Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury.
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.
Imai
Yumiko
Y
IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohrgasse 3, A-1030 Vienna, Austria. imai@med.akita-u.ac.jp
Kuba
Keiji
K
Neely
G Greg
GG
Yaghubian-Malhami
Rubina
R
Perkmann
Thomas
T
van Loo
Geert
G
Ermolaeva
Maria
M
Veldhuizen
Ruud
R
Leung
Y H Connie
YH
Wang
Hongliang
H
Liu
Haolin
H
Sun
Yang
Y
Pasparakis
Manolis
M
Kopf
Manfred
M
Mech
Christin
C
Bavari
Sina
S
Peiris
J S Malik
JS
Slutsky
Arthur S
AS
Akira
Shizuo
S
Hultqvist
Malin
M
Holmdahl
Rikard
R
Nicholls
John
J
Jiang
Chengyu
C
Binder
Christoph J
CJ
Penninger
Josef M
JM
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D006801:Humans; D007251:Influenza, Human / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000378:metabolism; D018384:Oxidative Stress; D010743:Phospholipids / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000378:metabolism*; D045169:Severe Acute Respiratory Syndrome / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D033942:Adaptor Proteins, Vesicular Transport; D015850:Interleukin-6; D016328:NF-kappa B; D010743:Phospholipids; D051197:Toll-Like Receptor 4; D019255:NADPH Oxidases