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

Shock. 2009 May;31(5):500-6. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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


  • Angiotensin II Type 1 Receptor Blockers
  • Interleukin-1beta
  • Interleukin-6
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Mitogen-Activated Protein Kinases
  • Losartan