Author/Authors :
Yumiko Imai، نويسنده , , Keiji Kuba، نويسنده , , G. Greg Neely، نويسنده , , Rubina Yaghubian-Malhami، نويسنده , , Thomas Perkmann، نويسنده , , Geert van Loo، نويسنده , , Maria Ermolaeva، نويسنده , , Ruud Veldhuizen، نويسنده , , Y.H. Connie Leung، نويسنده , , Hongliang Wang، نويسنده , , Haolin Liu، نويسنده , , Yang Sun، نويسنده , , Manolis Pasparakis، نويسنده , , Manfred Kopf، نويسنده , , Christin Mech، نويسنده , , Sina Bavari، نويسنده , , JS Malik Peiris، نويسنده , , Arthur S. Slutsky، نويسنده , , Shizuo Akira، نويسنده , , Malin Hultqvist، نويسنده , , et al.، نويسنده ,
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.
