Regulation of enteric functions by adenosine: Pathophysiological and pharmacological implications

Antonioli, Luca; Fornai, Matteo; Colucci, Rocchina; Ghisu, Narcisa; Tuccori, Marco; Tacca, M. Del; Blandizzi, Corrado

doi:10.1016/j.pharmthera.2008.08.010

Cited by 104 publications

(123 citation statements)

References 284 publications

(329 reference statements)

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“…Taken together these data support the concept that: 1) inhibitors of adenosine deaminase are effective not only in protecting bowel tissues from the onset of inflammation, but also in blunting the inflammatory response in the setting of established colitis; and 2) the antiinflammatory actions resulting from inhibition of the catabolic breakdown of endogenous adenosine are driven by the recruitment of A 2A and A 3 receptors. There is increasing evidence in the literature indicating a marked involvement of A 2A and A 3 receptors in the modulation of immune cell activity and inflammation (Antonioli et al, 2008a;Haskó et al, 2008). In particular, previous works have shown that A 2A is the primary receptor responsible for the inhibitory effect of adenosine on the production of proinflammatory cytokines and reactive oxygen species at sites of inflammation in different experimental models, including asthma, chronic obstructive pulmonary disease, and arthritis (Haskó et al, 2000(Haskó et al, , 2008Haskó and Cronstein, 2004).…”

Section: Controlmentioning

confidence: 99%

“…Several lines of evidence indicate that adenosine can play a significant part in the mitigation of abnormal inflammatory responses (Antonioli et al, 2008a). Indeed, under inflammatory conditions adenosine, through dynamic changes in the expression and/or function of its ectoenzymes, participates actively in a fine-tuning of immune cellular activities, thus playing an important role in limiting the inflammatory insults to host tissues (Desrosiers et al, 2007;Antonioli et al, 2008b).…”

Section: Introductionmentioning

confidence: 99%

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The Blockade of Adenosine Deaminase Ameliorates Chronic Experimental Colitis through the Recruitment of Adenosine A_2Aand A₃Receptors

Antonioli¹,

Fornai²,

Colucci³

et al. 2010

J Pharmacol Exp Ther

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Adenosine modulates immune/inflammatory reactions. This study investigates the expression of adenosine deaminase in the inflamed colon, the effects of adenosine deaminase inhibitors on established colitis, and the recruitment of adenosine receptors by endogenous adenosine after adenosine deaminase blockade. Adenosine deaminase expression was determined by Western blot. The effects of 4-amino-2-(2-hydroxy-1-decyl)pyrazole [3,4-d]pyrimidine (APP; a novel adenosine deaminase inhibitor), erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA; a reference adenosine deaminase inhibitor), dexamethasone, and selective adenosine receptor antagonists were tested in rats with 2,4-dinitrobenzenesulfonic acid-induced colitis. Systemic (food intake, body and spleen weight) and colonic [macroscopic/microscopic damage, tumor necrosis factor-␣ (TNF-␣), interleukin-6 (IL-6), and malondialdehyde (MDA)] inflammatory parameters were assessed. Test drugs were administered intraperitoneally for 6 days, starting at day 5 from colitis induction. Adenosine deaminase was detected in normal colon, and its expression was increased in inflamed tissues. Colitis was associated with decreased food intake and body weight, augmented spleen weight, and increased levels of colonic TNF-␣, IL-6, and MDA. APP or EHNA, but not dexamethasone, improved food intake and body weight. APP, EHNA, and dexamethasone counteracted the increments of spleen weight, ameliorated macroscopic and microscopic indexes of inflammation, and reduced TNF-␣, IL-6, and MDA levels. The beneficial effects of APP and EHNA on inflammatory parameters were prevented by the pharmacological blockade of A 2A or A 3 receptors, but not A 1 or A 2B . The present results show that: 1) bowel inflammation is associated with an enhanced adenosine deaminase expression; and 2) the anti-inflammatory actions of adenosine deaminase inhibitors against chronic established colitis depend on the sparing of endogenous adenosine, leading to enhanced A 2A and A 3 receptor activation.

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Section: Controlmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Blockade of Adenosine Deaminase Ameliorates Chronic Experimental Colitis through the Recruitment of Adenosine A_2Aand A₃Receptors

Antonioli¹,

Fornai²,

Colucci³

et al. 2010

J Pharmacol Exp Ther

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“…Adenosine (ADO) is a purinergic signaling molecule that profoundly affects gut function, including motility, ion secretion, and the modulation of inflammation (Antonioli et al, 2008;Ye and Rajendran, 2009). Most of the research regarding extracellular ADO signaling in the gut has addressed enteric neurons, smooth muscle, afferent neurons, and the immune system, with relatively few studies addressing its effect on epithelial secretory function.…”

Section: Introductionmentioning

confidence: 99%

Endogenous Luminal Surface Adenosine Signaling Regulates Duodenal Bicarbonate Secretion in Rats

Ham

Mizumori²,

Watanabe³

et al. 2010

J Pharmacol Exp Ther

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Luminal ATP increases duodenal bicarbonate secretion (DBS) via brush border P2Y receptors. Because ATP is sequentially dephosphorylated to adenosine (ADO) and the brush border highly expresses adenosine deaminase (ADA), we hypothesized that luminal [ADO] regulators and sensors, including P1 receptors, ADA, and nucleoside transporters (NTs) regulate DBS. We measured DBS with pH and CO 2 electrodes, perfusing ADO Ϯ adenosine receptor agonists or antagonists or the cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor CFTR inh -172 on DBS. Furthermore, we examined the effect of inhibitors of ADA or NT on DBS. Perfusion of AMP or ADO (0.1 mM) uniformly increased DBS, whereas inosine had no effect. The A 1/2 receptor agonist 5Ј-(N-ethylcarboxamido)-adenosine (0.1 mM) increased DBS, whereas ADO-augmented DBS was inhibited by the potent A 2B receptor antagonist N-(4-cyanophenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)phenoxy]-acetamide (MRS1754) (10 M). Other selective adenosine receptor agonists or antagonists had no effect. The A 2B receptor was immunolocalized to the brush border membrane of duodenal villi, whereas the A 2A receptor was immunolocalized primarily to the vascular endothelium. Furthermore, ADO-induced DBS was enhanced by 2Ј-deoxycoformycin (1 M) and formycin B (0.1 mM), but not by S-(4-nitrobenzyl)-6-thioinosine (0.1 mM), and it was abolished by CFTR inh -172 pretreatment (1 mg/kg i.p). Moreover, ATP (0.1 mM)-induced DBS was partially reduced by (1R,2S,4S,5S)-4-2-iodo-6-(methylamino)-9H-purin-9-yl]-2-(phosphonooxy)bicyclo[3.1.0] hexane-1-methanol dihydrogen phosphate ester tetraammonium salt (MRS2500) or 8-[4-[4-(4-chlorophenzyl)piperazide-1-sulfonyl) phenyl]]-1-propylxanthine (PSB603) and abolished by both, suggesting that ATP is sequentially degraded to ADO. Luminal ADO stimulates DBS via A 2B receptors and CFTR. ATP release, ectophosphohydrolases, ADA, and concentrative NT may coordinately regulate luminal surface ADO concentration to modulate ADO-P1 receptor signaling in rat duodenum.

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“…Several lines of evidence suggest that adenosine regulates immunity and inflammation (Amann and Peskar, 2002;Montesinos et al, 2007). The wide distribution of adenosine receptors (AR) as well as enzymes for purine metabolism in different gut regions suggests a complex role for this mediator in the regulation of gastrointestinal functions (Antonioli et al, 2008). Adenosine binds to four different types of G protein-coupled cell surface receptors referred to as A 1 R, A 2A R, A 2B R, and A 3 R, each having a unique pharmacological profile, tissue distribution and signalling pathway (Jacobson and Gao, 2006).…”

Section: Introductionmentioning

confidence: 99%

Adenosine Receptors: New Targets to Protect Against Tissue Damage in Inflammatory Bowel Symptoms

Michael¹,

Rauwald²,

Abdel-Aziz³

et al. 2012

Inflammatory Bowel Disease - Advances in Pathogenesis and Management

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Regulation of enteric functions by adenosine: Pathophysiological and pharmacological implications

Cited by 104 publications

References 284 publications

The Blockade of Adenosine Deaminase Ameliorates Chronic Experimental Colitis through the Recruitment of Adenosine A_2Aand A₃Receptors

The Blockade of Adenosine Deaminase Ameliorates Chronic Experimental Colitis through the Recruitment of Adenosine A_2Aand A₃Receptors

Endogenous Luminal Surface Adenosine Signaling Regulates Duodenal Bicarbonate Secretion in Rats

Adenosine Receptors: New Targets to Protect Against Tissue Damage in Inflammatory Bowel Symptoms

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Regulation of enteric functions by adenosine: Pathophysiological and pharmacological implications

Cited by 104 publications

References 284 publications

The Blockade of Adenosine Deaminase Ameliorates Chronic Experimental Colitis through the Recruitment of Adenosine A2Aand A3Receptors

The Blockade of Adenosine Deaminase Ameliorates Chronic Experimental Colitis through the Recruitment of Adenosine A2Aand A3Receptors

Endogenous Luminal Surface Adenosine Signaling Regulates Duodenal Bicarbonate Secretion in Rats

Adenosine Receptors: New Targets to Protect Against Tissue Damage in Inflammatory Bowel Symptoms

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Product

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The Blockade of Adenosine Deaminase Ameliorates Chronic Experimental Colitis through the Recruitment of Adenosine A_2Aand A₃Receptors

The Blockade of Adenosine Deaminase Ameliorates Chronic Experimental Colitis through the Recruitment of Adenosine A_2Aand A₃Receptors