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

Abstract

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.

Hydrogen-rich saline ameliorates lung injury associated with cecal ligation and puncture-induced sepsis in rats

“…Or inflammatory response activates p38MAPK? Please refer to page 12, the last paragraph) (Lentsch et al, 1998;Asaduzzaman et al, 2008;Shen et al, 2009). We proved that, in the present study, phosphorylation and consequent activation of p38MAPK and NF-κB were blocked by hydrogen-rich saline.…”

The ameliorative effects of a hypnotic bromvalerylurea in sepsis

“…The upper lobe of the right lung was removed 24 h after CLP, weighed, and then dried in an oven at 80 C for 48 h. The dry tissue weight was measured, and the wet-to-dry weight (w/d) ratio was calculated to evaluate the degree of lung edema [14].…”

Angiotensin II signaling through the AT1a and AT1b receptors does not have a role in the development of cerulein-induced chronic pancreatitis in the mouse

“…We are not aware of any reports using an ARB in a mouse model of pancreatitis. IP delivery of losartan was chosen because it was shown that IP injections of losartan in mice caused biological effects such as prevention of sepsis-induced acute lung injury (35) and regulation of blood pressure (27). We Expression of angiotensinogen and AT1b mRNA is normalized to acidic ribosomal phosphoprotein P0 and expressed as fold increase over the level in WT control mice.…”

“…To evaluate whether simultaneous blockade of AT1a and AT1b receptor isoforms affects the course of cerulein-induced pancreatitis, WT cerulein-treated mice (8 mice/group) were treated with AT1 receptor antagonist losartan and compared with control cerulein-treated mice (8 mice/group). Losartan was delivered by IP injection because it was demonstrated in several studies that IP delivery of losartan produces biological effects in mice (27,35). Several doses of losartan, 0.5 mg/kg per day, 2 mg/kg per day, 5 mg/kg per day, and 20 mg/kg per day were evaluated.…”