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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Angiotensin-converting enzyme 2 protects from severe acute lung failure</title><author><name sortKey="Imai, Yumiko" sort="Imai, Yumiko" uniqKey="Imai Y" first="Yumiko" last="Imai">Yumiko Imai</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.417521.4</institution-id><institution-id institution-id-type="ISNI">0000 0001 0008 2788</institution-id><institution>IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences,</institution></institution-wrap>A-1030 Vienna, Austria</nlm:aff></affiliation></author><author><name sortKey="Kuba, Keiji" sort="Kuba, Keiji" uniqKey="Kuba K" first="Keiji" last="Kuba">Keiji Kuba</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.417521.4</institution-id><institution-id institution-id-type="ISNI">0000 0001 0008 2788</institution-id><institution>IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences,</institution></institution-wrap>A-1030 Vienna, Austria</nlm:aff></affiliation></author><author><name sortKey="Rao, Shuan" sort="Rao, Shuan" uniqKey="Rao S" first="Shuan" last="Rao">Shuan Rao</name><affiliation><nlm:aff id="Aff2">National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 100005 Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Huan, Yi" sort="Huan, Yi" uniqKey="Huan Y" first="Yi" last="Huan">Yi Huan</name><affiliation><nlm:aff id="Aff2">National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 100005 Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Guo, Feng" sort="Guo, Feng" uniqKey="Guo F" first="Feng" last="Guo">Feng Guo</name><affiliation><nlm:aff id="Aff2">National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 100005 Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Guan, Bin" sort="Guan, Bin" uniqKey="Guan B" first="Bin" last="Guan">Bin Guan</name><affiliation><nlm:aff id="Aff2">National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 100005 Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Yang, Peng" sort="Yang, Peng" uniqKey="Yang P" first="Peng" last="Yang">Peng Yang</name><affiliation><nlm:aff id="Aff2">National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 100005 Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Sarao, Renu" sort="Sarao, Renu" uniqKey="Sarao R" first="Renu" last="Sarao">Renu Sarao</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.417521.4</institution-id><institution-id institution-id-type="ISNI">0000 0001 0008 2788</institution-id><institution>IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences,</institution></institution-wrap>A-1030 Vienna, Austria</nlm:aff></affiliation></author><author><name sortKey="Wada, Teiji" sort="Wada, Teiji" uniqKey="Wada T" first="Teiji" last="Wada">Teiji Wada</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.417521.4</institution-id><institution-id institution-id-type="ISNI">0000 0001 0008 2788</institution-id><institution>IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences,</institution></institution-wrap>A-1030 Vienna, Austria</nlm:aff></affiliation></author><author><name sortKey="Leong Poi, Howard" sort="Leong Poi, Howard" uniqKey="Leong Poi H" first="Howard" last="Leong-Poi">Howard Leong-Poi</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="GRID">grid.415502.7</institution-id><institution>Department of Cardiology,</institution><institution>St. Michael's Hospital,</institution></institution-wrap>Ontario M5B 1W8 Toronto, Canada</nlm:aff></affiliation></author><author><name sortKey="Crackower, Michael A" sort="Crackower, Michael A" uniqKey="Crackower M" first="Michael A." last="Crackower">Michael A. Crackower</name><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="GRID">grid.292545.d</institution-id><institution>Department of Biochemistry and Molecular Biology,</institution><institution>Merck Frosst Centre for Therapeutic Research,</institution></institution-wrap>Quebec H3R 4P8 Montreal, Canada</nlm:aff></affiliation></author><author><name sortKey="Fukamizu, Akiyoshi" sort="Fukamizu, Akiyoshi" uniqKey="Fukamizu A" first="Akiyoshi" last="Fukamizu">Akiyoshi Fukamizu</name><affiliation><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="GRID">grid.20515.33</institution-id><institution-id institution-id-type="ISNI">0000 0001 2369 4728</institution-id><institution>Center for Tsukuba Advanced Research Alliance,</institution><institution>University of Tsukuba,</institution></institution-wrap>305-8577 Tsukuba, Japan</nlm:aff></affiliation></author><author><name sortKey="Hui, Chi Chung" sort="Hui, Chi Chung" uniqKey="Hui C" first="Chi-Chung" last="Hui">Chi-Chung Hui</name><affiliation><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="GRID">grid.17063.33</institution-id><institution-id institution-id-type="ISNI">0000 0001 2157 2938</institution-id><institution>Program in Developmental Biology, The Hospital for Sick Children and Department of Molecular and Medical Genetics,</institution><institution>University of Toronto,</institution></institution-wrap>Ontario MG5 1X8 Toronto, Canada</nlm:aff></affiliation></author><author><name sortKey="Hein, Lutz" sort="Hein, Lutz" uniqKey="Hein L" first="Lutz" last="Hein">Lutz Hein</name><affiliation><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="GRID">grid.5963.9</institution-id><institution>Department of Pharmacology,</institution><institution>University of Freiburg,</institution></institution-wrap>79104 Freiburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Uhlig, Stefan" sort="Uhlig, Stefan" uniqKey="Uhlig S" first="Stefan" last="Uhlig">Stefan Uhlig</name><affiliation><nlm:aff id="Aff8"><institution-wrap><institution-id institution-id-type="GRID">grid.418187.3</institution-id><institution-id institution-id-type="ISNI">0000 0004 0493 9170</institution-id><institution>Division of Pulmonary Pharmacology,</institution><institution>Research Center Borstel,</institution></institution-wrap>23845 Borstel, Germany</nlm:aff></affiliation></author><author><name sortKey="Slutsky, Arthur S" sort="Slutsky, Arthur S" uniqKey="Slutsky A" first="Arthur S." last="Slutsky">Arthur S. Slutsky</name><affiliation><nlm:aff id="Aff9"><institution-wrap><institution-id institution-id-type="GRID">grid.17063.33</institution-id><institution-id institution-id-type="ISNI">0000 0001 2157 2938</institution-id><institution>Department of Medicine and Interdepartmental Division of Critical Care,</institution><institution>University of Toronto, St. Michael's Hospital,</institution></institution-wrap>Ontario M5B 1W8 Toronto, Canada</nlm:aff></affiliation></author><author><name sortKey="Jiang, Chengyu" sort="Jiang, Chengyu" uniqKey="Jiang C" first="Chengyu" last="Jiang">Chengyu Jiang</name><affiliation><nlm:aff id="Aff2">National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 100005 Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Penninger, Josef M" sort="Penninger, Josef M" uniqKey="Penninger J" first="Josef M." last="Penninger">Josef M. Penninger</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.417521.4</institution-id><institution-id institution-id-type="ISNI">0000 0001 0008 2788</institution-id><institution>IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences,</institution></institution-wrap>A-1030 Vienna, Austria</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">16001071</idno><idno type="pmc">7094998</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094998</idno><idno type="RBID">PMC:7094998</idno><idno type="doi">10.1038/nature03712</idno><date when="2005">2005</date><idno type="wicri:Area/Pmc/Corpus">000448</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000448</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Angiotensin-converting enzyme 2 protects from severe acute lung failure</title><author><name sortKey="Imai, Yumiko" sort="Imai, Yumiko" uniqKey="Imai Y" first="Yumiko" last="Imai">Yumiko Imai</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.417521.4</institution-id><institution-id institution-id-type="ISNI">0000 0001 0008 2788</institution-id><institution>IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences,</institution></institution-wrap>A-1030 Vienna, Austria</nlm:aff></affiliation></author><author><name sortKey="Kuba, Keiji" sort="Kuba, Keiji" uniqKey="Kuba K" first="Keiji" last="Kuba">Keiji Kuba</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.417521.4</institution-id><institution-id institution-id-type="ISNI">0000 0001 0008 2788</institution-id><institution>IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences,</institution></institution-wrap>A-1030 Vienna, Austria</nlm:aff></affiliation></author><author><name sortKey="Rao, Shuan" sort="Rao, Shuan" uniqKey="Rao S" first="Shuan" last="Rao">Shuan Rao</name><affiliation><nlm:aff id="Aff2">National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 100005 Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Huan, Yi" sort="Huan, Yi" uniqKey="Huan Y" first="Yi" last="Huan">Yi Huan</name><affiliation><nlm:aff id="Aff2">National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 100005 Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Guo, Feng" sort="Guo, Feng" uniqKey="Guo F" first="Feng" last="Guo">Feng Guo</name><affiliation><nlm:aff id="Aff2">National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 100005 Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Guan, Bin" sort="Guan, Bin" uniqKey="Guan B" first="Bin" last="Guan">Bin Guan</name><affiliation><nlm:aff id="Aff2">National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 100005 Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Yang, Peng" sort="Yang, Peng" uniqKey="Yang P" first="Peng" last="Yang">Peng Yang</name><affiliation><nlm:aff id="Aff2">National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 100005 Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Sarao, Renu" sort="Sarao, Renu" uniqKey="Sarao R" first="Renu" last="Sarao">Renu Sarao</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.417521.4</institution-id><institution-id institution-id-type="ISNI">0000 0001 0008 2788</institution-id><institution>IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences,</institution></institution-wrap>A-1030 Vienna, Austria</nlm:aff></affiliation></author><author><name sortKey="Wada, Teiji" sort="Wada, Teiji" uniqKey="Wada T" first="Teiji" last="Wada">Teiji Wada</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.417521.4</institution-id><institution-id institution-id-type="ISNI">0000 0001 0008 2788</institution-id><institution>IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences,</institution></institution-wrap>A-1030 Vienna, Austria</nlm:aff></affiliation></author><author><name sortKey="Leong Poi, Howard" sort="Leong Poi, Howard" uniqKey="Leong Poi H" first="Howard" last="Leong-Poi">Howard Leong-Poi</name><affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="GRID">grid.415502.7</institution-id><institution>Department of Cardiology,</institution><institution>St. Michael's Hospital,</institution></institution-wrap>Ontario M5B 1W8 Toronto, Canada</nlm:aff></affiliation></author><author><name sortKey="Crackower, Michael A" sort="Crackower, Michael A" uniqKey="Crackower M" first="Michael A." last="Crackower">Michael A. Crackower</name><affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="GRID">grid.292545.d</institution-id><institution>Department of Biochemistry and Molecular Biology,</institution><institution>Merck Frosst Centre for Therapeutic Research,</institution></institution-wrap>Quebec H3R 4P8 Montreal, Canada</nlm:aff></affiliation></author><author><name sortKey="Fukamizu, Akiyoshi" sort="Fukamizu, Akiyoshi" uniqKey="Fukamizu A" first="Akiyoshi" last="Fukamizu">Akiyoshi Fukamizu</name><affiliation><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="GRID">grid.20515.33</institution-id><institution-id institution-id-type="ISNI">0000 0001 2369 4728</institution-id><institution>Center for Tsukuba Advanced Research Alliance,</institution><institution>University of Tsukuba,</institution></institution-wrap>305-8577 Tsukuba, Japan</nlm:aff></affiliation></author><author><name sortKey="Hui, Chi Chung" sort="Hui, Chi Chung" uniqKey="Hui C" first="Chi-Chung" last="Hui">Chi-Chung Hui</name><affiliation><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="GRID">grid.17063.33</institution-id><institution-id institution-id-type="ISNI">0000 0001 2157 2938</institution-id><institution>Program in Developmental Biology, The Hospital for Sick Children and Department of Molecular and Medical Genetics,</institution><institution>University of Toronto,</institution></institution-wrap>Ontario MG5 1X8 Toronto, Canada</nlm:aff></affiliation></author><author><name sortKey="Hein, Lutz" sort="Hein, Lutz" uniqKey="Hein L" first="Lutz" last="Hein">Lutz Hein</name><affiliation><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="GRID">grid.5963.9</institution-id><institution>Department of Pharmacology,</institution><institution>University of Freiburg,</institution></institution-wrap>79104 Freiburg, Germany</nlm:aff></affiliation></author><author><name sortKey="Uhlig, Stefan" sort="Uhlig, Stefan" uniqKey="Uhlig S" first="Stefan" last="Uhlig">Stefan Uhlig</name><affiliation><nlm:aff id="Aff8"><institution-wrap><institution-id institution-id-type="GRID">grid.418187.3</institution-id><institution-id institution-id-type="ISNI">0000 0004 0493 9170</institution-id><institution>Division of Pulmonary Pharmacology,</institution><institution>Research Center Borstel,</institution></institution-wrap>23845 Borstel, Germany</nlm:aff></affiliation></author><author><name sortKey="Slutsky, Arthur S" sort="Slutsky, Arthur S" uniqKey="Slutsky A" first="Arthur S." last="Slutsky">Arthur S. Slutsky</name><affiliation><nlm:aff id="Aff9"><institution-wrap><institution-id institution-id-type="GRID">grid.17063.33</institution-id><institution-id institution-id-type="ISNI">0000 0001 2157 2938</institution-id><institution>Department of Medicine and Interdepartmental Division of Critical Care,</institution><institution>University of Toronto, St. Michael's Hospital,</institution></institution-wrap>Ontario M5B 1W8 Toronto, Canada</nlm:aff></affiliation></author><author><name sortKey="Jiang, Chengyu" sort="Jiang, Chengyu" uniqKey="Jiang C" first="Chengyu" last="Jiang">Chengyu Jiang</name><affiliation><nlm:aff id="Aff2">National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 100005 Beijing, China</nlm:aff></affiliation></author><author><name sortKey="Penninger, Josef M" sort="Penninger, Josef M" uniqKey="Penninger J" first="Josef M." last="Penninger">Josef M. Penninger</name><affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="GRID">grid.417521.4</institution-id><institution-id institution-id-type="ISNI">0000 0001 0008 2788</institution-id><institution>IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences,</institution></institution-wrap>A-1030 Vienna, Austria</nlm:aff></affiliation></author></analytic><series><title level="j">Nature</title><idno type="ISSN">0028-0836</idno><idno type="eISSN">1476-4687</idno><imprint><date when="2005">2005</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Drug hope for SARS</title><p id="Par1">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 (<italic>Nature</italic><bold>426</bold>, 450–454; 2003) to be a receptor for the SARS coronavirus.</p><sec><title>Supplementary information</title><p>The online version of this article (doi:10.1038/nature03712) contains supplementary material, which is available to authorized users.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Hudson, Ld" uniqKey="Hudson L">LD Hudson</name></author><author><name sortKey="Milberg, Ja" uniqKey="Milberg J">JA Milberg</name></author><author><name sortKey="Anardi, D" uniqKey="Anardi D">D Anardi</name></author><author><name sortKey="Maunder, Rj" uniqKey="Maunder R">RJ Maunder</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ware, Lb" uniqKey="Ware L">LB Ware</name></author><author><name sortKey="Matthay, Ma" uniqKey="Matthay M">MA 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uniqKey="Townsley M">MI Townsley</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Goggel, R" uniqKey="Goggel R">R Goggel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hansen, Tn" uniqKey="Hansen T">TN Hansen</name></author><author><name sortKey="Le Blanc, Al" uniqKey="Le Blanc A">AL Le Blanc</name></author><author><name sortKey="Gest, Al" uniqKey="Gest A">AL Gest</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Marshall, Rp" uniqKey="Marshall R">RP Marshall</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Nature</journal-id><journal-id journal-id-type="iso-abbrev">Nature</journal-id><journal-title-group><journal-title>Nature</journal-title></journal-title-group><issn pub-type="ppub">0028-0836</issn><issn pub-type="epub">1476-4687</issn><publisher><publisher-name>Nature Publishing Group UK</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">16001071</article-id><article-id pub-id-type="pmc">7094998</article-id><article-id pub-id-type="publisher-id">BFnature03712</article-id><article-id pub-id-type="doi">10.1038/nature03712</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Angiotensin-converting enzyme 2 protects from severe acute lung failure</article-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Imai</surname><given-names>Yumiko</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Kuba</surname><given-names>Keiji</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Rao</surname><given-names>Shuan</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Huan</surname><given-names>Yi</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Guo</surname><given-names>Feng</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Guan</surname><given-names>Bin</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Peng</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Sarao</surname><given-names>Renu</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Wada</surname><given-names>Teiji</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Leong-Poi</surname><given-names>Howard</given-names></name><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Crackower</surname><given-names>Michael A.</given-names></name><xref ref-type="aff" rid="Aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Fukamizu</surname><given-names>Akiyoshi</given-names></name><xref ref-type="aff" rid="Aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Hui</surname><given-names>Chi-Chung</given-names></name><xref ref-type="aff" rid="Aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Hein</surname><given-names>Lutz</given-names></name><xref ref-type="aff" rid="Aff7">7</xref></contrib><contrib contrib-type="author"><name><surname>Uhlig</surname><given-names>Stefan</given-names></name><xref ref-type="aff" rid="Aff8">8</xref></contrib><contrib contrib-type="author"><name><surname>Slutsky</surname><given-names>Arthur S.</given-names></name><xref ref-type="aff" rid="Aff9">9</xref></contrib><contrib contrib-type="author"><name><surname>Jiang</surname><given-names>Chengyu</given-names></name><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Penninger</surname><given-names>Josef M.</given-names></name><address><email>Josef.penninger@imba.oeaw.ac.at</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="GRID">grid.417521.4</institution-id><institution-id institution-id-type="ISNI">0000 0001 0008 2788</institution-id><institution>IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences,</institution></institution-wrap>A-1030 Vienna, Austria</aff><aff id="Aff2"><label>2</label>National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 100005 Beijing, China</aff><aff id="Aff3"><label>3</label><institution-wrap><institution-id institution-id-type="GRID">grid.415502.7</institution-id><institution>Department of Cardiology,</institution><institution>St. Michael's Hospital,</institution></institution-wrap>Ontario M5B 1W8 Toronto, Canada</aff><aff id="Aff4"><label>4</label><institution-wrap><institution-id institution-id-type="GRID">grid.292545.d</institution-id><institution>Department of Biochemistry and Molecular Biology,</institution><institution>Merck Frosst Centre for Therapeutic Research,</institution></institution-wrap>Quebec H3R 4P8 Montreal, Canada</aff><aff id="Aff5"><label>5</label><institution-wrap><institution-id institution-id-type="GRID">grid.20515.33</institution-id><institution-id institution-id-type="ISNI">0000 0001 2369 4728</institution-id><institution>Center for Tsukuba Advanced Research Alliance,</institution><institution>University of Tsukuba,</institution></institution-wrap>305-8577 Tsukuba, Japan</aff><aff id="Aff6"><label>6</label><institution-wrap><institution-id institution-id-type="GRID">grid.17063.33</institution-id><institution-id institution-id-type="ISNI">0000 0001 2157 2938</institution-id><institution>Program in Developmental Biology, The Hospital for Sick Children and Department of Molecular and Medical Genetics,</institution><institution>University of Toronto,</institution></institution-wrap>Ontario MG5 1X8 Toronto, Canada</aff><aff id="Aff7"><label>7</label><institution-wrap><institution-id institution-id-type="GRID">grid.5963.9</institution-id><institution>Department of Pharmacology,</institution><institution>University of Freiburg,</institution></institution-wrap>79104 Freiburg, Germany</aff><aff id="Aff8"><label>8</label><institution-wrap><institution-id institution-id-type="GRID">grid.418187.3</institution-id><institution-id institution-id-type="ISNI">0000 0004 0493 9170</institution-id><institution>Division of Pulmonary Pharmacology,</institution><institution>Research Center Borstel,</institution></institution-wrap>23845 Borstel, Germany</aff><aff id="Aff9"><label>9</label><institution-wrap><institution-id institution-id-type="GRID">grid.17063.33</institution-id><institution-id institution-id-type="ISNI">0000 0001 2157 2938</institution-id><institution>Department of Medicine and Interdepartmental Division of Critical Care,</institution><institution>University of Toronto, St. Michael's Hospital,</institution></institution-wrap>Ontario M5B 1W8 Toronto, Canada</aff></contrib-group><pub-date pub-type="ppub"><year>2005</year></pub-date><volume>436</volume><issue>7047</issue><fpage>112</fpage><lpage>116</lpage><history><date date-type="received"><day>11</day><month>2</month><year>2005</year></date><date date-type="accepted"><day>29</day><month>4</month><year>2005</year></date></history><permissions><copyright-statement>© Nature Publishing Group 2005</copyright-statement><license><license-p>This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.</license-p></license></permissions><abstract id="Abs1" abstract-type="LongSummary"><title>Drug hope for SARS</title><p id="Par1">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 (<italic>Nature</italic><bold>426</bold>, 450–454; 2003) to be a receptor for the SARS coronavirus.</p><sec><title>Supplementary information</title><p>The online version of this article (doi:10.1038/nature03712) contains supplementary material, which is available to authorized users.</p></sec></abstract><abstract id="Abs2"><p id="Par2">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 <xref ref-type="bibr" rid="CR1">1–3</xref>). Predisposing factors for ARDS are diverse<sup><xref ref-type="bibr" rid="CR1">1</xref>,<xref ref-type="bibr" rid="CR3">3</xref></sup> and include sepsis, aspiration, pneumonias and infections with the severe acute respiratory syndrome (SARS) coronavirus<sup><xref ref-type="bibr" rid="CR4">4</xref>,<xref ref-type="bibr" rid="CR5">5</xref></sup>. At present, there are no effective drugs for improving the clinical outcome of ARDS<sup><xref ref-type="bibr" rid="CR1">1</xref>,<xref ref-type="bibr" rid="CR2">2</xref>,<xref ref-type="bibr" rid="CR3">3</xref></sup>. Angiotensin-converting enzyme (ACE) and ACE2 are homologues with different key functions in the renin–angiotensin system<sup><xref ref-type="bibr" rid="CR6">6</xref>,<xref ref-type="bibr" rid="CR7">7</xref>,<xref ref-type="bibr" rid="CR8">8</xref></sup>. 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<sup><xref ref-type="bibr" rid="CR9">9</xref>,<xref ref-type="bibr" rid="CR10">10</xref></sup>. Here we report that ACE2 and the angiotensin II type 2 receptor (AT<sub>2</sub>) 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 (AT<sub>1</sub>a), promote disease pathogenesis, induce lung oedemas and impair lung function. We show that mice deficient for <italic>Ace</italic> 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.</p><sec><title>Supplementary information</title><p>The online version of this article (doi:10.1038/nature03712) contains supplementary material, which is available to authorized users.</p></sec></abstract><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© Springer Nature Limited 2005</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="Sec1"><title>Main</title><p id="Par3">The renin–angiotensin system has an important role in maintaining blood pressure homeostasis, as well as fluid and salt balance<sup><xref ref-type="bibr" rid="CR11">11</xref>,<xref ref-type="bibr" rid="CR12">12</xref>,<xref ref-type="bibr" rid="CR13">13</xref></sup>. ACE2 is a homologue of ACE, and functions a negative regulator of the renin–angiotensin system<sup><xref ref-type="bibr" rid="CR6">6</xref>,<xref ref-type="bibr" rid="CR7">7</xref>,<xref ref-type="bibr" rid="CR8">8</xref></sup>. Although ACE2 is expressed in the lungs of humans<sup><xref ref-type="bibr" rid="CR10">10</xref></sup> and mice (see <xref rid="MOESM1" ref-type="media">Supplementary Fig. 1a, b</xref>), nothing is known about its function in the lungs. However, mortality following SARS coronavirus infections approaches almost 10% owing to the development of ARDS<sup><xref ref-type="bibr" rid="CR14">14</xref>,<xref ref-type="bibr" rid="CR15">15</xref>,<xref ref-type="bibr" rid="CR16">16</xref></sup>. To elucidate the role of ACE2 in acute lung injury, we examined the effect of <italic>Ace2</italic> gene deficiency in mouse experimental models that mimic the common lung failure pathology observed in several human diseases, including sepsis, acid aspiration and pneumonias such as SARS and avian influenza A<sup><xref ref-type="bibr" rid="CR17">17</xref></sup>.</p><p id="Par4">Aspiration of gastric contents with a low pH is a frequent cause of acute lung injury/ARDS<sup><xref ref-type="bibr" rid="CR1">1</xref>,<xref ref-type="bibr" rid="CR2">2</xref>,<xref ref-type="bibr" rid="CR3">3</xref></sup>. Acid aspiration in wild-type mice, which mimics human acute lung injury<sup><xref ref-type="bibr" rid="CR18">18</xref>,<xref ref-type="bibr" rid="CR19">19</xref></sup>, resulted in rapid impairment of lung functions assessed by increased lung elastance (a measure of the change in pressure achieved per unit change in volume, representing the stiffness of the lungs) (<xref rid="Fig1" ref-type="fig">Fig. 1a</xref>), decreased blood oxygenation (<xref rid="Fig1" ref-type="fig">Fig. 1b</xref>) and the development of pulmonary oedema (<xref rid="Fig1" ref-type="fig">Fig. 1c</xref>). Acid aspiration resulted in increased alveolar wall thickness, oedema, bleeding, inflammatory cell infiltrates and formation of hyaline membranes (<xref rid="Fig1" ref-type="fig">Fig. 1d</xref>). Notably, acid-treated <italic>Ace2</italic> knockout mice<sup><xref ref-type="bibr" rid="CR8">8</xref></sup> showed significantly greater lung elastance compared with control wild-type mice, but there were no differences in lung elastance between saline-treated <italic>Ace2</italic> knockout and wild-type mice (<xref rid="Fig1" ref-type="fig">Fig. 1a</xref>). Moreover, loss of <italic>Ace2</italic> resulted in worsened oxygenation (<xref rid="Fig1" ref-type="fig">Fig. 1b</xref>), massive lung oedema (<xref rid="Fig1" ref-type="fig">Fig. 1c</xref>), increased inflammatory cell infiltration and hyaline membrane formations (<xref rid="Fig1" ref-type="fig">Fig. 1d</xref>) in response to acid aspiration. It should be noted that ACE2 protein expression is typically downregulated in wild-type mice following acid challenge (<xref rid="Fig1" ref-type="fig">Fig. 1e</xref>).<fig id="Fig1"><label>Figure 1</label><caption><title><bold>Loss of ACE2 worsens acid aspiration-induced acute lung injury.</bold></title><p><bold>a</bold>, Lung elastance after acid or saline treatment in wild type (WT) and <italic>Ace2</italic> knockout (<italic>Ace2</italic> KO) mice (<italic>n</italic> = 10 for acid-treated groups, <italic>n</italic> = 6 for saline-treated groups). <italic>P</italic> < 0.05 for the whole time course comparing acid-treated WT and <italic>Ace2</italic> knockout mice. <bold>b</bold>, Partial pressure of oxygen in arterial blood (<inline-formula id="IEq2"><mml:math id="M1"><mml:msub><mml:mi>p</mml:mi><mml:mrow><mml:msub><mml:mrow><mml:mtext>aO</mml:mtext></mml:mrow><mml:mn>2</mml:mn></mml:msub></mml:mrow></mml:msub></mml:math></inline-formula>) in acid-induced acute lung injury. <bold>c</bold>, Wet-to-dry weight ratios of lungs 3 h after acid injury. Single asterisk, <italic>P</italic> < 0.05; double asterisk, <italic>P</italic> < 0.01. <bold>d</bold>, Lung histopathology. Note the enhanced hyaline membrane formation, inflammatory cell infiltration and lung oedema in acid-treated <italic>Ace2</italic> knockout mice (H&E staining, ×200). <bold>e</bold>, ACE and ACE2 protein expression in total lysates from control lungs and lungs 3 h after acid injury. Error bars indicate s.e.m.</p></caption><graphic xlink:href="41586_2005_Article_BFnature03712_Fig1_HTML" id="d29e655"></graphic></fig></p><p id="Par5">Sepsis is the most common cause of acute lung injury/ARDS<sup><xref ref-type="bibr" rid="CR1">1</xref>,<xref ref-type="bibr" rid="CR2">2</xref>,<xref ref-type="bibr" rid="CR3">3</xref></sup>. We therefore examined the effect of <italic>Ace2</italic> gene deficiency on sepsis-induced acute lung injury using caecal ligation and perforation (CLP)<sup><xref ref-type="bibr" rid="CR20">20</xref></sup>. CLP causes lethal peritonitis and sepsis due to a polymicrobial infection that is accompanied by acute lung failure<sup><xref ref-type="bibr" rid="CR20">20</xref></sup>. Whereas all CLP-treated wild-type mice survived, only two out of ten CLP-treated <italic>Ace2</italic> knockout mice survived the 6 h experimental observation period (<xref rid="Fig2" ref-type="fig">Fig. 2a</xref>). CLP resulted in lung failure defined by increased elastance (<xref rid="Fig2" ref-type="fig">Fig. 2a</xref>), pulmonary oedema (<xref rid="Fig2" ref-type="fig">Fig. 2b</xref>) and leukocyte accumulation (<xref rid="Fig2" ref-type="fig">Fig. 2c</xref>) in wild-type mice. CLP-treated <italic>Ace2</italic> knockout mice had a marked worsening of lung functions (<xref rid="Fig2" ref-type="fig">Fig. 2a</xref>), increased oedema (<xref rid="Fig2" ref-type="fig">Fig. 2b</xref>) and leukocyte accumulation (<xref rid="Fig2" ref-type="fig">Fig. 2c</xref>) compared with wild-type mice. In addition, <italic>Ace2</italic> knockout mice also developed markedly enhanced acute lung injury after endotoxin challenge<sup><xref ref-type="bibr" rid="CR18">18</xref></sup> (see <xref rid="MOESM1" ref-type="media">Supplementary Fig. 2a–c</xref>). <italic>Ace2</italic> maps to the X chromosome, and it should be noted that loss of ACE2 expression resulted in equally severe acute lung injury phenotypes in male (<italic>Ace2</italic><sup>-/y</sup>) and female (<italic>Ace2</italic><sup>-/-</sup>) mice. Our data from three different acute lung injury models show that loss of <italic>Ace2</italic> expression precipitates severe acute lung failure.<fig id="Fig2"><label>Figure 2</label><caption><title><bold>ACE2 controls acute lung failure.</bold></title><p><bold>a</bold>, Lung elastance after acute lung injury in WT and <italic>Ace2</italic> knockout (KO) mice induced by caecal ligation perforation (CLP). Eighteen hours after sham or CLP surgery, animals received mechanical ventilation for 6 h (<italic>n</italic> = 10 in CLP-treated groups, <italic>n</italic> = 6 in sham-treated groups). As 8/10 CLP-treated <italic>Ace2</italic> knockout mice died at 4–4.5 h, only data up to 4 h are shown. CLP-treated <italic>Ace2</italic> knockout mice had significantly higher elastance than CLP-treated WT mice (<italic>P</italic> < 0.01). <bold>b</bold>, <bold>c</bold>, Wet-to-dry weight ratios of lungs (<bold>b</bold>) and lung histopathology (<bold>c</bold>) in sham or CLP-treated WT and <italic>Ace2</italic> knockout mice determined after 4 h of ventilation. Asterisk denotes a significant difference (<italic>P</italic> < 0.05) between CLP-treated WT and <italic>Ace2</italic> knockout mice. Note the enhanced lung oedema and inflammatory infiltrates in <italic>Ace2</italic> knockout mice (H&E staining, ×200). <bold>d</bold>, <bold>e</bold>, Lung elastance (<bold>d</bold>) and wet-to-dry weight ratios (<bold>e</bold>) after acid or saline instillation of <italic>Ace2</italic> knockout mice injected intraperitoneally with recombinant human ACE2 protein (rhuACE2; 0.1 mg kg<sup>-1</sup>), mutant rhuACE2 (mut-rhuACE2; 0.1 mg kg<sup>-1</sup>) or vehicle (<italic>n</italic> = 6 per group). Asterisk denotes a significant difference (<italic>P</italic> < 0.05) comparing rhuACE2-treated <italic>Ace2</italic> knockout mice with mut-rhuACE2-treated and vehicle-treated <italic>Ace2</italic> knockout mice at 3 h. <bold>f</bold>, Lung elastance after acid instillation in WT mice treated with rhuACE2 protein (0.1 mg kg<sup>-1</sup>), mut-rhuACE2 protein (0.1 mg kg<sup>-1</sup>) or vehicle (<italic>n</italic> = 6–8 per group). Asterisk denotes a significant difference (<italic>P</italic> < 0.05) between WT mice treated with rhuACE2 and mut-rhuACE2 or with vehicle at 3 h. Errors bars indicate s.e.m.</p></caption><graphic xlink:href="41586_2005_Article_BFnature03712_Fig2_HTML" id="d29e843"></graphic></fig></p><p id="Par6">To test whether loss of ACE2 is essential for disease pathogenesis, we performed a rescue experiment using recombinant human ACE2 protein (rhuACE2) (see <xref rid="MOESM1" ref-type="media">Supplementary Fig. 3a, b</xref>). Injection of rhuACE2 into acid-treated <italic>Ace2</italic> knockout mice decreased the degree of acute lung injury, as assessed by lung elastance (<xref rid="Fig2" ref-type="fig">Fig. 2d</xref>) and pulmonary oedema formation (<xref rid="Fig2" ref-type="fig">Fig. 2e</xref>). When we injected rhuACE2 protein into acid-treated wild-type mice, lung function (<xref rid="Fig2" ref-type="fig">Fig. 2f</xref>) and oedema formation (see <xref rid="MOESM1" ref-type="media">Supplementary Fig. 3c</xref>) were also rescued. In saline-treated wild-type or <italic>Ace2</italic> knockout mice, injections of rhuACE2 did not affect pulmonary functions (<xref rid="Fig2" ref-type="fig">Fig. 2d–f</xref>). Catalytically inactive ACE2 protein (mut-rhuACE2) (see <xref rid="MOESM1" ref-type="media">Supplementary Fig. 3a, b</xref>) did not rescue the severe lung phenotype in <italic>Ace2</italic> knockout mice (<xref rid="Fig2" ref-type="fig">Fig. 2d</xref>, <xref rid="Fig2" ref-type="fig">e</xref>) and had no effect on the severity of acute lung injury in wild-type animals (<xref rid="Fig2" ref-type="fig">Fig. 2f</xref> and <xref rid="MOESM1" ref-type="media">Supplementary Fig. 3c</xref>). These results show that the catalytic activity of ACE2 can directly protect lungs from acute lung injury.</p><p id="Par7">ACE2 is a homologue of ACE, both of which are central enzymes in the renin–angiotensin system<sup><xref ref-type="bibr" rid="CR6">6</xref>,<xref ref-type="bibr" rid="CR7">7</xref>,<xref ref-type="bibr" rid="CR8">8</xref></sup>. ACE cleaves the decapeptide angiotensin (Ang)I into the octapeptide AngII (refs <xref ref-type="bibr" rid="CR11">11</xref>, <xref ref-type="bibr" rid="CR12">12</xref>). ACE2 cleaves a single residue from AngI to generate Ang1–9 (refs <xref ref-type="bibr" rid="CR6">6</xref>, <xref ref-type="bibr" rid="CR7">7</xref>), and a residue from AngII to generate Ang1–7 (ref. <xref ref-type="bibr" rid="CR6">6</xref>). In this way, ACE2 negatively regulates the renin–angiotensin system by inactivating AngII (<xref rid="Fig3" ref-type="fig">Fig. 3a</xref>). Acid aspiration in wild-type mice resulted in marked downregulation of ACE2 protein, but ACE levels remained constant (<xref rid="Fig1" ref-type="fig">Fig. 1e</xref>). Moreover, only catalytically active ACE2 improved the acute lung injury phenotype in mutant and wild-type mice (<xref rid="Fig2" ref-type="fig">Fig. 2d–f</xref>). To clarify whether acute lung injury shifts the functional equilibrium between ACE and ACE2, we measured AngII levels in acid-treated and control mice. Acid aspiration markedly increased AngII levels in lungs (<xref rid="Fig3" ref-type="fig">Fig. 3b</xref>) and plasma (see <xref rid="MOESM1" ref-type="media">Supplementary Fig. 4a</xref>) of wild-type mice. We observed a further, significant increase in AngII levels in the lungs (<xref rid="Fig3" ref-type="fig">Fig. 3b</xref>) and plasma (see <xref rid="MOESM1" ref-type="media">Supplementary Fig. 4a</xref>) of acid-treated <italic>Ace2</italic> knockout mice. Thus, acute lung injury results in decreased ACE2 expression and increased production of AngII.<fig id="Fig3"><label>Figure 3</label><caption><title><bold>ACE deficiency reduces the severity of acute lung injury.</bold></title><p><bold>a</bold>, Schematic diagram of the renin–angiotensin system. <bold>b,</bold> Lung levels of AngII in control and acid-treated WT and <italic>Ace2</italic> knockout (KO) mice determined at 3 h by enzyme immunoassay (<italic>n</italic> = 3–5 per group). Asterisk denotes a significant difference (<italic>P</italic> < 0.05) between acid-treated WT and <italic>Ace2</italic> knockout mice. <bold>c</bold>, Lung elastance after acid instillation in <italic>Ace</italic><sup>+/+</sup> (WT), <italic>Ace</italic><sup>+/-</sup> and <italic>Ace</italic><sup>-/-</sup> mice (<italic>n</italic> = 4–6 mice per group). Asterisk denotes a significant difference (<italic>P</italic> < 0.05) comparing <italic>Ace</italic><sup>+/+</sup> with <italic>Ace</italic><sup>+/-</sup> and <italic>Ace</italic><sup>-/-</sup> mice at 3 h. <bold>d</bold>, <bold>e</bold>, Lung elastance (<bold>d</bold>) and wet-to-dry lung weight ratios (<bold>e</bold>) in acid- or saline-treated <italic>Ace</italic><sup>+/+</sup><italic>Ace2</italic> KO, <italic>Ace</italic><sup>+/-</sup><italic>Ace2</italic> KO, <italic>Ace</italic><sup>-/-</sup><italic>Ace2</italic> KO and WT mice (<italic>n</italic> = 5 per group). Asterisk denotes a significant difference (<italic>P</italic> < 0.05) comparing <italic>Ace2</italic> KO with WT, <italic>Ace</italic><sup>+/-</sup><italic>Ace2</italic> KO or <italic>Ace</italic><sup>-/-</sup><italic>Ace2</italic> KO mice 3 h after acid-treatment. <bold>f</bold>, Lung histopathology. Severe lung interstitial oedema and leukocyte infiltration in <italic>Ace2</italic> KO mice are attenuated by homozygous (<italic>Ace</italic><sup>-/-</sup>) or heterozygous (<italic>Ace</italic><sup>+/-</sup>) mutations of <italic>Ace</italic> (H&E staining, ×200). Error bars indicate s.e.m.</p></caption><graphic xlink:href="41586_2005_Article_BFnature03712_Fig3_HTML" id="d29e1092"></graphic></fig></p><p id="Par8">On the basis of these results we speculated that, in contrast to ACE2, ACE promotes disease pathogenesis through increased AngII production (<xref rid="Fig3" ref-type="fig">Fig. 3a</xref>). Indeed, genetic inactivation of <italic>Ace</italic> on an <italic>Ace2</italic> wild-type or <italic>Ace2</italic> knockout background markedly decreased AngII levels in lung and plasma in our acid injury model (see <xref rid="MOESM1" ref-type="media">Supplementary Fig. 4b, c</xref>). Moreover, treatment with rhuACE2 protein attenuated lung injury (<xref rid="Fig2" ref-type="fig">Fig. 2d–f</xref>) and further reduced AngII levels in the lungs of acid-treated mice (<xref rid="MOESM1" ref-type="media">Supplementary Fig. 4d</xref>). In contrast to <italic>Ace2</italic> knockout mice, <italic>Ace</italic><sup>-/-</sup> mice<sup><xref ref-type="bibr" rid="CR21">21</xref></sup> were partly protected against acute lung injury induced by acid-aspiration (<xref rid="Fig3" ref-type="fig">Fig. 3c</xref> and <xref rid="MOESM1" ref-type="media">Supplementary Fig. 5</xref>). These effects were dependent on gene dosage and were observed to a lesser extent in <italic>Ace</italic><sup>+/-</sup> mice. In addition, inactivation of <italic>Ace</italic> on an <italic>Ace2</italic> knockout background rescued the severe lung failure (<xref rid="Fig3" ref-type="fig">Fig. 3d</xref>), oedema formation (<xref rid="Fig3" ref-type="fig">Fig. 3e</xref>) and histological changes (<xref rid="Fig3" ref-type="fig">Fig. 3f</xref>) compared with <italic>Ace2</italic> knockout mice. Similarly, in endotoxin-induced acute lung injury, the severe lung impairments in <italic>Ace2</italic> knockout mice were reversed by additional <italic>Ace</italic> gene deficiency (see <xref rid="MOESM1" ref-type="media">Supplementary Fig. 6</xref>). Thus, ACE promotes acute lung injury pathology and ACE2 alleviates it.</p><p id="Par9">Both ACE and ACE2 are non-specific proteases that cleave additional substrates<sup><xref ref-type="bibr" rid="CR11">11</xref>,<xref ref-type="bibr" rid="CR12">12</xref></sup>. Thus, although increased levels of AngII have been correlated with <italic>Ace2</italic> deficiency, it has not been shown that upregulation of the AngII pathway accounts for the observed phenotypes of <italic>Ace2</italic> knockout mice <italic>in vivo</italic>. The receptors for AngII in mice are angiotensin II type 1a (AT<sub>1</sub>a) receptor<sup><xref ref-type="bibr" rid="CR22">22</xref></sup>, the type 1b (AT<sub>1</sub>b) receptor and the type 2 (AT<sub>2</sub>) receptor<sup><xref ref-type="bibr" rid="CR23">23</xref></sup>. AT<sub>1</sub>a and AT<sub>2</sub>, but not AT<sub>1</sub>b receptor expression is found in the lungs<sup><xref ref-type="bibr" rid="CR25">25</xref></sup>. We therefore explored which AngII receptor subtypes are responsible for ACE/ACE2 regulated acute lung injury, and whether AngII signalling through its receptors is responsible for ACE2-regulated lung pathology (<xref rid="Fig3" ref-type="fig">Fig. 3a</xref>). Compared with wild-type mice, genetic loss of AT<sub>1</sub>a receptor expression in <italic>Agtr1a</italic><sup>-/-</sup> mice<sup><xref ref-type="bibr" rid="CR24">24</xref></sup> markedly improved lung function (<xref rid="Fig4" ref-type="fig">Fig. 4a</xref>) and reduced oedema formation (see <xref rid="MOESM1" ref-type="media">Supplementary Fig. 7a</xref>). In contrast, inactivation of the AT<sub>2</sub> receptor (<italic>Agtr2</italic><sup>-/y</sup>)<sup><xref ref-type="bibr" rid="CR25">25</xref></sup> aggravated acute lung injury (<xref rid="Fig4" ref-type="fig">Fig. 4a</xref> and <xref rid="MOESM1" ref-type="media">Supplementary Fig. 7a</xref>). AngII levels induced by acid aspiration in both <italic>Agtr1a</italic><sup>-/-</sup> and <italic>Agtr2</italic><sup>-/y</sup> mice were comparable to those in wild-type controls (not shown).<fig id="Fig4"><label>Figure 4</label><caption><title><bold>The AngII receptor AT</bold><sub><bold>1</bold></sub><bold>a controls acute lung injury severity and pulmonary vascular permeability.</bold></title><p><bold>a</bold>, Lung elastance measurements in <italic>Agtr1a</italic><sup>-/-</sup> mice, <italic>Agtr2</italic><sup>-/<italic>y</italic></sup> mice and WT mice after acid aspiration (<italic>n</italic> = 4–6 per group). All acid-treated <italic>Agtr2</italic><sup>-/<italic>y</italic></sup> mice died after 2 h. There is a significant difference (<italic>P</italic> < 0.01) between acid-treated WT and acid-treated <italic>Agtr1a</italic><sup>-/-</sup> mice over the whole time course. Double asterisk denotes a significant difference (<italic>P</italic> < 0.01) between WT and <italic>Agtr2</italic><sup>-/<italic>y</italic></sup> mice at 2 h. <bold>b</bold>, Lung elastance measurements in <italic>Ace2</italic> knockout mice treated with vehicle or inhibitors to AT<sub>1</sub> (Losartan, 15 mg kg<sup>-1</sup>) or AT<sub>2</sub> (PD123.319, 15 mg kg<sup>-1</sup>) after acid or saline instillation (see Methods, <italic>n</italic> = 4–6 per group). Double asterisk denotes a significant difference (<italic>P</italic> < 0.01) comparing <italic>Ace2</italic> knockout mice treated with AT<sub>1</sub> inhibitor with vehicle or AT<sub>2</sub> inhibitor treatment at 3 h. <bold>c</bold>, Pulmonary vascular permeability as determined by intravenous injection of Evans Blue. Extravascular Evans Blue in lungs was measured in WT and <italic>Ace2</italic> knockout mice 3 h after acid injury (<italic>n</italic> = 5 per group). Double asterisk denotes a significant difference (<italic>P</italic> < 0.01) between acid-treated WT and <italic>Ace2</italic> knockout mice. <bold>d</bold>, Representative images of Evans Blue-injected lungs of WT and <italic>Ace2</italic> knockout mice 3 h after acid aspiration. <bold>e</bold>, Extravascular Evans Blue in lungs of WT and <italic>Agtr1a</italic><sup>-/-</sup> mice 3 h after acid injury (<italic>n</italic> = 5 per group). Asterisk denotes a significant difference (<italic>P</italic> < 0.05) between acid-treated WT and <italic>Agtr1a</italic><sup>-/-</sup> mice at 3 h. Error bars indicate s.e.m.</p></caption><graphic xlink:href="41586_2005_Article_BFnature03712_Fig4_HTML" id="d29e1408"></graphic></fig></p><p id="Par10">We next attempted to rescue acute lung injury in <italic>Ace2</italic> knockout mice using specific AT<sub>1</sub> and AT<sub>2</sub> receptor blockers. Pharmacological inhibition of AT<sub>1</sub> attenuated the severity of acid-induced lung injury in <italic>Ace2</italic> knockout mice (<xref rid="Fig4" ref-type="fig">Fig. 4b</xref> and <xref rid="MOESM1" ref-type="media">Supplementary Fig. 7b</xref>). Inhibition of AT<sub>2</sub> had no apparent effect on the acute lung injury phenotypes of <italic>Ace2</italic> knockout mice (<xref rid="Fig4" ref-type="fig">Fig. 4b</xref>). These data show that the AT<sub>1</sub>a and AT<sub>2</sub> receptors have opposite functions in controlling the severity of acute lung injury, and that actions of AngII through the AT<sub>1</sub>a receptor have a causative role in acute lung failure.</p><p id="Par11">Pulmonary oedema could arise from increased hydrostatic pressure (due to pulmonary vascular constriction) and/or enhanced microvascular permeability<sup><xref ref-type="bibr" rid="CR26">26</xref></sup>. We first tested whether AngII can increase hydrostatic pressure using isolated, perfused murine lungs <italic>ex vivo</italic><sup><xref ref-type="bibr" rid="CR27">27</xref></sup>. In this system, pulmonary perfusion pressures were comparable between wild-type and <italic>Ace2</italic> knockout mice under baseline control conditions (wild-type 3.0 ± 1.9 cm H<sub>2</sub>O, <italic>n</italic> = 6 versus <italic>Ace2</italic> knockout 1.8 ± 1.6 cm H<sub>2</sub>O, <italic>n</italic> = 9; mean ± s.e.m,), and these values were not changed by either acid-treatment or continuous perfusion of the bacterial endotoxin lipopolysaccharide (LPS). Pulmonary perfusion pressures generated by AngI or AngII injection into lungs of acid-instilled animals or into lungs perfused with LPS were also similar between wild-type and <italic>Ace2</italic> knockout mice (see <xref rid="MOESM1" ref-type="media">Supplementary Fig. 8a, b</xref>). Moreover, fractional shortening using echocardiography (an indicator of left ventricular systolic function) and mean arterial pressures were comparable between <italic>Ace2</italic> knockout and wild-type mice during the experimental period (see <xref rid="MOESM1" ref-type="media">Supplementary Fig. 9a, b</xref>). Thus, the severe lung oedemas in <italic>Ace2</italic> knockout mice do not seem to be secondary to systemic haemodynamic alterations.</p><p id="Par12">As enhanced pulmonary vascular permeability is a hallmark of acute lung injury/ARDS in humans<sup><xref ref-type="bibr" rid="CR2">2</xref></sup>, we examined whether loss of <italic>Ace2</italic> results in increased vascular permeability using Evans Blue dye injections as an <italic>in vivo</italic> indicator of albumin leakage<sup><xref ref-type="bibr" rid="CR28">28</xref></sup>. Acid aspiration increased vascular permeability in wild-type mice. In <italic>Ace2</italic> knockout mice, pulmonary Evans Blue accumulation was greatly increased after acid aspiration (<xref rid="Fig4" ref-type="fig">Fig. 4c</xref>, <xref rid="Fig4" ref-type="fig">d</xref>). These results were confirmed using fluorescein isothiocyanate (FITC)-conjugated dextran (40 kDa) as another marker to assess vascular leakage of macromolecules (data not shown). Vascular permeability was significantly attenuated in the lungs of <italic>Agtr1a</italic><sup>-/-</sup> mice (<xref rid="Fig4" ref-type="fig">Fig. 4e</xref>). We suggest that loss of ACE2 expression in acute lung injury leads to leaky pulmonary blood vessels through AT<sub>1</sub>a receptor stimulation. However, hydrostatic oedemas cannot be excluded, and the effects of local AngII production on lung blood vessels require further investigation<sup><xref ref-type="bibr" rid="CR27">27</xref>,<xref ref-type="bibr" rid="CR29">29</xref></sup>.</p><p id="Par13">ARDS is the most severe form of a wide spectrum of pathological processes designated as acute lung injury<sup><xref ref-type="bibr" rid="CR2">2</xref></sup>. ARDS is characterized by pulmonary oedema due to increased vascular permeability, the accumulation of inflammatory cells and severe hypoxia<sup><xref ref-type="bibr" rid="CR2">2</xref></sup>. Predisposing factors for ARDS include sepsis, aspiration and pneumonias (including infections with SARS coronavirus<sup><xref ref-type="bibr" rid="CR1">1</xref>,<xref ref-type="bibr" rid="CR2">2</xref>,<xref ref-type="bibr" rid="CR3">3</xref>,<xref ref-type="bibr" rid="CR4">4</xref>,<xref ref-type="bibr" rid="CR5">5</xref></sup> or avian and human influenza viruses<sup><xref ref-type="bibr" rid="CR17">17</xref></sup>). Our data show that acute lung injury results in a marked downregulation of ACE2, a key enzyme involved in the regulation of the renin–angiotensin system.</p><p id="Par14">It has been previously shown that an insertion/deletion ACE polymorphism that affects ACE activity is associated with ARDS susceptibility and outcome<sup><xref ref-type="bibr" rid="CR30">30</xref></sup>. Our data provide a mechanistic explanation for these clinical findings and indicate that, in the pathogenesis of acute lung injury, AngII is upregulated by ACE and drives severe lung failure through the AT<sub>1</sub>a receptor. On the other hand, ACE2 and the AT<sub>2</sub> receptor protect against lung injury. Exogenous recombinant human ACE2 attenuates acute lung failure in <italic>Ace2</italic> knockout as well as in wild-type mice. This combination of genetic, pharmacological and protein rescue experiments defines a new and critical role for the renin–angiotensin system in the pathogenesis of acute lung injury, and show that ACE2 is a key molecule involved in the development and progression of acute lung failure.</p></sec><sec id="Sec2"><title>Methods</title><p id="Par15">For detailed methods please refer to the <xref rid="MOESM1" ref-type="media">Supplementary Information</xref>.</p><sec id="Sec3"><title>Animals</title><p id="Par16"><italic>Ace2</italic>, <italic>Ace,</italic><italic>Agtr1a</italic> and <italic>Agtr2</italic> mutant mice have previously been described<sup><xref ref-type="bibr" rid="CR2">2</xref>,<xref ref-type="bibr" rid="CR4">4</xref>,<xref ref-type="bibr" rid="CR5">5</xref>,<xref ref-type="bibr" rid="CR6">6</xref></sup>. Sex-, age-, and background-matched mice were used as controls. Basal lung functions and lung structure were comparable among all the mice tested. Mice were handled in accordance with institutional guidelines.</p></sec><sec id="Sec4"><title>Experimental murine models of acute lung injury</title><p id="Par17">For acid aspiration-induced acute lung injury, anaesthesized mice were intratracheally instilled with HCl (pH 1.5; 2 ml kg<sup>-1</sup>) and ventilated for 3 h (refs <xref ref-type="bibr" rid="CR18">18</xref>, <xref ref-type="bibr" rid="CR19">19</xref>). To study sepsis-induced acute lung injury, we performed caecal ligation perforation (CLP)<sup><xref ref-type="bibr" rid="CR20">20</xref></sup>. Sham-operated mice underwent the same procedure without ligation and puncture of the caecum. Eighteen hours after sham/CLP surgery, animals were subjected to mechanical ventilation for up to 6 h. For endotoxin-induced acute lung injury, anaesthetized mice received LPS and zymosan intratracheally immediately after starting mechanical ventilation and 1 h later, respectively<sup><xref ref-type="bibr" rid="CR18">18</xref></sup>. In all acute lung injury models, total positive end expiratory pressure (<italic>PEEP</italic><sub><italic>t</italic></sub>) and plateau pressure (<italic>P</italic><sub>plat</sub>) were measured at the end of expiratory and inspiratory occlusion, respectively. Elastance was calculated as (<italic>P</italic><sub>plat</sub> - <italic>PEEP</italic><sub><italic>t</italic></sub>) divided by tidal volume (<italic>V</italic><sub>T</sub>) every 30 min during the ventilation periods.</p></sec><sec id="Sec5"><title>Blood oxygenation, pulmonary oedema, pulmonary vascular permeability and histology</title><p id="Par18">Blood samples were obtained from the left heart ventricle and partial pressure of oxygen in arterial blood (<inline-formula id="IEq1"><mml:math id="M2"><mml:msub><mml:mi>p</mml:mi><mml:mrow><mml:msub><mml:mrow><mml:mtext>aO</mml:mtext></mml:mrow><mml:mn>2</mml:mn></mml:msub></mml:mrow></mml:msub></mml:math></inline-formula>) was measured. To assess pulmonary oedemas, the lung wet-to-dry weight ratios were calculated. Pulmonary vascular permeability was assessed by measuring the pulmonary extravasation of Evans Blue. For histological analysis, 5-µm thick sections were cut and stained with haematoxylin and eosin (H&E).</p></sec><sec id="Sec6"><title>Recombinant ACE2 and AT<sub>1</sub>/AT<sub>2</sub> receptor inhibitors</title><p id="Par19">Thirty minutes before acid instillation, mice received intraperitoneal injections of recombinant human ACE2 (rhuACE2) protein (0.1 mg kg<sup>-1</sup>) (R&D Systems or our own rhuACE2 preparation), catalytically inactive (H374N, H378N)<sup><xref ref-type="bibr" rid="CR10">10</xref></sup> mutant recombinant human ACE2 (mut-rhuACE2) or vehicle (0.1% BSA/PBS). All animals were then ventilated for 3 h. RhuACE2 protein and mut-rhuACE2 protein were purified from transfected CHO cells by affinity chromatography. The catalytic activities of purified recombinant ACE2 proteins were measured using the fluorogenic peptide Substrate VI (R&D Systems). Mut-rhuACE2-Fc showed >95% loss of catalytic activity (see <xref rid="MOESM1" ref-type="media">Supplementary Fig. 3a</xref>). For inhibitor studies, mice received intraperitoneal injections of the AT<sub>1</sub> inhibitor Losartan (15 mg kg<sup>-1</sup>), the AT<sub>2</sub> inhibitor PD123.319 (15 mg kg<sup>-1</sup>) or control vehicle 30 min before surgical procedures.</p></sec><sec id="Sec7"><title>Angiotensin II peptide levels and western blotting</title><p id="Par20">AngII peptide levels were measured as described<sup><xref ref-type="bibr" rid="CR8">8</xref></sup>. For western blotting, rabbit polyclonal anti-ACE2 antibody<sup><xref ref-type="bibr" rid="CR8">8</xref></sup> and rabbit polyclonal anti-mouse ACE antibody (R&D Systems) were used.</p></sec><sec id="Sec8"><title>Statistical analyses</title><p id="Par21">All data are shown as mean ± s.e.m.. Measurements at single time points were analysed by analysis of variance (ANOVA). Time courses were analysed by repeated measurements ANOVA with Bonferroni post-tests.</p></sec></sec><sec sec-type="supplementary-material"><title>Supplementary information</title><sec id="Sec9"><p><supplementary-material content-type="local-data" id="MOESM1"><media xlink:href="41586_2005_BFnature03712_MOESM1_ESM.ppt"><caption><p>Supplementary Figures S1-S9 (PPT 3809 kb)</p></caption></media></supplementary-material></p><p><supplementary-material content-type="local-data" id="MOESM2"><media xlink:href="41586_2005_BFnature03712_MOESM2_ESM.rtf"><caption><title>Supplementary Notes</title><p>Legends for Supplementary Figures S1-S9 and Supplementary Methods. (RTF 163 kb)</p></caption></media></supplementary-material></p></sec></sec></body><back><fn-group><fn><p>Yumiko Imai and Keiji Kuba: *These authors contributed equally to this work</p></fn></fn-group><ack><title>Acknowledgements</title><p>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. 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