Identification of Oxidative Stress and Toll-like Receptor 4 Signaling as a Key Pathway of Acute Lung Injury

Imai Y, Kuba K, Neely GG, Yaghubian-Malhami R, Perkmann T, van Loo G, Ermolaeva M, Veldhuizen R, Leung YH, Wang H, Liu H, Sun Y, Pasparakis M, Kopf M, Mech C, Bavari S, Peiris JS, Slutsky AS, Akira S, Hultqvist M, Holmdahl R, Nicholls J, Jiang C, Binder CJ, PenningerJM            

Cell 133, 235-249 (2008)

Speaker: 張竣泓                          Time: 15:00~16:00, Sep 17, 2008

Commentator: 蘇益仁 老師                Place: Room 601

Abstract:

    Acute respiratory distress syndrome (ARDS), the most sever form of acute lung injury (ALI), makes it an important cause of morbidity. It is characterized by inflammation of the lung leading to impaired gas-exchange ability and frequently resulting in multiple organ failure. Beside bacteria and viral infections are main factors for ALI/ARDS, other risk such as aspiration of gastric contents, major trauma, and repeated transfusion also lead to ALI/ARDS. However, the mechanism underlying ALI/ARDS is not clear. Beginning with the study on different strains mice, authors report that TLR4 mutant mice can resist to acid-induced ALI/ARDS. And then they show TLR4-TRIF-TRAF6-NFκB pathway as a central pathway for ALI/ARDS. Deletion of TLR4 or TRIF in mice resists to both acid- and H5N1-induced injury. Besides, they identify that an oxidized phospholipids (OxPL), OxPAPC, are formed under oxidative stress and trigger IL-6 production and induce the severity of ALI/ARDS via this pathway. Neutralization of OxPL or loss of ncf1 gene expression also improves the severity of ALI/ARDS. Moreover, OxPL can be detected in the lungs of human and other animals challenged with SARS, Anthrax, or H5N1. Therefore, modulation of this injury pathway could be useful to protect patients infected with H5N1 avian influenza virus, SARS-coronavirus, Anthrax, or other unknown lethal lung pathogens from developing ALI/ARDS.

References:

1.        Ware, LB., and Matthay, M.A. (2000). The acute respiratory distress syndrome. N. Engl. J. Med. 342, 1334-1349

2.        Veldhuizen, R., Nag, K.,Oregeig, S., and Possmayer, F. (1998). The role of lipids in pulmonary surfactant. Biochim. Biophys. Acta 1408, 90-108