Cardioprotective effects of low dose bacterial lipopolysaccharide may not be directly associated with prostacyclin production

Sublethal dose of bacterial lipopolysaccharide (LPS) would induce protection against cardiac ischemic/ reperfusion (I/R) injury. This study examines the following areas: 1) the temporal induction of the cardioprotection produced by LPS; and 2) the relations between a degree of protection and the myocardial prostacyclin (PGI2) production. Rats were administered LPS (2 mg/kg, i.v.), and hearts were removed 1, 4, 8, 14, 24, 48, 72, and 96 h later. Using Langendorff apparatus, haemodynamic differences during 25 min of global ischemia/30 min reperfusion were investigated. The concentration of PGI2 in aliquots of the coronary effluent was determined by radioimmunoassay as its stable hydrolysis product 6-keto-PGF1alpha and lactate dehydrogenase release were measured as an indicative of cellular injury. LPS-induced cardiac protection against I/R injury appeared 4 h after LPS treatment and remained until 96 h after treatment. PGI2 release increased 2-3 fold at the beginning of reperfusion compared to basal level except in hearts treated with LPS for 48 and 72 h. In hearts removed 48 and 72 h after LPS treatment, basal PGI2 Was increased. To determine the enzymatic step in relation to LPS-induced basal PGI2 production, we examined prostaglandin H synthase (PGHS) protein expression, a rate limiting enzyme of prostaglandin production, by using Western blot analysis. LPS increased PGHS protein expression in hearts at 24, 48, 72, 96 h after LPS treatment. Induction of PGHS expression appeared in both isotypes of PGHS, a constitutive PGHS-1 and an inducible PGHS-2. To identify the correlationship between PGI2 production and the cardioprotective effect against I/R injury, indomethacin was administered in vivo or in vitro. Indomethacin did not inhibit LPS-induced cardioprotection, which was not affected by the duration of LPS treatment. Taken together, our results suggest that PGI2 might not be the major endogenous mediator of LPS-induced cardioprotection.

Effect of NG-nitro-L-arginine methyl ester and Methylene Blue on the Endotoxin-induced Vascular Hyporesponsiveness / 영남의대학술지

The study was undertaken to examine the intensity of involvement of inducible nitric oxide synthase(iNOS) and cyclic GMP signal transduction pathway as one of the mechanisms of vaso-relaxative action of bacterial lipopolysaccharide (LPS) on the canine femoral artery strips. Canine femoral arteries were isolated and spiral strips of 10 mm long and 2 mm wide were made in the Tyroad solution of 0-4degrees C. The strips were prepared for isometric myography in Biancani's isolated muscle chamber contaning 1 ml of Tyrode solution, which was maintained with pH 7.4 by areation with 95% O2/5% CO2 at 37degrees C and nitric oxide (NO) production was measured simulltaneously with isolated nitric oxide mrter. LPS induced NO production, suppressed the phenylephrine (PE) induced contraction and enhanced the acetylcholine (ACh) induced relaxation. NG-nitro-L-arginine methyl ester (L-NAME), an NOS inhibitor, methylene blue, a guanylyl cyclase inhibitor, potentiated PE induced contraction and suppressed ACh induced relaxation on the LPS treated strips. The inhibitory potency of methylene blue for LPS induced vascular hyporeponsiveness was stronger than that of L-NAME. These result suggest that in canine femoral artery, both iNOS and cyclic GMP signal transduction pathway are related with LPS indused vascular hyporeponsiveness, but in minor with iNOS and in major with cyclic GMP signal transduction pathway.

Induction of hepatic acute phase reactants by conditioned medium from lipopolysaccharide treated human dermal fibroblasts / 第二军医大学学报

To test the hypothesis that dermal fibroblasts (DF) are an important source of cytokines which elicit major changes in hepatic synthesis of acute phase reactants(APRs). Metkods: Condi-tioned medium(CM) from human DF challenged with bacterial lipopolysaccharide (I,PS) was collected andIL-10 and IL-6 levels were measured- The ability of DF conditioned medium(fLPS) and dexamethasone(Dex) to mediate an hepatic acute phase response was tested on rat hepatoma H4 cells- Various concentra-tions and combinations of CM (?LPS), recombinant IL-6 (rhIL-6) and Dex were tested for their abilitiesto stimulate albumin, Q,-acid glycoprotein (AGP), a,-antitrypsin (AT) and transferrin mRNA synthesis.Results: LPS stimulated IL-6 production by DF and Dex inhibited this producti0n. IL-6 and CM+LPS in-hibited the production of albumin mRNA,while the expression of AT and AGP 0ccurred 0nly with CM+LPS+Dex. However,IL-6 alone had an inhibitory effect 0n albumin and transferrin mRNA producti0n.Dex maximized the effects 0f lL-6 and CM, and was essential f0r AGP gene expression. C0nclusion: (l)LPS-treated human DF can secrete IL-6, but not IL-101 (2)DF may als0 pr0duce other cyt0kines whichmodulate hepatic pr0tein synthesis during the acute phase response l (3) Dex inhibits IL-6 production byDF, but enhances its ability to stimulate the acute phase response.