Inhibiting the inflammatory response in joint sepsis

Purpose: We created a rabbit model of infectious arthritis to test the effe cts of WRC-0470 (2-cyclohexylmethylidenehydarazinoadenosine), an adenosine analogue, and rolipram, a type IV phosphodiesterase inhibitor, on intra-art icular white blood cell recruitment. Type of Study: Randomized trial involv ing mature rabbits. Methods: Intra-articular injections ranging from 0 to 2 ,000 ng of Escherichia coli lipopolysaccharide (LPS) were tested as the inf ectious stimulus. The optimal LPS amount was determined based on synovial f luid analysis for white blood cell counts. A sepal-ate cohort of rabbits th en received various intravenous concentrations of tither rolipram, WRC-0470 , or a combination of the 2 medications. Synovial fluid aspirations after a 6-hour incubation were analyzed fur white blood cell counts. Results: Intr a-articular injections of 209 ng of LPS reproducibly generated an inflammat ory response of 4,000 cells/mL of synovial fluid, establishing the use of t his dose of LPS fur our septic arthritis model. Following infusions of 10 m ug/kg/min, the average white blood cell count dropped to 800 cells/ml for W RC-0470 (P < .01) and 1,225 cells/ml for rolipram (P < .05). A synergistic effect was seen with the combination of both medications at just 1.0 mug/kg /min, with a mean white blood cell count of 1,090 cells/ml (P < .01). Concl usions: Septic arthritis is a common clinical entity that frequently result s in major long-term morbidity. Although bacteria. can directly damage the articular surface, the cytokine-mediated immune response to the infection c an exacerbate the insult by promoting the release of proteolytic enzymes by white blood cells. Currently, no established intervention exists that will decrease the inflammatory response to infectious challenges. Our study sho ws that WRC-0470 and rolipram effectively reduce the intraarticular recruit ment of white blood cells in a septic arthritis model. Future investigation s of these drugs will determine their ultimate degree of efficacy at limiti ng the joint destruction associated with septic arthritis.