LOSARTAN PREVENTS SEPSIS-INDUCED ACUTE LUNG INJURY AND DECREASES ACTIVATION OF NUCLEAR FACTOR kappa B AND MITOGEN-ACTIVATED PROTEIN KINASES

作者：Shen, Lihan; Mo, Hongying; Cai, Lin; Kong, Tianhan; Zheng, Weihao; Ye, Jihui; Qi, Junhua; Xiao, Zhenglun^*

来源：Shock, 2009, 31(5): 500-506.

DOI：10.1097/SHK.0b013e318189017a

• ARDS
• renin-angiotensin system
• angiotensin II
• NF-kappa B
• MAPK
• signal transduction

Lack of specific and efficient therapy leads to the high mortality rate of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Losartan is a potent pharmaceutical drug for ALI/ARDS. However, the protective effects and mechanisms of losartan remain incompletely known. This study evaluates the effects of losartan on ALI/ARDS and further investigates the possible mechanisms of these protective effects. Mice received i.p. injections of the AT1 inhibitor losartan (15 mg/kg), or control vehicle, half hour after cecal ligation and puncture (CLP). Plasma TNF-alpha, IL-1 beta, and IL-6 cytokines were assayed 6 h after CLP. Blood gas, wet/dry lung weight ratio, lung tissue histology for occurrence of ALI/ARDS, and survival were examined. Lastly, nuclear factor kappa B (NF-kappa B) activations, I kappa B-alpha degradations, phosphorylations of p38 MAPK, extracellular signal-regulated kinase 1/2, and c-Jun N-terminal kinase expressions were evaluated in lung tissue. Losartan treatment significantly attenuated TNF-alpha, IL-6, and IL-1 beta 6 h after CLP. Furthermore, losartan prevented blood gas and histopathologic appearance of ALI/ARDS after sepsis and significantly improved survival. Finally, losartan given after sepsis led to inhibition of lung tissue NF-kappa B activation (P < 0.01 vs. CLP group), attenuated degradation of I kappa B-alpha, and inhibited phosphorylation of p38MAPK, extracellular signal-regulated kinase 1/2, and c-Jun N-terminal kinase, pathways critical for cytokine release. These data reveal that losartan exerts a protective effect on ALI/ARDS, and this protective effect may be dependent, at least in part, on NF-kappa B and MAPK mechanisms.

• 出版日期2009-5
• 单位广州医科大学