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.

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Immunologi inom det medicinska området hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Immunology in the medical area hsv//eng
SYNCYTIAL VIRUS
PULMONARY SURFACTANT
APOLIPOPROTEIN-E
APOPTOTIC CELLS
1918 PANDEMIC
RESPIRATORY-DISTRESS-SYNDROME
LOW-DENSITY-LIPOPROTEIN
OXIDIZED PHOSPHOLIPIDS
TRANSCRIPTION FACTORS
VIRUS
FACTOR-KAPPA-B

Kuba, K. (author)
Neely, G. G. (author)
Yaghubian-Malhami, R. (author)
Perkmann, T. (author)
van Loo, G. (author)
Ermolaeva, M. (author)
Veldhuizen, R. (author)
Leung, Y. H. C. (author)
Wang, H. L. (author)
Liu, H. L. (author)
Sun, Y. (author)
Pasparakis, M. (author)
Kopf, M. (author)
Mech, C. (author)
Bavari, S. (author)
Peiris, J. S. M. (author)
Slutsky, A. S. (author)
Akira, S. (author)
Hultqvist, MalinLund University,Lunds universitet,Immunologi,Forskargrupper vid Lunds universitet,Immunology,Lund University Research Groups(Swepub:lu)infl-mhu (author)
Holmdahl, RikardLund University,Lunds universitet,Immunologi,Forskargrupper vid Lunds universitet,Immunology,Lund University Research Groups(Swepub:lu)infl-rho (author)
Nicholls, J. (author)
Jiang, C. Y. (author)
Binder, C. J. (author)
Penninger, J. M. (author)
ImmunologiForskargrupper vid Lunds universitet (creator_code:org_t)

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Immunology in th ...

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