Purinergic receptors in gastrointestinal inflammation

Kolachala, Vasantha L.; Bajaj, Rahul; Chalasani, Meghana; Sitaraman, Shanthi V.

doi:10.1152/ajpgi.00454.2007

Cited by 78 publications

(83 citation statements)

References 135 publications

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“…It has become increasingly evident that extracellular purinergic signaling is disordered during disease and may play a role in pathogenesis (3,18). In the present study, we have identified an important role for ENTPD1 in defective vascular regulation during colitis.…”

Section: Discussionmentioning

confidence: 51%

“…The RNA was reprecipitated using LiCl precipitation solution (Ambion). Subsequently, cDNA was reverse transcribed from 1 g of total RNA using SuperScript III (Invitrogen) and oligo(dT) [12][13][14][15][16][17][18] primers (Invitrogen). Real-time PCR was performed using the primers listed in Table 2 with a Roche Lightcycler and the Quantitech SYBR Green PCR kit (Qiagen).…”

Section: Animals and Materialsmentioning

confidence: 99%

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Loss of purinergic vascular regulation in the colon during colitis is associated with upregulation of CD39

Neshat¹,

deVries²,

Barajas-Espinosa³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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Neshat S, deVries M, Barajas-Espinosa AR, Skeith L, Chisholm SP, Lomax AE. Loss of purinergic vascular regulation in the colon during colitis is associated with upregulation of CD39. Am J Physiol Gastrointest Liver Physiol 296: G399 -G405, 2009. First published December 12, 2008 doi:10.1152/ajpgi.90450.2008.-Evidence from patients with inflammatory bowel disease (IBD) and animal models suggests that inflammation alters blood flow to the mucosa, which precipitates mucosal barrier dysfunction. Impaired purinergic sympathetic regulation of submucosal arterioles, the resistance vessels of the splanchnic vasculature, is one of the defects identified during IBD and in mouse models of IBD. We hypothesized that this may be a consequence of upregulated catabolism of ATP during colitis. In vivo and in vitro video microscopy techniques were employed to measure the effects of purinergic agonists and inhibitors of CD39, an enzyme responsible for extracellular ATP catabolism, on the diameter of colonic submucosal arterioles from control mice and mice with dextran sodium sulfate [DSS, 5% (wt/vol)] colitis. Using a luciferase-based ATP assay, we examined the degradation of ATP and utilized real-time PCR, Western blotting, and immunohistochemistry to examine the expression and localization of CD39 during colitis. Arterioles from mice with DSS colitis did not constrict in response to ATP (10 M) but did constrict in the presence of its nonhydrolyzable analog ␣,␤-methylene ATP (1 M). ␣,␤-Methylene ADP (100 M), an inhibitor of CD39, restored ATP-induced vasoconstriction in arterioles from mice with DSS-induced colitis. CD39 protein and mRNA expression was markedly increased during colitis. Immunohistochemical analysis demonstrated that, in addition to vascular CD39, F4/80-immunoreactive macrophages accounted for a large proportion of submucosal CD39 staining during colitis. These data implicate upregulation of CD39 in impaired sympathetic regulation of gastrointestinal blood flow during colitis. purinergic neurotransmission; ectonucleotidase; inflammation; sympathetic; vasoconstriction STUDIES OF PATIENTS WITH INFLAMMATORY bowel disease (IBD) and animal models of IBD have revealed alterations in gastrointestinal (GI) blood flow (2,15,22,26) and angiogenesis (4 -6). These changes may contribute to disease pathogenesis, inasmuch as defects in mucosal perfusion render the mucosal barrier susceptible to breakdown. One potential mechanism of altered mucosal blood flow is defective neural regulation of GI blood vessels during inflammation.Submucosal arterioles are the resistance vessels of the splanchnic vasculature and thus regulate mucosal perfusion (13,23,31). We previously identified a defect in sympathetic vasoconstrictor regulation of colonic submucosal arterioles in the 2,4,6-trinitrobenzene sulfonic acid (TNBS) mouse model of IBD (22). Neurally evoked vasoconstrictions in control mice were sensitive to ␣ 1 -adrenoceptor and purinergic receptor antagonism, and superfusion of ATP and phenylephrine caused robust vasoconstrictions. I...

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Section: Discussionmentioning

confidence: 51%

Section: Animals and Materialsmentioning

confidence: 99%

Loss of purinergic vascular regulation in the colon during colitis is associated with upregulation of CD39

Neshat¹,

deVries²,

Barajas-Espinosa³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…A2bR is the only receptor expressed in epithelial cells of cecum and colon. A3R can be detected in jejunum and proximal colon [45,46] . Adenosine receptors are members of the G protein-coupled family of receptors [47] .…”

Section: Physiology Of Adenosine Metabolism By Intestinal Epithelium mentioning

confidence: 99%

Adenosine: An immune modulator of inflammatory bowel diseases

Ye¹,

Rajendran²

2009

WJG

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Inflammatory bowel disease (IBD) is a common and lifelong disabling gastrointestinal disease. Emerging treatments are being developed to target inflammatory cytokines which initiate and perpetuate the immune response. Adenosine is an important modulator of inflammation and its anti-inflammatory effects have been well established in humans as well as in animal models. High extracellular adenosine suppresses and resolves chronic inflammation in IBD models. High extracellular adenosine levels could be achieved by enhanced adenosine absorption and increased de novo synthesis. Increased adenosine concentration leads to activation of the A2a receptor on the cell surface of immune and epithelial cells that would be a potential therapeutic target for chronic intestinal inflammation.Adenosine is transported via concentrative nucleoside transporter and equilibrative nucleoside transporter transporters that are localized in apical and basolateral membranes of intestinal epithelial cells, respectively. Increased extracellular adenosine levels activate the A2a receptor, which would reduce cytokines responsible for chronic inflammation.

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“…It is reasonable then to suggest that these abnormalities in purinergic receptors or signaling pathways would have a significant impact on the overall behavior of the gut, enteric reflexes, and secretomotor behavior of the gut in bowel diseases. Purinergic receptors in gastrointestinal inflammation were the subject of a recent review by Kolachala et al [61]. A recent study by Guzman et al [45] using high-density oligonucleotide microarray analysis and SYBR-Green RT-PCR validation provided direct proof for differential dysregulation (upregulation or downregulation depending on the purine gene) of P2X 1 , P2X 2 , P2X 4 , P2X 7 , P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , A 2a , A 2b , A 1 , or A 3 receptors in whole thickness gut specimens of experimental trinitrobenzene sulfonic acid (TNBS) colitis in rats .…”

Section: Differential Dysregulation Of Purinoceptors In Gi Disease Stmentioning

confidence: 99%

Purinergic receptors and gastrointestinal secretomotor function

Christofi

2008

Purinergic Signalling

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Secretomotor reflexes in the gastrointestinal (GI) tract are important in the lubrication and movement of digested products, absorption of nutrients, or the diarrhea that occurs in diseases to flush out unwanted microbes. Mechanical or chemical stimulation of mucosal sensory enterochromaffin (EC) cells triggers release of serotonin (5-HT) (among other mediators) and initiates local reflexes by activating intrinsic primary afferent neurons of the submucous plexus. Signals are conveyed to interneurons or secretomotor neurons to stimulate chloride and fluid secretion. Inputs from myenteric neurons modulate secretory rates and reflexes, and special neural circuits exist to coordinate secretion with motility. Cellular components of secretomotor reflexes variably express purinergic receptors for adenosine (A1, A2a, A2b, or A3 receptors) or the nucleotides adenosine 5′-triphosphate (ATP), adenosine diphosphate (ADP), uridine 5′-triphosphate (UTP), or uridine diphosphate (UDP) (P2X 1-7 , P2Y 2 , P2Y 4 , P2Y 6 , P2Y 12 receptors). This review focuses on the emerging concepts in our understanding of purinergic regulation at these receptors, and in particular of mechanosensory reflexes. Purinergic inhibitory (A 1 , A 3 , P2Y 12 ) or excitatory (A 2 , P2Y 1 ) receptors modulate mechanosensitive 5-HT release. Excitatory (P2Y 1 , other P2Y, P2X) or inhibitory (A 1 , A 3 ) receptors are involved in mechanically evoked secretory reflexes or "neurogenic diarrhea." Distinct neural (pre-or postsynaptic) and non-neural distribution profiles of P2X 2 , P2X 3 , P2X 5 , P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , or P2Y 12 receptors, and for some their effects on neurotransmission, suggests their role in GI secretomotor function. Luminal A 2b , P2Y 2 , P2Y 4 , and P2Y 6 receptors are involved in fluid and Cl -, HCO 3 -, K + , or mucin secretion. Abnormal receptor expression in GI diseases may be of clinical relevance. Adenosine A 2a or A 3 receptors are emerging as therapeutic targets in inflammatory bowel diseases (IBD) and gastroprotection; they can also prevent purinergic receptor abnormalities and diarrhea. Purines are emerging as fundamental regulators of enteric secretomotor reflexes in health and disease.

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Purinergic receptors in gastrointestinal inflammation

Cited by 78 publications

References 135 publications

Loss of purinergic vascular regulation in the colon during colitis is associated with upregulation of CD39

Loss of purinergic vascular regulation in the colon during colitis is associated with upregulation of CD39

Adenosine: An immune modulator of inflammatory bowel diseases

Purinergic receptors and gastrointestinal secretomotor function

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