Identification of oxidative stress and toll-like receptor 4 signaling as a key pathway of acute lung injury

被引：1211

作者：

Imai, Yumiko ^{[19
]}

Kuba, Keiji ^{[1
,19
]}

Neely, G. Greg ^{[19
]}

Yaghubian-Malhami, Rubina ^{[19
]}

Perkmann, Thomas ^{[2
,3
]}

van Loo, Geert ^{[4
]}

Ermolaeva, Maria ^{[4
,5
]}

Veldhuizen, Ruud ^{[6
,7
]}

Leung, Y. H. Connie ^{[9
]}

Wang, Hongliang ^{[10
,11
]}

Liu, Haolin ^{[10
,11
]}

Sun, Yang ^{[10
,11
]}

Pasparakis, Manolis ^{[4
,5
]}

Kopf, Manfred ^{[12
]}

Mech, Christin ^{[13
]}

Bavari, Sina ^{[13
]}

Peiris, J. S. Malik ^{[9
]}

Slutsky, Arthur S. ^{[14
,15
]}

Akira, Shizuo ^{[16
]}

Hultqvist, Malin ^{[17
,18
]}

Holmdahl, Rikard ^{[17
,18
]}

Nicholls, John ^{[8
]}

Jiang, Chengyu ^{[10
,11
]}

Binder, Christoph J. ^{[2
,3
]}

Penninger, Josef M. ^{[19
]}

机构：

[1] Tokyo Med & Dent Univ, Med Res Inst, Chiyoda Ku, Tokyo 1010062, Japan

[2] Med Univ Vienna, Inst Med & Chem Lab Diagnost, A-1090 Vienna, Austria

[3] Austrian Acad Sci, CeMM, Res Ctr Mol Med, A-1090 Vienna, Austria

[4] European Mol Biol Lab, Mouse Biol Unit, I-00016 Monterotondo, Italy

[5] Univ Cologne, Inst Genet, D-50674 Cologne, Germany

[6] Univ Western Ontario, Lawson Hlth Res Inst, Dept Med, London, ON N6A 4V2, Canada

[7] Univ Western Ontario, Lawson Hlth Res Inst, Dept Physiol & Pharmacol, London, ON N6A 4V2, Canada

[8] Univ Hong Kong, Dept Pathol, Hong Kong, Hong Kong, Peoples R China

[9] Univ Hong Kong, Dept Microbiol, Hong Kong, Hong Kong, Peoples R China

[10] Peking Union Med Coll, Natl Key Lab Med Mol Biol, Sch Basic Med, Beijing 100005, Peoples R China

[11] Chinese Acad Med Sci, Beijing 100005, Peoples R China

[12] Swiss Fed Inst Technol, CH-8952 Zurich, Switzerland

[13] USA, Med Res Inst Infect Dis, Frederick, MD 21701 USA

[14] Univ Toronto, Interdepartmental Div Crit Care Med, Toronto, ON M5B 1W8, Canada

[15] Univ Toronto, Dept Crit Care, St Michaels Hosp, Toronto, ON M5B 1W8, Canada

[16] Osaka Univ, Dept Host Def, Res Inst Microbial Dis, Suita, Osaka 5650871, Japan

[17] BMC, Med Inflammat Res, Lund, Sweden

[18] Karolinska Inst, Med Inflammat Res, MBB, Stockholm, Sweden

[19] Austrian Acad Sci, IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria

来源：

CELL | 2008年 / 133卷 / 02期

基金：

中国国家自然科学基金; 加拿大创新基金会;

关键词：

D O I：

10.1016/j.cell.2008.02.043

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：235 / 249

页数：15

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