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

Yumiko Imai, Keiji Kuba, G. Greg Neely, Rubina Yaghubian-Malhami, Thomas Perkmann, Geert van Loo, Maria Ermolaeva, Ruud Veldhuizen, Y. H.Connie Leung, Hongliang Wang, Haolin Liu, Yang Sun, Manolis Pasparakis, Manfred Kopf, Christin Mech, Sina Bavari, J. S.Malik Peiris, Arthur S. Slutsky, Shizuo Akira, Malin HultqvistRikard Holmdahl, John Nicholls, Chengyu Jiang, Christoph J. Binder, Josef M. Penninger

Research output: Contribution to journalArticlepeer-review

1139 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)235-249
Number of pages15
Issue number2
Publication statusPublished - Apr 18 2008
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Biochemistry,Genetics and Molecular Biology


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