eritoran and Shock--Septic

Toll-like receptors (TLRs) comprise a group of recently discovered receptors which are essential molecular structures in the activation of immunity. The discovery of TLRs has provided a substantial increase in the knowledge of immunologic aspects of disease pathology and is presently giving rise to new treatment strategies. This review summarizes the current knowledge on TLRs functioning in infections, their possible roles in inflammatory bowl disease and the pivotal role for TLRs in endotoxic shock, an area which is currently subject to development of a new farmakon.

Topics: Animals; Bacterial Infections; Disaccharides; Humans; Immunity, Innate; Inflammatory Bowel Diseases; Shock, Septic; Sugar Phosphates; Toll-Like Receptors; Virus Diseases

Topics: Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Disaccharides; Drug Discovery; Humans; Lipopolysaccharides; Research Design; Sepsis; Shock, Septic; Sugar Phosphates; Toll-Like Receptor 4

Aim was to assess whether lipopolysaccharide (LPS)-induced decrease of total peripheral resistance depends on Toll-like receptor (TLR)4 signaling and whether it is sensitive to NO-synthase or TLR4 antagonists.. C3H/HeN mice (control), expressing a functional, and C3H/HeJ mice, expressing a nonfunctional TLR4, were compared. LPS (20 mg/kg) was injected i.p. 6 hours before hemodynamic measurements. L-NAME and SMT, inhibitors of NO production, and Eritoran, a TLR4 antagonist, were tested for their impact on vascular contractility. Aortic rings were incubated for 6 hours with or without LPS (1 microg/mL), or with LPS+Eritoran (2 microg/mL) and their phenylephrine-induced contractility was measured using a myograph. The expression of cytokines in aortic tissue was examined by real-time polymerase chain reaction. In control mice LPS induced a significant decrease of blood pressure and an increase of heart rate, whereas C3H/HeJ remained unaffected. LPS induced an increase of cytokine expression and a depression of vascular contractility only in control mice but not in C3H/HeJ. L-NAME and SMT increased contractility in all rings and restored LPS-dependent depression of contractility. Eritoran prevented LPS-induced loss of contractility.. LPS upregulates cytokine expression via TLR4 and induces attenuation of smooth muscle contractility which can be effectively antagonized.

Topics: Animals; Aorta; Blood Pressure; Cytokines; Disaccharides; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Heart Rate; Isothiuronium; Lipopolysaccharides; Mice; Mice, Inbred C3H; Mice, Mutant Strains; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type II; Point Mutation; RNA, Messenger; Shock, Septic; Signal Transduction; Sugar Phosphates; Time Factors; Toll-Like Receptor 4; Vasoconstriction