Inhibiting the inflammatory response in joint sepsis.
PURPOSE: We created a rabbit model of infectious arthritis to test the effects of WRC-0470 (2-cyclohexylmethylidenehydarazinoadenosine), an adenosine analogue, and rolipram, a type IV phosphodiesterase inhibitor, on intra-articular white blood cell recruitment. Type of Study: Randomized trial involving mature rabbits. METHODS: Intra-articular injections ranging from 0 to 2,000 ng of Escherichia coli lipopolysaccharide (LPS) were tested as the infectious stimulus. The optimal LPS amount was determined based on synovial fluid analysis for white blood cell counts. A separate cohort of rabbits then received various intravenous concentrations of either rolipram, WRC-0470, or a combination of the 2 medications. Synovial fluid aspirations after a 6-hour incubation were analyzed for white blood cell counts. RESULTS: Intra-articular injections of 200 ng of LPS reproducibly generated an inflammatory response of 4,000 cells/mL of synovial fluid, establishing the use of this dose of LPS for our septic arthritis model. Following infusions of 10 µg/kg/min, the average white blood cell count dropped to 800 cells/mL for WRC-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 µg/kg/min, with a mean white blood cell count of 1,090 cells/mL (P <.01). CONCLUSIONS: Septic arthritis is a common clinical entity that frequently results in major long-term morbidity. Although bacteria can directly damage the articular surface, the cytokine-mediated immune response to the infection can 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 shows that WRC-0470 and rolipram effectively reduce the intra-articular recruitment of white blood cells in a septic arthritis model. Future investigations of these drugs will determine their ultimate degree of efficacy at limiting the joint destruction associated with septic arthritis.
Hogan
Christopher J.
CJ
Departments of Orthopaedic Surgery (C.J.H., D.R.D.) and Infectious Diseases (G-D.F., W.M.S., J.L.), The University of Virginia School of Medicine, Charlottesville, Virginia, U.S.A.
Fang
Guo-Dong
GD
Scheld
W. Michael
WM
Linden
Joel
J
Diduch
David R.
DR