Abstract
Sepsis is a systemic inflammatory disorder, accompanied with elevated oxidative stress, leading to multiple organ dysfunction syndrome (MODS), and disseminated intravascular coagulation. 17-Dimethylaminoethylamino- 17-demethoxygeldanamycin (17-DMAG), a heat shock protein (HSP) 90 inhibitor, has been reported to possess anti-inflammatory effects. In this study, the beneficial effects of 17-DMAG on lipopolysaccharide (LPS) induced MODS and DIC was evaluated in anesthetized rats. 17-DMAG (5 mg/kg, i.p.) was significantly increased survival rate, and prevented hypotension in LPS (30 mg/kg i.v. infused for 4 h) induced endotoxemia. The elevated levels of alanine aminotransferase (ALT), creatine phosphokinase (CPK), lactate dehydrogenase, creatinine, nitric oxide (NO) metabolites, IL-6, and TNF-α in LPS-exposed rat plasma were significantly reduced by 17-DMAG. Moreover, 17-DMAG suppressed LPS-induced superoxide anion production and caspase 3 activation in heart tissues. LPS induced the prolongation of prothrombin time, and a pronounced decrease in platelet count, which were improved by 17-DMAG. 17-DMAG markedly induced HSP70 and heme oxygenase (HO)-1, and suppressed inducible nitric oxide synthase (iNOS) and phosphorylated NF-κB p65 protein expression in organs 6 h after LPS initiation. Pretreatment with high dose of quercetin (300 mg/kg, i.p.), as an HSP70 inhibitor, reversed the beneficial effects of 17-DMAG on survival rate, plasma levels of ALT, CPK, creatinine, IL-6, and NO metabolites, iNOS induction, and caspase-3 activation in LPS-treated rats. In conclusion, 17-DMAG possesses the anti-inflammatory and antioxidant effects that were proved through LPS-induced acute inflammation, which is associated with induction of HSP70 and HO-1, leading to prevent MODS in sepsis.
Highlights
Sepsis is the clinical syndrome of a systemic inflammatory response that complicates severe infection
We found that 17-DMAG improved multiple organ dysfunction syndrome (MODS) and survival rate, accompanied by suppressive effects on inflammatory responses and oxidative stress during sepsis
The primary antibodies used in this experiment were mouse monoclonal anti-inducible nitric oxide synthase (iNOS) (1:1000; BD, USA), monoclonal antiHO-1 (1:2000; Santa Cruz, USA), monoclonal anti-Heat shock protein 70 (HSP70) (1:1000; Assay Designs, USA), monoclonal anti-plasminogen activator inhibitor-1 (PAI-1) (1:10000; BD, USA), monoclonal anti-β-actin (1:5000; Cell Signaling, USA), monoclonal anti-α-actin (1:2000; Sigma, USA) and rabbit polyclonal phosphorylated NF-κB p65 antibody (1:2000; Millipore, USA)
Summary
Sepsis is the clinical syndrome of a systemic inflammatory response that complicates severe infection. The activation of macrophages and neutrophils release a large number of superoxide anions and other oxidants in infected cells and organs Those factors would induce the systemic inflammatory response syndrome, and multiple organ dysfunction syndrome (MODS) [3]. Prophylactic intravenous injection of HSP70 significantly reduces mortality rates and inflammatory responses in lipoteichoic acid-induced sepsis, and attenuates reactive oxygen species (ROS) production in neutrophils [8]. These evidences demonstrate that HSP70 plays an important role in maintaining cellular homeostasis to defend organs from bacterial infection and acute inflammation-evoked damages. Induction of HSP70 and HO-1 is associated in the perceived beneficial effect
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