Rat Air Pouch Model Of Inflammation Research Articles

S100A8 Triggers Oxidation-sensitive Repulsion of Neutrophils

The inflammatory response to tissue injury is a multi-faceted process. During this process, neutrophils migrate in the extravascular spaces, directed to the site of injury by chemical gradients generated by chemotactic molecules. S100A8, a protein associated with a wide variety of inflammatory conditions, is heavily over-expressed in association with inflammation. We hypothesized that human S100A8 possesses neutrophil-repelling properties that result in an anti-inflammatory effect in vivo. The chemotactic activity of S100A8 on neutrophils was tested in Transwell chemotaxis assays. Analysis of the data indicates that S100A8 causes a repulsion of peripheral neutrophils, an activity that S100A8 loses upon its oxidation. Using a mutant of S100A8 resistant to oxidation and consistent with the in vitro findings, we demonstrated that S100A8 causes a strong anti-inflammatory effect in the rat air-pouch model of inflammation in vivo. These data highlight a naturally occurring novel anti-inflammatory pathway and provide potential molecular targets for the development of novel anti-inflammatory therapeutics. Abbrevations: ethylene diamine tetraacetic acid (EDTA); limulus amoebocyte lysate assay (LAL); pertussis toxin (PTX); forward scatter (FSC); Interleukin-8 (IL-8); formyl-Met-Leu-Phe (fMLP); monocyte chemotactic protein 1 (MCP1).

Comparative study of anti-inflammatory and ulcerogenic activities of different cyclo-oxygenase inhibitors

The aim of the present work was to study the in vivo anti-inflammatory activity of six NSAIDs, ibuprofen, diclofenac, nimesulide, meloxicam, celecoxib and rofecoxib, using the rat air-pouch model of inflammation to characterize the ability of these drugs to induce gastric damage and PGE(2) inhibition. Selective compounds were observed to have no ulcerogenic properties at anti-inflammatory doses; however, these drugs were weaker inhibitors of several inflammatory aspects such as cell influx and exudate formation. In contrast, the non-selective and preferential compounds present anti-inflammatory properties at lower doses than presented by selective drugs. At anti-inflammatory doses, only meloxicam and ibuprofen produced gastric damage and inhibition of PGE(2) synthesis, suggesting that ulcerogenic properties of NSAIDs cannot be predicted by their selectivity index, since meloxicam demonstrates ulcerogenic properties despite its preferential profile.

The effects of calcium pentosan polysulfate on inflammatory mediators in the rat air-pouch model of inflammation

A new calcium-chelated derivative of pentosan polysulfate (CaPPS) is currently under investigation as a potential disease-modifying antiarthritic agent. In the present study the effects of CaPPS on edema production, cellular infiltration, and activity of inflammatory mediators (prostaglandin E 2 [PGE 2], interleukin [IL]-1β, IL-6, and tumor necrosis factor [TNF]-α) using the rat subcutaneous air-pouch model of inflammation are reported. CaPPS or saline was injected subcutaneously daily for 7 days (study days 8 to 14) at concentrations of 0.5 to 10 mg/kg of body weight into the abdomen of rats with preformed noninflamed or peptone-inflamed dorsal pouches. The pouch fluid volume, white cell count, differential white cell count, PGE 2, TNF-α, IL-6, and IL-1β levels were determined using standard methods after the rats were sacrificed on day 15. In saline-treated control animals, injection of peptone into rat air pouches provoked a large influx of fluid and white cells, with a concomitant increase in levels of PGE 2, TNF-α, IL-6, and IL-1β. Although subcutaneously administered CaPPS had no effect on the accumulation of fluid, white cell numbers, or PGE 2 levels within the pouch, there was a 38% reduction in TNF-α activity in the presence of 2.5 to 10 mg/kg body weight of drug ( P < 0.05). In contrast, IL-6 activity increased 21% to 47% compared with saline-treated control rats ( P < 0.05) when CaPPS concentrations of 0.5 to 10 mg/kg body weight were used. The levels of IL-1β in pouch fluid remained the same as saline-treated rats over this dose range. These findings indicated that CaPPS could elicit specific effects on cytokine production by leukocytes and synovial cells. It is proposed that the reduction by CaPPS in TNF-α levels in inflamed rat air pouches, combined with the ability of CaPPS to elevate IL-6, may enhance the known chondroprotective activity of this drug.

Tumour necrosis factor production in a rat airpouch model of inflammation: role of eicosanoids.

TNF is a potent cytokine which can induce many of the pathological changes associated with inflammatory disease. In vitro studies have demonstrated that 5-lipoxygenase products promote the production of TNF by activated macrophages, suggesting that 5-lipoxygenase inhibitors may have therapeutic utility for the treatment of inflammatory conditions. A rat airpouch model of inflammation has been used to investigate the relationship between eicosanoid generation and TNF production in vivo. Injection of zymosan into the airpouch caused a time-dependent stimulation of TNF production which preceded leukotriene generation by at least 30 minutes. Injection of LPS into the airpouch also stimulated TNF production but not leukotriene generation. The selective 5-lipoxygenase inhibitors, ICI207968, A64077 and BWA4C, and the 5-lipoxygenase translocation inhibitor MK886, decreased leukotriene generation but enhanced TNF production. Taken together, these results do not support a role for 5-lipoxygenase products in the regulation of TNF production in vivo.