Abstract
BackgroundEthyl pyruvate (EP) was recently identified as an experimental therapeutic agent in a wide variety of model systems for inflammation-mediated tissue and cellular injury.ObjectiveTo evaluate the effect of ethyl EP on improving the survival in mice with LPS-induced acute lung injury (ALI).MethodsALI was induced by administering lipopolysaccharide (LPS) intratracheally. The mice were treated intraperitoneally (i.p.) with 100, 50 and 10 mg/kg EP immediately before intratracheal instillation of LPS, and 100 mg/kg EP was administered 0, 12, 24 and 48 hours after induction of ALI. The mortality rate was recorded and analyzed by the Kaplan-Meier method. Serum tumor necrosis factor (TNF)-α, interleukin (IL) -6 and IL-1 β were measured in bronchial alveolar lavage fluid using an enzyme-linked immunosorbent assay. High-mobility group box 1 levels were measured by Western immunoblotting.ResultsTreatment with EP significantly inhibited the release of HMGB1, TNF-α, IL-6 and IL-1β into bronchoalveolar lavage (BAL) fluids of ALI mice, and reduced the permeability index of the injured lung. High EP doses reduced the mortality from ALI and the permeability index (100 mg/kg and 50 mg/kg EP versus control; P < 0.0001). Early administration of high-dose EP significantly increased survival rate (0, 12 and 24 h versus control; P < 0.0001, P < 0.0001 and P = 0.01 respectively by log-rank test). There was no survival advantage when EP was initiated at 48 h.ConclusionEthyl pyruvate improves survival and reduces the lung permeability index in mice with LPS-induced ALI.
Highlights
Despite significant advances in understanding the pathogenesis of acute lung injury (ALI) and its management, the mortality rate from ALI remains unacceptably high [1,2].It is well known that the pathogenesis of ALI is mediated by pro-inflammatory cytokines, including tumor necrosis factor (TNF), interleukin (IL)-1, IL-6 and high-mobility group box (HMGB) 1, which are released from macro-(page number not for citation purposes)Respiratory Research 2009, 10:91 http://respiratory-research.com/content/10/1/91 phages, neutrophils and other cells of the innate immune system [3,4]
The effect of ethyl pyruvate on pro-inflammatory cytokines in bronchoalveolar lavage (BAL) fluids and permeability index of experimental ALI mice
To determine the levels of pro-inflammatory cytokines in BAL fluids, we flushed the airways with 1.0 ml PBS and Treatment with Ethyl pyruvate (EP) (100 mg/kg, i.p., immediately before intratracheal LPS instillation) significantly inhibited the release of highmobility group box 1 (HMGB1), TNF, IL-6 and IL-1 into the BAL fluids of ALI mice (Table 1), indicating that EP prevented LPS-induced ALI by attenuating the release of early (TNF, IL-6, and IL-1 ) and late (HMGB1) systemic proinflammatory cytokines associated with lethality
Summary
Despite significant advances in understanding the pathogenesis of acute lung injury (ALI) and its management, the mortality rate from ALI remains unacceptably high [1,2].It is well known that the pathogenesis of ALI is mediated by pro-inflammatory cytokines, including tumor necrosis factor (TNF)- , interleukin (IL)-1 , IL-6 and high-mobility group box (HMGB) 1, which are released from macro-(page number not for citation purposes)Respiratory Research 2009, 10:91 http://respiratory-research.com/content/10/1/91 phages, neutrophils and other cells of the innate immune system [3,4]. HMGB1 is a late mediator of lethal systemic inflammation in animal models of cytokine-mediated disease. It is released by macrophages only after a delay of 12-18 h during endotoxemia [7]. HMGB1 stimulates the release of TNF- , IL-1 and other inflammatory cytokines from macrophages and pituicytes, and mediates ALI and lethality [8,9]. In patients with severe infection, increased serum HMGB1 levels correlated with non-survival [7]. These results suggest that HMGB1 is an important mediator in ALI and that its inhibition may be a key to improving clinical outcomes. Ethyl pyruvate (EP) was recently identified as an experimental therapeutic agent in a wide variety of model systems for inflammation-mediated tissue and cellular injury
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