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 E2 [PGE2], interleukin [IL]-1beta, IL-6, and tumor necrosis factor [TNF]-alpha) 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, PGE2, TNF-alpha, IL-6, and IL-1beta 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 PGE2, TNF-alpha, IL-6, and IL-1beta. Although subcutaneously administered CaPPS had no effect on the accumulation of fluid, white cell numbers, or PGE2 levels within the pouch, there was a 38% reduction in TNF-alpha 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-1beta 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-alpha 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.