Therapeutic cocktails for rheumatoid arthritis: the mixmaster's guide.
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Antirheumatic Agents↗
Biomedical subjects
Bruce N Cronstein
Publications and source records attributed to Bruce N Cronstein.
Adenosine: an endogenous regulator of innate immunity.
Although inflammatory and immunological reactions protect the host from invasion by microorganisms and eliminate debris at sites of tissue injury, they can also be responsible for significant tissue damage. Thus, regulatory mechanisms that limit damage from an overly exuberant immune response have evolved. It is increasingly apparent that adenosine, a purine nucleoside that is elaborated at injured and inflamed sites, has a central role in the regulation of inflammatory responses and in limiting inflammatory tissue destruction. Adenosine, called a 'retaliatory metabolite' because it is a regulatory autocoid that is generated as a result of cellular injury or stress, interacts with specific G protein-coupled receptors on inflammatory and immune cells to regulate their function. The effects of adenosine, acting at its receptors, on the functions of the cells that mediate innate immune responses, will be reviewed.
Adenosine↗
Adenosine A(2A) receptor activation promotes wound neovascularization by stimulating angiogenesis and vasculogenesis.
Recent reports indicate that circulating endothelial progenitor cells (EPCs) may be recruited to sites of neovascularization where they differentiate into endothelial cells (EC). As we have previously demonstrated that adenosine A(2A) agonists promote neovascularization in wounds, we sought to determine whether adenosine A(2A) receptor agonist-augmented wound healing involves vessel sprouting (angiogenesis) or EPC recruitment (vasculogenesis) or both. Four weeks after bone marrow reconstitution from donor FVB/N Tie2GFP transgenic mice, two full-thickness excisional wounds were performed on the dorsum of FVB/N wild-type mice and treated with either an A(2A) receptor agonist (CGS-21680) or vehicle alone. Vessel density, as measured by CD31 staining, and density of EPC-derived vessels, as measured by GFP expression, were quantified in a blinded fashion using two-color fluorescence microscopy. We observed nearly a threefold increase in CD31-positive vessels and a more than 10-fold increase in GFP-positive cells in A(2A) agonist-treated 3-day old wounds, but by 6 days after wounding the differences between A(2A) agonist-treated and vehicle-treated wounds were no longer statistically significant. In conclusion, this is the first evidence that an exogenous agent such as an adenosine A(2A) receptor agonist increases neovascularization in the early stages of wound repair by increasing both EPC recruitment (vasculogenesis) and local vessel sprouting (angiogenesis).
Adenosine↗
Th1 cytokines regulate adenosine receptors and their downstream signaling elements in human microvascular endothelial cells.
We and others have shown that adenosine, acting at its receptors, is a potent modulator of inflammation and angiogenesis. To better understand the regulation of adenosine receptors during these processes we studied the effects of IL-1, TNF-alpha, and IFN-gamma on expression and function of adenosine receptors and select members of their coupling G proteins in human dermal microvascular endothelial cells (HMVEC). HMVEC expressed message and protein for A(2A) and A(2B), but not A(1) or A(3) receptors. IL-1 and TNF-alpha treatment increased message and protein expression of A(2A) and A(2B) receptor. IFN-gamma treatment also increased the expression of A(2B) receptors, but decreased expression of A(2A) receptors. Resting HMVEC and IFN-gamma-treated cells showed minimal cAMP response to the selective A(2A) receptor agonist 2-[2-(4-chlorophenyl)ethoxy]adenosine (MRE0094). In contrast, MRE0094 stimulated a dose-dependent increase in cAMP levels in TNF-alpha-treated cells that was almost completely blocked by the A(2A) receptor antagonist ZM-241385 (4-[2-[7-amino-2-(2-furyl)[1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-ylamino]ethyl]phenol). The nonselective adenosine receptor agonist 5'-(N-ethylcarboxamido)adenosine increased cAMP levels in both TNF-alpha- and IFN-gamma-treated cells, but not control cells, and its effect was only partially reversed by ZM-241385 in TNF-alpha-treated cells and not affected in IFN-gamma-treated cells. HMVEC expressed a higher level of G protein beta1 isoform than beta4 isoform. Although none of the cytokines tested affected G(beta1) expression, both IL-1 and TNF-alpha significantly up-regulated G(beta4) expression. These findings indicate that inflammatory cytokines modulate adenosine receptor expression and function on HMVECs and suggest that the interaction between proinflammatory cytokines and adenosine receptors may affect therapeutic responses to anti-inflammatory drugs that act via adenosine-dependent mechanisms.
3' Flanking Region↗
Adenosine A2A or A3 receptors are required for inhibition of inflammation by methotrexate and its analog MX-68.
OBJECTIVE: Low-dose weekly methotrexate therapy remains a mainstay in the treatment of inflammatory arthritis. Results of previous studies demonstrated that adenosine, acting at one or more of its receptors, mediates the antiinflammatory effects of methotrexate in animal models of both acute and chronic inflammation. We therefore sought to establish which receptor(s) is involved in the modulation of acute inflammation by methotrexate and its nonpolyglutamated analog MX-68 (N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]-carbonyl]-L-homoglutamic acid). METHODS: We studied the effects of low-dose methotrexate (0.75 mg/kg intraperitoneally [IP] every week for 5 weeks), MX-68 (2 mg/kg IP 2 days and 1 hour before induction of inflammation), dexamethasone (1.5 mg/kg IP 1 hour before induction of inflammation), or vehicle control on acute inflammation in an air-pouch model in A(2A) and A(3) receptor knockout mice. RESULTS: Low-dose weekly methotrexate treatment increased the adenosine concentration in the exudates of all mice studied and reduced leukocyte and tumor necrosis factor alpha accumulation in the exudates of wild-type mice, but not in those of A(2A) or A(3) receptor knockout mice. Dexamethasone, an agent that suppresses inflammation by a different mechanism, was equally effective at suppressing leukocyte accumulation in A(2A) knockout, A(3) knockout, and wild-type mice, indicating that the lack of response was specific for methotrexate and MX-68. CONCLUSION: These findings confirm that adenosine, acting at A(2A) and A(3) receptors, is a potent regulator of inflammation. Moreover, these results provide strong evidence that adenosine, acting at either or both of these receptors, mediates the antiinflammatory effects of methotrexate and its analog MX-68.
2-Aminoadipic Acid↗
Bovine thrombin and systemic autoimmunity.
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Administration, Topical↗
Molecular action of methotrexate in inflammatory diseases.
Despite the recent introduction of biological response modifiers and potent new small-molecule antirheumatic drugs, the efficacy of methotrexate is nearly unsurpassed in the treatment of inflammatory arthritis. Although methotrexate was first introduced as an antiproliferative agent that inhibits the synthesis of purines and pyrimidines for the therapy of malignancies, it is now clear that many of the anti-inflammatory effects of methotrexate are mediated by adenosine. This nucleoside, acting at one or more of its receptors, is a potent endogenous anti-inflammatory mediator. In confirmation of this mechanism of action, recent studies in both animals and patients suggest that adenosine-receptor antagonists, among which is caffeine, reverse or prevent the anti-inflammatory effects of methotrexate.
Adenosine↗
Non-prostaglandin effects of aspirin III and salicylate: inhibition of integrin-dependent human neutrophil aggregation and inflammation in COX 2- and NF kappa B (P105)-knockout mice.
Two, non-prostaglandin effects of antiinflammatory levels of salicylates (i.e. aspirin III) are shown here: 1) Exposure of neutrophils to aspirin or sodium salicylate inhibited Erk activity and integrin-dependent aggregation of neutrophils, consistent with antiinflammation but not COX inhibition. Inhibition of Mek (proximal activator of Erk) also blocked stimulation of Erk and neutrophil aggregation by FMLP and arachidonic acid. Thus, the antiinflammatory effects of salicylates may be mediated by inhibition of Erk signaling required for integrin-mediated responses. 2) Acute inflammation was induced in murine air-pouches of wild-type mice and mice rendered deficient in either COX-2 or p105, the precursor of p50 of NF kappa B. The antiinflammatory effects of aspirin and sodium salicylate were independent of the presence of COX-2 or p105 component of NF kappa B or the levels of prostaglandins at the inflammatory site. In contrast, glucocorticoid action depended on the p105.
Acetaminophen↗
Adenosine promotes wound healing and mediates angiogenesis in response to tissue injury via occupancy of A(2A) receptors.
Recent evidence indicates that topical application of adenosine A(2A) receptor agonists, unlike growth factors, increases the rate at which wounds close in normal animals and promotes wound healing in diabetic animals as well as growth factors, yet neither the specific adenosine receptor involved nor the mechanism(s) by which adenosine receptor occupancy promotes wound healing have been fully established. To determine which adenosine receptor is involved and whether adenosine receptor-mediated stimulation of angiogenesis plays a role in promotion of wound closure we compared the effect of topical application of the adenosine receptor agonist CGS-21680 (2-p-[2-carboxyethyl]phenethyl-amino-5'-N-ethylcarboxamido-adenosine) on wound closure and angiogenesis in adenosine A(2A) receptor knockout mice and their wild-type littermates. There was no change in the rate of wound closure in the A(2A) receptor knockout mice compared to their wild-type littermates although granulation tissue formation was nonhomogeneous and there seemed to be greater inflammation at the base of the wound. Topical application of CGS-21680 increased the rate of wound closure and increased the number of microvessels in the wounds of wild-type mice but did not affect the rate of wound closure in A(2A) receptor knockout mice. Similarly, in a model of internal trauma and repair (murine air pouch model), endogenously produced adenosine released into areas of internal tissue injury stimulates angiogenesis because there was a marked reduction in blood vessels in the walls of healing air pouches of A(2A) receptor knockout mice compared to their wild-type controls. Inflammatory vascular leakage and leukocyte accumulation in the inflamed air pouch were similarly reduced in the A(2A) receptor knockout mice reflecting the reduced vascularity. Thus, targeting the adenosine A(2A) receptor is a novel approach to promoting wound healing and angiogenesis in normal individuals and those suffering from chronic wounds.
Adenosine↗
Adenosine A2A receptor agonists promote more rapid wound healing than recombinant human platelet-derived growth factor (Becaplermin gel).
Animal studies of the topical application of adenosine A2A receptor agonists show that it promotes wound closure. To further confirm the efficacy of adenosine A2A receptor agonists as promoters of wound healing, we compared the effect of MRE0094, a novel selective adenosine A2A receptor agonist, to CGS-21680, a reference selective adenosine A2A receptor agonist, as well as to recombinant human platelet-derived growth factor (0.01% Becaplermin gel), an agent currently used to promote healing of diabetic ulcers, on wound closure in healthy BALB/C mice. Wounds (approximately 12 mm diameter) were created on the dorsum of mice (two per mouse) and then treated daily with vehicle, 0.01% Becaplermin gel, or different doses of the adenosine A2A receptor agonists. The wound margins were traced onto plastic sheets, and the wound areas were digitized, quantitated, and compared. We found that application of MRE0094 (1 microg/wound and 10 microg/wound) and CGS-21680 (1 microg/wound and 5 microg/wound) achieved 50% wound closure significantly more rapidly than control application (day 1.9, 1.9, 3.5, 3.2, respectively, versus control day 4, p < 0.05 ANOVA). Surprisingly, neither higher nor lower concentrations of CGS-21680 affected the rate of wound closure, as compared to control. In contrast, Becaplermin gel did not increase the rate at which wounds closed (50% closure by day 7.2, p = NS versus control). These data confirm our prior observations that adenosine A2A receptor agonists promote wound closure, and they suggest that these agents may be as effective if not more effective than Becaplermin gel for the treatment of poorly healing wounds.
Adenosine↗
Cyclooxygenase-2-selective inhibitors: translating pharmacology into clinical utility.
Anti-inflammatory agents have been used for centuries, but only in the last few decades has medical science gained insight into the complex biologic roles of the primary mediators of inflammation, the eicosanoids and their derivatives. Detailed understanding of the prostaglandins and leukotrienes provides a framework for the treatment of pain, inflammation, and fever with aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), but these agents have exacted a substantial side effect burden. The discovery of cyclooxygenase-2 (COX-2) has guided development of rationally designed therapeutic agents that have the benefits of older NSAIDs with reduced gastrointestinal toxicity. Elucidation of the structure of COX isoenzymes has been key in the development of coxibs, the COX-2-selective subset of NSAIDs. Methods to determine the degree of COX-2 selectivity have been refined and are indispensable for comparing the relative selectivity of these agents. This review summarizes some of the key aspects of COX biochemistry, structure, and function and the evolution of understanding the mechanism of action of COX-2-selective inhibitors. The clinical relevance of COX-1 compared with COX-2 inhibition is discussed to provide a framework upon which clinicians can better appreciate current and future therapeutic applications of coxibs.
Anti-Inflammatory Agents, Non-Steroidal↗