Abstract

Background. Increased oxidant stress has been implicated in a number of disease states, including systemic inflammation caused by ischemia/reperfusion injury or sepsis. We have demonstrated previously that oxidants enhance the proinflammatory response to endotoxin (lipopolysaccharide), although antioxidants inhibit this response. Heme-oxygenase 1 (HO-1) is an inducible, cytoprotective enzyme, which is up-regulated under conditions of oxidant stress. We hypothesized that the induction of HO-1 protein would attenuate the proinflammatory response of endothelial cells to lipopolysaccharide and oxidant stress. Methods. Human umbilical vein endothelial cells were pretreated with hemin (100 μmol/L) for 5 hours, and the induction of HO-1 was confirmed by Western blot. After hemin exposure, cells were treated for 1 hour with either diamide, buthione sulfoximine, xanthine oxidase, or glucose oxidase to induce oxidant stress or lipopolysaccharide to induce an inflammatory response. Interleukin 8 (IL-8) and prostaglandin I2 (PGI2) production were measured by enzyme-linked immunosorbent assay; p38 kinase, p42/44 extracellular regulated kinase, and c-jun N terminal kinase activation were measured by Western blot. Results. HO-1 protein was increased 3-fold by exposure to hemin under all conditions. IL-8 production in response to lipopolysaccharide and xanthine oxidase was inhibited significantly by hemin exposure, although PGI2 production was not affected. The up-regulation of HO-1 protein levels resulted in the inhibition of the lipopolysaccharide- and oxidant-induced activation of all 3 mitogen-activated protein kinases: p38 kinase, p42/44 extracellular regulated kinase, and c-jun N terminal kinase. Conclusion. The induction of HO-1 by hemin results in inhibition of the proinflammatory response of endothelial cells, as evidenced by the inhibition of IL-8 production without affecting PGI2 production. All 3 mitogen-activated protein kinase signaling cascades are affected, which suggests that the mechanism of this effect may be proximal in the cell signaling process. (Surgery 2003;134:146-52.)

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