title: Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury.
abstract: 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.
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohrgasse 3, A-1030 Vienna, Austria. imai@med.akita-u.ac.jp
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Imai
authors.forename: Keiji
authors.initials: K
authors.lastname: Kuba
authors.forename: G Greg
authors.initials: GG
authors.lastname: Neely
authors.forename: Rubina
authors.initials: R
authors.lastname: Yaghubian-Malhami
authors.forename: Thomas
authors.initials: T
authors.lastname: Perkmann
authors.forename: Geert
authors.initials: G
authors.lastname: van Loo
authors.forename: Maria
authors.initials: M
authors.lastname: Ermolaeva
authors.forename: Ruud
authors.initials: R
authors.lastname: Veldhuizen
authors.forename: Y H Connie
authors.initials: YH
authors.lastname: Leung
authors.forename: Hongliang
authors.initials: H
authors.lastname: Wang
authors.forename: Haolin
authors.initials: H
authors.lastname: Liu
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
authors.forename: Manfred
authors.initials: M
authors.lastname: Kopf
authors.forename: Christin
authors.initials: C
authors.lastname: Mech
authors.forename: Sina
authors.initials: S
authors.lastname: Bavari
authors.forename: J S Malik
authors.initials: JS
authors.lastname: Peiris
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Slutsky
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Malin
authors.initials: M
authors.lastname: Hultqvist
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
authors.forename: John
authors.initials: J
authors.lastname: Nicholls
authors.forename: Chengyu
authors.initials: C
authors.lastname: Jiang
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Binder
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
mesh_terms: 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*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D015850:Interleukin-6; D016328:NF-kappa B; D010743:Phospholipids; D051197:Toll-Like Receptor 4; D019255:NADPH Oxidases