Losartan prevents sepsis-induced acute lung injury and decreases activation of nuclear factor kappaB and mitogen-activated protein kinases

• Published in: Shock (Augusta, Ga.) Vol. 31; no. 5; p. 500
• Main Authors: Shen, Lihan, Mo, Hongying, Cai, Lin, Kong, Tianhan, Zheng, Weihao, Ye, Jihui, Qi, Junhua, Xiao, Zhenglun
• Format: Journal Article
• Language: English
• Published: United States 01.05.2009
• Subjects: Acute Lung Injury - drug therapy; Acute Lung Injury - etiology; Acute Lung Injury - metabolism; Acute Lung Injury - pathology; Angiotensin II Type 1 Receptor Blockers - pharmacology; Angiotensin II Type 1 Receptor Blockers - therapeutic use; Animals; Blotting, Western; Interleukin-1beta - metabolism; Interleukin-6 - metabolism; Losartan - pharmacology; Losartan - therapeutic use; Male; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinases - metabolism; NF-kappa B - metabolism; Phosphorylation - drug effects; Sepsis - complications; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1540-0514
• DOI: 10.1097/SHK.0b013e318189017a

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-1beta, 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 kappaB (NF-kappaB) activations, IkappaB-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-1beta 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-kappaB activation (P < 0.01 vs. CLP group), attenuated degradation of IkappaB-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-kappaB and MAPK mechanisms.