interleukin-8 and nafamostat

In cardiac operations endopeptidase (protease) inhibitor may be beneficial in reducing myocardial injury when administered in the cardiopulmonary bypass prime. Nafamostat mesilate was evaluated in 20 patients who underwent coronary artery bypass grafting. The patients were divided into a control group (n = 10) and a nafamostat group (n = 10). Nafamostat (2 mg/kg per hour) was continuously given during cardiopulmonary bypass in the nafamostat group. The age, number of grafts, cardiopulmonary bypass time, and aortic crossclamp time were similar between groups. In the control group, neither tumor necrosis factor-alpha nor interleukin-1 levels showed any significant change during cardiopulmonary bypass, whereas interleukin-6 and interleukin-8 levels, percent expression of adhesion molecule (CD18) on neutrophils, and CH50 assay results increased significantly during cardiopulmonary bypass. As compared with the control group, the nafamostat group showed significantly lower levels of interleukin-6 (123 +/- 57 versus 40 +/- 22 pg/ml, respectively) and interleukin-8 (96 +/- 13 versus 66 +/- 14 pg/ml, respectively). The nafamostat group showed a significantly lower difference of CH50 assay results and malondialdehyde levels between coronary sinus blood and arterial blood and peak values of creatine kinase MB (43 +/- 12 IU/L versus 19 +/- 6 IU/L) during the postoperative course compared with findings in the control group. These results demonstrated that inflammatory reactions induced by cardiopulmonary bypass had adverse effects on myocardial recovery after aortic crossclamping and that nafamostat mesilate given during cardiopulmonary bypass appeared to reduce myocardial reperfusion injury by attenuating such inflammatory reactions. Attenuation of inflammatory reactions of cardiopulmonary bypass should be considered in the strategy of myocardial protection.

Topics: Benzamidines; Cardiopulmonary Bypass; CD18 Antigens; Complement Hemolytic Activity Assay; Coronary Artery Bypass; Creatine Kinase; Cytokines; Fibrinolysin; Guanidines; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Isoenzymes; Malondialdehyde; Middle Aged; Myocardial Reperfusion Injury; Neutrophil Activation; Serine Proteinase Inhibitors; Tumor Necrosis Factor-alpha

Constitutive activation of nuclear factor kappa-B (NF-κB) contributes to the aggressive behavior of pancreatic cancer. Over-expression of downstream target genes of NF-κB such as intercellular adhesion molecule-1 (ICAM-1), interleukin-8 (IL-8), vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) leads to the promotion of cell adhesion, angiogenesis, invasion and metastasis. We previously reported that nafamostat mesilate, a synthetic serine protease inhibitor, blocks NF-κB activation in pancreatic cancer. We hypothesized that nafamostat mesilate may inhibit cell adhesion, angiogenesis, invasion and metastases in peritoneal dissemination of pancreatic cancer.. In vitro, we assessed inhibition of NF-κB, phosphorylated IκBα, ICAM-1, VEGF and MMP-9 activity by nafamostat mesilate using human pancreatic cancer cell lines (AsPC-1, BxPC-3 and PANC-1). Changes in adhesion and invasion abilities of cancer cells were then evaluated by nafamostat mesilate treatment. In vivo, the efficacy of nafamostat mesilate treatment was assessed using peritoneal dissemination of pancreatic cancer in mice.. In vitro, nafamostat mesilate inhibited activities of NF-κB, phosphorylated IκBα, ICAM-1, VEGF and MMP-9. Moreover, nafamostat mesilate not only inhibited cell adhesion and invasion but also increased the sensitivity of anoikis. In vivo, tumor growth using AsPC-1 cells of the treatment group was significantly slower, and survival rate was significantly better, than those in control group (p < 0.05).. Nafamostat mesilate reduced peritoneal metastasis and prolonged survival of pancreatic cancer-bearing mice.

Topics: Animals; Benzamidines; Blotting, Western; Cell Adhesion; Cell Line, Tumor; Cell Proliferation; Enzyme-Linked Immunosorbent Assay; Guanidines; Humans; Interleukin-8; Male; Mice; Mice, Inbred BALB C; Neoplasm Invasiveness; Neoplasms, Experimental; NF-kappa B; Pancreatic Neoplasms; Peritoneal Neoplasms; Protease Inhibitors; Tumor Cells, Cultured

Recently, it has been shown that serine proteases derived from microorganisms stimulate epithelial cells to produce inflammatory mediators through protease-activated receptor (PAR). We investigated the involvement of PAR2 in the interleukin (IL)-8 production by Helicobacter pylori-infected gastric epithelial cells.. Human gastric epithelial cells, MKN45 cells, were used. The expression of PAR2 was assessed by real-time PCR and immunocytochemistry, and IL-8 protein was measured by an enzyme-linked immunosorbent assay. PAR2 mRNA and protein were constitutively expressed on unstimulated MKN45 cells. The treatment of cells with H. pylori resulted in a significant increase in PAR2 expression. In addition, trypsin (a natural PAR2 agonist), SLIGKV amide (a synthetic PAR2 agonist), H. pylori live bacteria or H. pylori culture supernatant significantly induced IL-8 production from MKN45 cells. H. pylori-induced IL-8 production was inhibited by nafamostat mesilate (a serine protease inhibitor), neutralizing antibody to PAR2 and in PAR2-deficient cells treated with siRNA.. These results reveal that H. pylori-derived protease activates gastric epithelial cells to produce inflammatory cytokines through PAR2, suggesting an important role for PAR2 in the modulation of gastric inflammation associated with H. pylori.

Topics: Antibodies; Benzamidines; Cell Line, Tumor; Epithelial Cells; Gastric Mucosa; Gene Expression; Guanidines; Helicobacter Infections; Helicobacter pylori; Humans; Interleukin-8; Receptor, PAR-2; RNA, Small Interfering; Serine Proteinase Inhibitors; Transfection

We investigated the inhibitory effects of a protease inhibitor, FUT-175, on the production of interleukin 8 (IL-8) and polymorphonuclear leukocyte elastase (PMNE) by polymorphonuclear leukocytes (PMN) and vascular endothelial cells. IL-8 production by PMN and vascular endothelial cells stimulated with lipopolysaccharide (LPS) was inhibited by FUT-175. This compound also inhibited PMNE production by PMN following LPS stimulation.

Topics: Benzamidines; Endothelium, Vascular; Guanidines; Humans; Interleukin-8; Leukocyte Elastase; Lipopolysaccharides; Neutrophils; Pancreatic Elastase; Protease Inhibitors; Stimulation, Chemical