Lewis Neville

Effects of a metalloporphyrinic peroxynitrite decomposition catalyst, ww-85, in a mouse model of spinal cord injury

The aim of the present study was to assess the effect of a metalloporphyrinic peroxynitrite decomposition catalyst, ww-85, in the pathophysiology of spinal cord injury (SCI) in mice. Spinal cord trauma was induced by the application of vascular clips to the dura via a four-level T5–T8 laminectomy. SCI in mice resulted in severe trauma characterized by oedema, neutrophil infiltration, production of inflammatory mediators, tissue damage and apoptosis. ww-85 treatment (30–300 µg/kg, i.p. 1 h after the SCI) significantly reduced in a dose-dependent manner: (1) the degree of spinal cord inflammation and tissue injury, (2) neutrophil infiltration (myeloperoxidase activity), (3) nitrotyrosine formation and PARP activation, (4) pro-inflammatory cytokines expression, (5) NF-κB activation and (6) apoptosis. Moreover, ww-85 significantly ameliorated the recovery of limb function (evaluated by motor recovery score) in a dose-dependent manner. The results demonstrate that ww-85 treatment reduces the development of inflammation and tissue injury associated with spinal cord trauma.

Therapy with anti-flagellin A monoclonal antibody limits Pseudomonas aeruginosa invasiveness in a mouse burn wound sepsis model

BACKGROUND The aim of this study was to evaluate the effect of an anti-flagellin sub-type monoclonal antibody (anti-fla-a) on Pseudomonas aeruginosa infection in a mouse burn model and to assay bacterial dissemination and invasiveness. METHODS After immediate post-burn infection with P. aeruginosa, mortality and morbidity (daily weight changes) were monitored in mice treated with anti-fla-a as compared to untreated mice. Bacterial dissemination and invasiveness were monitored by bacterial counts at the burn site and spleen. Three different timing regimens for anti-fla-a treatment were studied: (a) prophylaxis (pre-infection), (b) therapeutic (post-infection), and (c) combined mode. RESULTS Combined regimen of anti-fla-a markedly improved survival of mice infected with P. aeruginosa from 6% to 96% (p<0.0001), similar to treatment with Imipenem. Furthermore, a significant improvement in survival was obtained when anti-fla-a was given prior to (75% survival) or post-infection (50% survival). It reduced bacterial load in the spleen (p=0.01), preventing bacterial sepsis. CONCLUSION Anti-fla-a is effective in reducing mortality and morbidity in murine P. aeruginosa-infected burn model.

Efficacy of antibodies against the N-terminal of Pseudomonas aeruginosa flagellin for treating infections in a murine burn wound model.

Background: In an era of increasing drug resistance, immunotherapy is a desirable treatment against Pseudomonas aeruginosa infections. The flagellum, which is an important pseudomonal virulence factor, was targeted for immunotherapy. The aim of the study was to evaluate the efficacy of polyclonal immunotherapy targeted against the N-terminal of flagellin (anti-N′-fla-b) for treating severe P. aeruginosa infection in a murine burn wound model. Methods: Groups of 12 mice were infected (subeschar) with P. aeruginosa strain PA01, and were treated either with systemic anti-N′-fla-b immunoglobulin G (IgG), nonspecific IgG, or imipenem. The control groups included mice with burn alone, mice with untreated infected burn, and mice without burn infected with P. aeruginosa. Three separate regimens were examined: prophylaxis (preinfection), therapeutic (postinfection), and combined. The efficacy of anti-N′-fla-b was evaluated by monitoring the mortality and morbidity (relative weight loss) during a period of 2 weeks. Results: Anti-N′-fla-b IgG immunotherapy significantly decreased the mortality rate of infected burned mice followed by severe P. aeruginosa infection. The mortality rate in the anti-N′-fla-b–treated groups ranged from 0 to 17 percent compared with 58 to 83 percent in nontreated groups infected with 2 to 5 × 106 colony-forming units of P. aeruginosa (p < 0.05). The mortality rate in the anti-N′-fla-b–treated groups was similar to that of groups treated with imipenem. The three tested regimens yielded similar results. Morbidity paralleled survival results. Histopathologic examination revealed an earlier reepithelialization of the infected wound in the anti-N′-fla-b–treated mice compared with untreated mice. Conclusion: Immunotherapy with anti-N′-fla-b IgG, given either as prophylaxis or therapeutically, effectively reduced mortality and morbidity and improved wound healing in a severely P. aeruginosa–infected murine burn model.