A crucial role for TNF-alpha in mediating neutrophil influx induced by endogenously generated or exogenous chemokines, KC/CXCL1 and LIX/CXCL5.

BACKGROUND AND PURPOSE: Chemokines orchestrate neutrophil recruitment to inflammatory foci. In the present study, we evaluated the participation of three chemokines, KC/CXCL1, MIP-2/CXCL2 and LIX/CXCL5, which are ligands for chemokine receptor 2 (CXCR2), in mediating neutrophil recruitment in immune inflammation induced by antigen in immunized mice. EXPERIMENTAL APPROACH: Neutrophil recruitment was assessed in immunized mice challenged with methylated bovine serum albumin, KC/CXCL1, LIX/CXCL5 or tumour necrosis factor (TNF)-alpha. Cytokine and chemokine levels were determined in peritoneal exudates and in supernatants of macrophages and mast cells by elisa. CXCR2 and intercellular adhesion molecule 1 (ICAM-1) expression was determined using immunohistochemistry and confocal microscopy. KEY RESULTS: Antigen challenge induced dose- and time-dependent neutrophil recruitment and production of KC/CXCL1, LIX/CXCL5 and TNF-alpha, but not MIP-2/CXCL2, in peritoneal exudates. Neutrophil recruitment was inhibited by treatment with reparixin (CXCR1/2 antagonist), anti-KC/CXCL1, anti-LIX/CXCL5 or anti-TNF-alpha antibodies and in tumour necrosis factor receptor 1-deficient mice. Intraperitoneal injection of KC/CXCL1 and LIX/CXCL5 induced dose- and time-dependent neutrophil recruitment and TNF-alpha production, which were inhibited by reparixin or anti-TNF-alpha treatment. Macrophages and mast cells expressed CXCR2 receptors. Increased macrophage numbers enhanced, while cromolyn sodium (mast cell stabilizer) diminished, LIX/CXCL5-induced neutrophil recruitment. Macrophages and mast cells from immunized mice produced TNF-alpha upon LIX/CXCL5 stimulation. Methylated bovine serum albumin induced expression of ICAM-1 on mesenteric vascular endothelium, which was inhibited by anti-TNF-alpha or anti-LIX/CXCL5. CONCLUSION AND IMPLICATIONS: Following antigen challenge, CXCR2 ligands are produced and act on macrophages and mast cells triggering the production of TNF-alpha, which synergistically contribute to neutrophil recruitment through induction of the expression of ICAM-1.

Effects of nitric oxide on neutrophil influx depends on the tissue: role of leukotriene B4 and adhesion molecules.

BACKGROUND AND PURPOSE: We investigated the effect of nitric oxide synthase (NOS) inhibition on polymorphonuclear cell (PMN) influx in zymosan or lipopolysaccharide (LPS)-induced arthritis and peritonitis. EXPERIMENTAL APPROACH: Wistar rats received intra-articular (i.art.) zymosan (30-1000 microg) or LPS (1-10 microg). Swiss C57/Bl6 mice genetically deficient in intercellular adhesion molecule-1 (ICAM-1(-/-)) or in beta(2)-integrin (beta(2)-integrin(-/-)) received zymosan either i.art. or i.p. PMN counts, leukotriene B(4) (LTB(4)), tumour necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) levels were measured in joint and peritoneal exudates. Groups received the NOS inhibitors N(G)-nitro-L-arginine methyl ester (LN), nitro-L-arginine, N-[3-(aminomemethyl)benzyl] acetamide or aminoguanidine, prior to zymosan or LPS, given i.p. or s.c. in the arthritis and peritonitis experiments respectively. A group of rats received LN locally (i.art. or i.p.), 30 min prior to 1 mg zymosan i.art. KEY RESULTS: Systemic or local NOS inhibition significantly prevented PMN migration in arthritis while increasing it in peritonitis, regardless of stimuli, concentration of NOS inhibitors and species. NOS inhibition did not alter TNF-alpha and IL-10 but decreased LTB(4) in zymosan-induced arthritis. LN administration significantly inhibited PMN influx into the joints of ICAM-1(-/-) and beta(2)-integrin(-/-) mice with zymosan-arthritis, while not altering PMN influx into the peritoneum of mice with zymosan-peritonitis. CONCLUSIONS AND IMPLICATIONS: Nitric oxide has a dual modulatory role on PMN influx into joint and peritoneal cavities that is stimulus- and species-independent. Differences in local release of LTB(4) and in expression of ICAM-1 and beta(2)-integrin account for this dual role of NO on PMN migration.

Peroxynitrite mediates the failure of neutrophil migration in severe polymicrobial sepsis in mice.

BACKGROUND AND PURPOSE: Sepsis is a systemic inflammatory response resulting from the inability of the host to restrict local infection. The failure of neutrophil migration to the infection site is one of the mechanisms involved in this process. Recently, it was demonstrated that this event is mediated by nitric oxide (NO). The present study addresses the possibility that peroxynitrite (ONOO(-)), a NO-derived powerful oxidizing and nitrating compound, could also be involved in neutrophil migration failure. EXPERIMENTAL APPROACH: Male C57Bl/6 mice were subjected to moderate (MSI) or severe (SSI) septic injury, both induced by cecal ligation and puncture (CLP). The leukocyte rolling and adhesion in the mesentery was evaluated by intravital microscopy. Cytokines (TNF-alpha and MIP-1alpha) were measured by ELISA and 3-nitrotyrosine (3-NT) by immunofluorescence. KEY RESULTS: Compared with saline pretreatment of SSI mice, pre-treatment with uric acid, a ONOO(-) scavenger, partially restored the failure of neutrophil rolling, adhesion and migration to the site of infection. These mice also presented low circulating bacterial counts and diminished systemic inflammatory response. Pretreatment with uric acid reduced 3-NT labelling in leukocytes in mesenteric tissues and in neutrophils obtained from peritoneal exudates. Finally, uric acid pretreatment enhanced significantly the survival rate in the SSI mice. Similarly, treatment with FeTPPs, a more specific ONOO(-) scavenger, re-established neutrophil migration and increased mice survival rate. CONCLUSIONS AND IMPLICATIONS: These results indicate that ONOO(-) contributed to the reduction of neutrophil/endothelium interaction and the consequent failure of neutrophil migration into infection foci and hence susceptibility to severe sepsis.

Common misconceptions about oral health in the older adult: nursing practices.

A survey of nurses, director-supervisors, and nursing home health aides who provide home care in Iowa showed that many misconceptions exist about what constitutes appropriate oral and dental care practices for the older adult. Despite differences in formal education among these nursing personnel, several misunderstandings about dental problems among older adults were common to all three employment groups. These misconceptions represented a broad range of topics from the characteristics of oral cancer lesions to the appropriate use of denture adhesives; two dealt specifically with the recognition of potential oral cancer lesions. This paper describes attitudes and misinformation held by the respondents, and suggests ways to correct these fallacies through in-service training programs.