An adenosine A_2A receptor agonist reduces interleukin‐8 expression and glycosaminoglycan loss following septic arthrosis

Abstract

The purpose of this study was to determine whether an adenosine AZA receptor agonist (ATL146e) might augment the current treatment regimen of antibiotics plus irrigation and debridement to prevent the arthritic effects associated with joint sepsis. Staph-~ZOCOCCUS aureus bacteria were injected into knees of rabbits, which were divided into 4 treatment groups (12 rabbits per group): no treatment, ATL146e only, antibiotics only, or antibiotics plus ATL146e. Analysis at days 1,3, and 7 consisted of gross joint appearance, synovial fluid, serum, histologic, immunohistochemical, and biochemical analysis.Synovial fluid cultures at day 7 were negative in all antibiotic and antibiotic plus ATL146e treated knees indicating clearance of bacteria. Average WBC counts from synovial fluid aspirates significantly decreased with treatment of antibiotics alone and antibiotics plus ATL146e. Treatment with antibiotics plus ATL146e significantly decreased the Interleukin-8 content when compared to other treatment groups (p < 0.001) indicating inflammatory response suppression. Histologic grading resulted in notably improved scores in the antibiotics plus ATL146e group compared to other treatment groups (p < 0.001). Glycosaminoglycan assay values were significantly greater in the ATL146e plus antibiotics group compared to the untreated control group (p < 0.04) indicating chondroprotection.agonist in combination with antibiotic therapy diminishes joint WBC chemotaxis and reduces joint inflammation, while not compromising the clearance of intraarticular bacteria in a rabbit model. Early bacterial clearance with modulation of the inflammatory response appears to prevent the early degradative effects of joint sepsis.

Cartilage repair with osteochondral autografts in sheep: Effect of biophysical stimulation with pulsed electromagnetic fields

“…23,24 The effect of PEMFs on cartilage has been attributed to the A 2A adenosine receptor agonist activity, as demonstrated by saturation binding experiments conducted in neutrophils 25 ; the activation of this receptor plays a fundamental role in the prevention of cartilage degeneration also in a septic osteoarthritis model in rabbits. [26][27][28] In vitro and in vivo research support the hypothesis that PEMFs may influence both subchondral bone and cartilage tissue, and thus exert a positive effect on osteochondral graft healing by favoring early subchondral bone integration and by limiting inflammation and cartilage degeneration.…”

Electromagnetic fields (EMFs) and adenosine receptors modulate prostaglandin E2 and cytokine release in human osteoarthritic synovial fibroblasts

“…Both in basal conditions and in the presence of IL‐1β, we did not observe any effect induced by EMFs and/or ARs in the modulation of the enzymes analyzed, showing that, at least in OASFs, the matrix degradative pathway does not seem to be affected by EMFs or ARs. On the other hand, in vivo, the separate ability of adenosine analogs and EMFs to limit joint destruction has been previously proven in animal models (Cohen et al, 2005; Fini et al, 2005; Ochaion et al, 2008). In this view, the present results suggest that these chondroprotective effects might result from the control of the inflammatory microenvironment associated to OA (Goldring and Goldring, 2007; De Mattei et al, 2009; Martel‐Pelletier and Pelletier, 2010; Kapoor et al, 2011) as well as from the EMF anabolic role on cartilage (De Mattei et al, 2003, 2004, 2007; Ongaro et al, 2011).…”

“…Recently, the four subtypes of ARs have been pharmacologically characterized in human SFs from OA patients (OASFs) and a role for A 2A and A 3 ARs in the inhibition of inflammation has been suggested (Varani et al, 2010). The role played by adenosine receptors is supported by the observation that “in vivo” adenosine analogs inhibit joint destruction when used in the treatment of septic arthrosis and adjuvant induced arthritis (Cohen et al, 2005; Ochaion et al, 2008).…”

Adenosine Receptors: What We Know and What We are Learning

“…In several different in vivo models of inflammation selective A 2A AR agonists decreased the inflammatory response: decreased pleocytosis and reduced blood brain barrier permeability in a rat model of endotoxin-stimulated meningitis [192], decreased transmigration of leukocytes in endotoxin-stimulated rabbit knee joint septic arthritis [193], and reduced tissues injury and inflammation in mice with toxin A-induced enteritis (infection immunity) [194]. Additionally, in non-infectious animal models, A 2A AR activation also induced reperfusion injury, in part by decreasing the inflammatory response [195].…”