ARDS1,2,3. Angiotensin-converting enzyme (ACE) and ACE2 are homologues with different key functions in the renin–angiotensin system6,7,8. 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 lungs9,10. 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.