Identification of Oxidative Stress and Toll-like Receptor 4 Signaling as a Key Pathway of Acute Lung Injury

[sharon sanders]

Article

Identification of Oxidative Stress and Toll-like Receptor 4 Signaling as a Key Pathway of Acute Lung Injury

<!-- articleText --> Yumiko Imai¹^,¹⁶^,^,, Keiji Kuba¹^,², G. Greg Neely¹, Rubina Yaghubian-Malhami¹, Thomas Perkmann³, Geert van Loo⁴, Maria Ermolaeva⁴^,⁵, Ruud Veldhuizen⁶, Y.H. Connie Leung⁸, Hongliang Wang⁹, Haolin Liu⁹, Yang Sun⁹, Manolis Pasparakis⁴^,⁵, Manfred Kopf¹⁰, Christin Mech¹¹, Sina Bavari¹¹, J.S. Malik Peiris⁸, Arthur S. Slutsky¹²^,¹³, Shizuo Akira¹⁴, Malin Hultqvist¹⁵, Rikard Holmdahl¹⁵, John Nicholls⁷, Chengyu Jiang⁹, Christoph J. Binder³ and Josef M. Penninger¹^,^,

<!-- authorsNoEnt --> ¹IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohrgasse 3, A-1030 Vienna, Austria
²Medical Research Institute, Tokyo Medical and Dental University, Kandasurugadai 2-3-10, Chiyoda-ku, Tokyo 101-0062, Japan
³CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences and Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, W&#228;hringer G&#252;rtel 18-20, A-1090 Vienna, Austria
⁴European Molecular Biology Laboratory (EMBL), Mouse Biology Unit, Via Ramarini 32, Monterotondo-Scalo, Rome 00016, Italy
⁵Institute for Genetics, University of Cologne, Z&#252;lpicher Str. 47, D-50674 Cologne, Germany
⁶Lawson Health Research Institute, Departments of Medicine and Physiology and Pharmacology, The University of Western Ontario, London Ontario, N6A 4V2, Canada
⁷Department of Pathology, University of Hong Kong, SAR
⁸Department of Microbiology, University of Hong Kong, SAR
⁹National Key Laboratory of Medical Molecular Biology, School of Basic Medicine Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100005, China
¹⁰Molecular Biomedicine, Swiss Federal Institute of Technology, Wagistrasse 27, CH-8952 Z&#252;rich-Schlieren, Switzerland
¹¹US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21701, USA
¹²Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto M5B 1W8, Canada
¹³Department of Critical Care, St. Michael's Hospital, University of Toronto, Toronto M5B 1W8, Canada
¹⁴Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
¹⁵Medical Inflammation Research, MBB, Karolinska Institutet, Stockholm, Sweden and Medical Inflammation Research BMC I11 Lund, Sweden

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Received 25 April 2007;
<!-- graphText, refText -->revised 10 December 2007;
<!-- graphText, refText -->accepted 29 February 2008.
<!-- graphText, refText -->Published: April 17, 2008.
<!-- graphText, refText -->Available online 17 April 2008.




Summary

Multiple lung pathogens such as chemical agents, H5N1 avian flu, or SARS cause high lethality due to acute respiratory distress syndrome. Here we report that Toll-like receptor 4 (TLR4) mutant mice display natural resistance to acid-induced acute lung injury (ALI). We show that TLR4-TRIF-TRAF6 signaling is a key disease pathway that controls the severity of ALI. The oxidized phospholipid (OxPL) OxPAPC was identified to induce lung injury and cytokine production by lung macrophages via TLR4-TRIF. We observed OxPL production in the lungs of humans and animals infected with SARS, Anthrax, or H5N1. Pulmonary challenge with an inactivated H5N1 avian influenza virus rapidly induces ALI and OxPL formation in mice. Loss of TLR4 or TRIF expression protects mice from H5N1-induced ALI. Moreover, deletion of ncf1, which controls ROS production, improves the severity of H5N1-mediated ALI. Our data identify oxidative stress and innate immunity as key lung injury pathways that control the severity of ALI.

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