Inhibiting glycogen synthase kinase 3beta in sepsis.

The serine-threonine protein kinase glycogen synthase kinase (GSK)-3 is involved in the regulation of many cell functions, but its role in the regulation of the inflammatory response is unknown. Here we investigate the effects of GSK-3beta inhibition on organ injury/dysfunction caused by endotoxaemia or severe inflammation in the rat. Rats received either intravenous Escherichia coli lipopolysaccharide (LPS) (6 mg/kg) or LPS (1mg/kg) plus Staphylococcus aureus peptidoglycan (PepG) (0.

Glycogen synthase kinase 3beta as a target for the therapy of shock and inflammation.

After the discovery that glycogen synthase kinase (GSK) 3beta plays a fundamental role in the regulation of the activity of nuclear factor kappaB, a number of studies have investigated the effects of this protein kinase in the regulation of the inflammatory process. The GSK-3beta inhibition, using genetically modified cells and chemically different pharmacological inhibitors, affects the regulation of various inflammatory mediators in vitro and in vivo. Insulin, an endogenous inhibitor of GSK-3 in the pathway leading to the regulation of glycogen synthase activity, has recently been clinically used in the therapy for septic shock.

Lysophosphatidic acid reduces the organ injury caused by endotoxemia-a role for G-protein-coupled receptors and peroxisome proliferator-activated receptor-gamma.

Exogenous lysophosphatidic acid (LPA) has been shown to beneficial in renal ischemia/reperfusion injury, wound healing and colitis. LPA acts via specific G-protein-coupled receptors and also peroxisome proliferator-activated receptor-gamma (PPAR-gamma). However, activation of PPAR-gamma is dependent on the presence of an unsaturated acyl chain.

Lipoproteins in inflammation and sepsis. I. Basic science.

Background: High-density lipoproteins (HDL) have been shown to bind and neutralize lipopolysaccharide (LPS) and are regarded as possible therapeutic agents for sepsis and conditions associated with local or systemic inflammation. However, in recent years, a multitude of possible immunomodulatory properties other than LPS neutralization have become evident.

Discussion: This review highlights the advances in the understanding of how HDL is protective in both in vitro and in vivo inflammatory settings, including the ability of HDL to modulate adhesion molecule expression, upregulate endothelial nitric oxide synthase and counteract oxidative stress.

Lysophosphatidylcholine reduces the organ injury and dysfunction in rodent models of gram-negative and gram-positive shock.

1. Lysophosphatidylcholine (LPC) modulates the inflammatory response and reduces mortality in animal models of sepsis. Here, we investigate the effects of LPC from synthetic (sLPC) and natural, soy bean derived LPC, (nLPC) sources on the organ injury/dysfunction caused by systemic administration of lipopolysaccharide (LPS) or peptidoglycan (PepG) and lipoteichoic acid (LTA).

Glycogen synthase kinase-3beta inhibition attenuates the degree of arthritis caused by type II collagen in the mouse.

Recently, glycogen synthase kinase-3 (GSK-3) has being identified as an ubiquitous serine-threonine protein kinase that participates in a multitude of cellular processes and plays an important role in the pathophysiology of a number of diseases. The aim of this study was to investigate the effects of GSK-3beta inhibition on the degree of arthritis caused by type II collagen (CII) in the mouse (collagen-induced arthritis; CIA). Mice developed erosive hind paw arthritis when immunized with CII in an emulsion in complete Freund's adjuvant (CFA).

Glycogen synthase kinase-3 beta inhibition reduces secondary damage in experimental spinal cord trauma.

Glycogen synthase kinase-3 (GSK-3) has recently been identified as an ubiquitous serine-threonine protein kinase that participates in a multitude of cellular processes and plays an important role in the pathophysiology of a number of diseases. The aim of this study was to investigate the effects of GSK-3beta inhibition on the degree of experimental spinal cord trauma induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. Spinal cord injury (SCI) in mice resulted in severe trauma characterized by edema, neutrophil infiltration, production of a range of inflammatory mediators, tissue damage, and apoptosis.

Insulin reduces the multiple organ injury and dysfunction caused by coadministration of lipopolysaccharide and peptidoglycan independently of blood glucose: role of glycogen synthase kinase-3beta inhibition.

Objective: Insulin reduces morbidity and mortality among critically ill patients, but the molecular mechanisms of its effect remain unknown. Insulin is a well-known inhibitor of glycogen synthase kinase-3, which may play an important role in systemic inflammation and shock. Here we investigate the role of blood glucose and glycogen synthase kinase-3beta inhibition in the protective effect of insulin on the organ injury/dysfunction associated with excessive systemic inflammation.

Peroxisome proliferator-activated receptor-gamma antagonists GW9662 and T0070907 reduce the protective effects of lipopolysaccharide preconditioning against organ failure caused by endotoxemia.

Objective: There is evidence that a) ligands of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-gamma and b) lipopolysaccharide preconditioning protect the organs against the multiple organ injury and dysfunction caused by endotoxemia. Here we investigate the hypothesis that the protective effects of lipopolysaccharide preconditioning are due to an enhanced formation of endogenous ligands of PPAR-gamma.

Design: Prospective, randomized study.

Reduction of experimental colitis in the rat by inhibitors of glycogen synthase kinase-3beta.

The effects of the inhibitors of glycogen synthase kinase-3beta (GSK-3beta), TDZD-8 and SB 415286, which can substantially reduce the systemic inflammation associated with endotoxic shock in vivo, have now been investigated on the acute colitis provoked by trinitrobenzene sulphonic acid (TNBS) in the rat. Administration of the GSK-3beta inhibitor TDZD-8 (0.1, 0.

GSK-3beta inhibitors attenuate the organ injury/dysfunction caused by endotoxemia in the rat.

Objective: Serine-threonine protein kinase glycogen synthase kinase (GSK)-3 is involved in regulation of many cell functions, but its role in regulation of inflammatory response is unknown. Here we investigate the effects of GSK-3beta inhibition on organ injury/dysfunction caused by lipopolysaccharide or coadministration of lipopolysaccharide and peptidoglycan in the rat.

Design: Prospective, randomized study.

Inhibition of endogenous hydrogen sulfide formation reduces the organ injury caused by endotoxemia.

Hydrogen sulfide (H2S) is a naturally occurring gaseous transmitter, which may play important roles in normal physiology and disease. Here, we investigated the role of H2S in the organ injury caused by severe endotoxemia in the rat. Male Wistar rats were subjected to acute endotoxemia (Escherichia coli lipopolysaccharide (LPS) 6 mg kg(-1) intravenously (i.

The selective PPARgamma antagonist GW9662 reverses the protection of LPS in a model of renal ischemia-reperfusion.

Background: We have recently reported that pretreatment of rats with endotoxin (lipopolysaccharide, LPS) and selective agonists of the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) protect the kidney against ischemia/reperfusion (I/R) injury. Here we investigate the hypothesis that the renoprotective effects of LPS may be due to an enhanced formation of endogenous ligands of PPARgamma, rather than an up-regulation of PPARgamma expression.

Methods: Rats were pretreated with LPS (1 mg/kg, IP, 24 hours prior to ischemia) in the absence (control) or presence of the selective PPARgamma antagonist GW9662 (1 mg/kg, IP, 24 and 12 hours prior to ischemia).

The peroxisome proliferator-activated receptor-gamma ligand 15-deoxyDelta12,14 prostaglandin J2 reduces the organ injury in hemorrhagic shock.

The cyclopentenone prostaglandin 15-deoxyDelta12,14PGJ2 (15d-PGJ2) exerts potent anti-inflammatory effects in vivo, which are in part caused by the activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Here we investigate the effects of 15d-PGJ2 on the multiple organ injury/dysfunction associated with severe hemorrhage and resuscitation. Male Wistar rats were subjected to hemorrhage (to lower mean arterial blood pressure to 45 mmHg) for 90 min and subsequently resuscitated with shed blood for 4 h.

15d-prostaglandin J2 reduces multiple organ failure caused by wall-fragment of Gram-positive and Gram-negative bacteria.

Septic shock is still the major cause of death in surgical intensive care units. Both gram-positive (G+) and gram-negative (G-) bacteria have been isolated in the blood of a large portion of septic patients, and these polymicrobial infections often have a higher mortality than infections due to a single organism. Cell wall fragments from G+ and G- bacteria synergise to cause shock and multiple organ dysfunction in vivo (G+/G- shock).

Effects of long-term intervention with Lactobacillus helveticus-fermented milk on bone mineral density and bone mineral content in growing rats.

Background: Lactobacillus helveticus-fermented milk has been shown to increase calcium absorption compared to ordinary sour milk. In the present study the possible effect of L. helveticus-fermented milk on bone was studied in growing rats.

Reduction of the multiple organ injury and dysfunction caused by endotoxemia in 5-lipoxygenase knockout mice and by the 5-lipoxygenase inhibitor zileuton.

The role of 5-lipoxygenase (5-LOX) in the pathophysiology of the organ injury/dysfunction caused by endotoxin is not known. Here, we investigate the effects of treatment with 5-LOX inhibitor zileuton in rats and targeted disruption of the 5-LOX gene in mice (5-LOX(-/-)) on multiple organ injury/dysfunction caused by severe endotoxemia. We also investigate the expression of beta2-integrins CD11a/CD18 and CD11b/CD18 on rat leukocytes by flow cytometry.

Urocortin does not reduce the renal injury and dysfunction caused by experimental ischaemia/reperfusion.

Recent evidence indicates that activators of the serine/threonine kinase pathway protect against ischaemia/reperfusion. Here, we investigate the effects of renal ischaemia/reperfusion on the degree of renal dysfunction and injury with urocortin in rats. Rats treated with urocortin or its vehicle (saline) were subjected to bilateral renal artery occlusion (45 min) and reperfusion (6 h).

Erythropoietin attenuates the tissue injury associated with hemorrhagic shock and myocardial ischemia.

Here we investigate the effects of erythropoietin (EPO) on the tissue/organ injury caused by hemorrhagic shock (HS), endotoxic shock, and regional myocardial ischemia and reperfusion in anesthetized rats. Male Wistar rats were anesthetized with thiopental sodium (85 mg/kg i.p.

Role of peroxisome proliferator-activated receptor-gamma in the protection afforded by 15-deoxydelta12,14 prostaglandin J2 against the multiple organ failure caused by endotoxin.

Objective: The cyclopentenone prostaglandin 15-deoxydelta-prostaglandin J2 (15 d-PGJ2) exerts potent anti-inflammatory effects in vivo, which are in part due to the activation of peroxisome proliferator-activated receptor (PPAR)-gamma. Here we investigate the effects of 15 d-PGJ2 on the multiple organ injury/dysfunction associated with severe endotoxemia.

Design: Prospective, randomized study.

Endogenous ligands of PPAR-gamma reduce the liver injury in haemorrhagic shock.

We demonstrate here for the first time that the novel, potent peroxisome proliferator-activated receptor (PPAR)-gamma antagonist GW9662 (2-chloro-5-nitrobenzanilide) augments the degree of liver injury associated with haemorrhagic (haemorrhage for 90 min and resuscitation for 4 h), but not endotoxic (6 mg/kg E. coli endotoxin i.v.

The PPAR-gamma ligand 15-deoxy(delta12,14) prostaglandin J2 reduces the liver injury in endotoxic shock.

We demonstrate here for the first time that the endogenous cyclopentenone prostaglandin 15-deoxy-Delta12,14-prostaglandin J2 (15d-prostaglandin J2) reduces the liver injury (rise in serum transaminases) caused by severe endotoxaemia (6 mg/kg Escherichia coli endotoxin i.v. for 6 h) in the anaesthetised rat.