Angiotensin-converting enzyme 2 protects from severe acute lung failure

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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 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.

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Figure 1: Loss of ACE2 worsens acid aspiration-induced acute lung injury.
Figure 2: ACE2 controls acute lung failure.
Figure 3: ACE deficiency reduces the severity of acute lung injury.
Figure 4: The AngII receptor AT 1 a controls acute lung injury severity and pulmonary vascular permeability.

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Acknowledgements

We thank M. Chappell, C. Richardson, B. Seed, U. Eriksson, J. Ishida and all members of our laboratory for discussions and reagents. This work is supported by the Institute for Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) and the Jubilaeumsfonds of the Austrian National Bank. This work is in part supported by the Canadian Institutes of Health Research (CIHR) and the Canada Foundation for Innovation (CFI). K.K. is supported by a Marie Curie Fellowship from the EU. C.J. is supported a Beijing Committee of Science and Technology grant and the Natural Science Fundation of China. L.H. is supported by the Deutsche Forschungsgemeinschaft.

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Correspondence to Josef M. Penninger.

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J.M.P. declares personal financial interests.

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Supplementary Figures S1-S9 (PPT 3809 kb)

Supplementary Notes

Legends for Supplementary Figures S1-S9 and Supplementary Methods. (RTF 163 kb)

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Imai, Y., Kuba, K., Rao, S. et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 436, 112–116 (2005) doi:10.1038/nature03712

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