Purinergic regulation of bradykinin-induced plasma extravasation and adjuvant-induced arthritis in the rat.

Abstract

We assessed the contribution of ATP and adenosine (i) to a major sign of acute inflammation, plasma extravasation (PE), in the rat knee joint and (ii) to the severity of joint injury in adjuvant-induced experimental arthritis, a chronic inflammatory disease. PE induced by local infusion of bradykinin, which we have previously shown to depend on the sympathetic postganglionic neuron terminal, was markedly enhanced by coinfusion of either ATP or the adenosine A2-receptor agonist 2-[4-(2-carboxyethyl)phenylethylaminoJ-5'-Nethylcarboxamidoadenosine. Bradykinin-induced PE was inhibited by coinfusion of the ATP receptor antagonist adenosine 5'-[a,4-methyleneltripbosphate, the A2-receptor antagonist 3-(5H-thiozolo[2,3b]quinazolin-3-yl)phenol monohydrochloride, or the adenosine Al-receptor agonist N6-cyclopentyladenosine. The joint injury associated with experimental arthritis, which is reduced in severity in sympathectomized rats, was also markedly attenuated by daily administration of either ATP (40% reduction) or adenosine (55% reduction). These results demonstrate that the purines ATP and adenosine (acting at the A2 receptor), cotransmitters in the sympathetic postganglionic neuron terminal, enhance bradykinin-induced sympathetic postganglionic neuron terminal-dependent PE but inhibit the joint injury of arthritis. These opposing purinergic effects on PE and joint hijury suggest that enhanced PE protects against joint iury.A contribution of the peripheral limb of the sympathetic nervous system to inflammation has been demonstrated in a variety of animal models (1,2) and also in patients with inflammatory diseases, such as rheumatoid arthritis (3, 4). For example, sympathetic nerve stimulation increases vascular permeability, even though it also produces vasoconstriction (5). Consistent with these data, surgical (6, 7) or chemical (8-10) sympathectomy strongly inhibits noxious stimulus-evoked plasma extravasation (PE), a major sign of acute inflammation. Sympathectomy also markedly reduces inflammation and joint injury in rats with adjuvant-induced arthritis (11).We have recently shown that the PE produced by bradykinin (BK), a potent inflammatory agent, is mediated via an action on the sympathetic postganglionic neuron (SPGN) terminal (12). Specifically, sympathectomy significantly reduced PE evoked by infusion of BK into the knee joint of the rat. Although many SPGN neurotransmitters have been identified, our results suggested that release of the known sympathetic "cotransmitters" (i.e., norepinephrine, neuropeptide Y, and ATP) could not alone account for the PE produced by SPGN-terminal stimulation. Thus, norepinephrine inhibited PE, and neuropeptide Y had no effect on PE.Although ATP increased-PE, its effect, even at the highest doses, was smaller in amplitude and much shorter in duration than that produced by BK or by acute activation of SPGN terminals with 6-hydroxydopamine (12). Because indomethacin, a prostaglandin synthesis inhibitor, markedly reduced the PE produced by BK and because SPGNs synthesiz...

Inosine Inhibits Inflammatory Cytokine Production by a Posttranscriptional Mechanism and Protects Against Endotoxin-Induced Shock

“…The selective A 1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), A 2 antagonist 3,7-dimethyl-1-propargylxanthine (DMPX), 3-isobutyl-1-methylxanthine, protein kinase inhibitor (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24), dipyridamole, and S-(4-nitrobenzyl)-6-thioinosine (NBTI) were obtained from Research Biochemicals (Natick, MA). RPMI 1640, FCS, and penicillin-streptomycin were obtained from Life Technologies (Grand Island, NY).…”

“…The nucleoside adenosine is the best characterized of these purines, as both extracellular and intracellular adenosine have been shown to affect almost all aspects of an immune response (1)(2)(3). Adenosine and its analogues can alter the course of a variety of immunemediated/inflammatory diseases such as endotoxin shock (4,5), rheumatoid arthritis (6,7), pleural inflammation (8), nephritis (9), or uveitis (10). Adenosine is also recognized as one of the most important endogenous molecules able to prevent tissue injury in ischemia-reperfusion (11).…”

Adenosine A2 receptor‐induced inhibition of leukotriene B4 synthesis in whole blood ex vivo

“…In lymphocytes, adenosine inhibits the synthesis of immunoglobulins (Moroz & Stevens, 1980) and lymphocyte-mediated cytolysis (Wolberg et al, 1975). Recent in vivo studies have demonstrated a protective role of adenosine and its structural analogues in models of acute inflammation such as experimental adjuvant arthritis (Green et al, 1991), ischaemia-reperfusion (Grisham et al, 1989;Kaminski & Proctor, 1989;Forman et al, 1993;Marts et al, 1993) and carregeenin-induced pleural inflammation (Schrier et al, 1990). Furthermore, methotrexate, an antifolate commonly used in the treatment of rheumatoid arthritis patients, causes accumulation of adenosine and inhibition of leukocyte migration in inflammatory exudates in mice (Cronstein et al, 1993).…”

Adenosine suppresses activation of nuclear factor-κB selectively induced by tumor necrosis factor in different cell types

“…Adenosine is an endogeneous immunomodulator with anti-inflammatory properties (Daval et al, 1991(Daval et al, , 1996Cronstein, 1994). This purine nucleoside ameliorates the fate of a variety of immune-mediated diseases such as pleural inflammation (Schrier et al, 1990), ischemia-reperfusion injury (Janier et al, 1993;Bouma et al, 1997), brain ischemia and trauma (Marangos et al, 1990), rheumatoid arthritis (RA) (Green et al, 1991;Szabo et al, 1998), and endotoxin-mediated shock (Parmely et al, 1993;Hasko et al, 1996). Several of these effects could be explained by the ability of adenosine to suppress TNF produced by activated macrophages and Kupffer cells (Bouma et al, 1994;Reinstein et al, 1994;McWhinney et al, 1996;Bowlin et al, 1997;Hasko et al, 2000a) and to suppress expression of adhesion molecules by activated human endothelial cells (Bouma et al, 1996).…”