Disordered Pancreatic Inflammatory Responses and Inhibition of Fibrosis in CD39-Null Mice

Künzli, Beat; Nuhn, Philipp; Enjyoji, Keiichi; Banz, Yara; Smith, Rex Neal; Csizmadia, Eva; Schuppan, Detlef; Berberat, Pascal O.; Frieß, Helmut; Robson, Simon C.

doi:10.1053/j.gastro.2007.10.030

Cited by 42 publications

(44 citation statements)

References 27 publications

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“…The CD39 family and CD73 participate in an adaptive response to the increase in extracellular nucleotide concentration by increasing their expression and activity to decrease ATP and increase adenosine (7). Increased CD39 expression has been reported in coronary vasculature, lungs, and pancreas during inflammation and tissue damage (8,9,19). Transgenic mice that lack ENTPD1 develop increased pulmonary edema and inflammation compared with control littermates in a ventilator-induced model of lung injury (8).…”

Section: Discussionmentioning

confidence: 99%

“…Transgenic mice that lack ENTPD1 develop increased pulmonary edema and inflammation compared with control littermates in a ventilator-induced model of lung injury (8). In the cerulein model of pancreatitis, mice that lack ENTPD1 exhibited less severe atrophy and fibrosis, suggesting that upregulation of ENTPD1 is not protective in this tissue (19). It therefore appears that inhibition of extracellular ATP catabolism can have positive or negative effects, depending on the nature of inflammation.…”

Section: Discussionmentioning

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: 99%

Section: Discussionmentioning

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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“…Kunzli et al [80] showed P2X 7 R upregulation in pancreatic tissue samples isolated from patients affected by CP with respect to control samples. Moreover, in a study to understand the impact of CD39 gene deletion using a mouse model of the disease, they noted P2X 7 R upregulation [80,81]. Thus, P2X 7 R might be linked with pancreatic remodeling and fibrogenesis.…”

Section: Pancreatic Fibrosismentioning

confidence: 99%

The role of P2X7 receptors in tissue fibrosis: a brief review

Gentile

Natale

Lazzerini

et al. 2015

Purinergic Signalling

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Many previous studies have demonstrated that P2X 7 receptors (P2X 7 Rs) have a pleiotropic function in different pathological conditions and could represent a novel target for the treatment of a range of diseases. In particular, recent studies have explored the role of P2X 7 R in fibrosis, the pathological outcome of most chronic inflammatory diseases. The aim of this review is to discuss the biological features of P2X 7 R and summarize the current knowledge about the putative role of the P2X 7 R in triggering fibrosis in a wide spectrum of organs such as the lung, kidney, liver, pancreas, and heart.

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“…Recently, a study using CD39-null mice demonstrated the importance of CD39 and purinergic signaling, potentially acting by P2X7, impacting fibrosis and playing an important role in modulating extracellular matrix remodeling in inflammatory diseases of the pancreas [69].…”

Section: Immunomodulation and Cell-cell Interactionsmentioning

confidence: 99%

NTPDase and 5'‐nucleotidase activities in physiological and disease conditions: New perspectives for human health

et al. 2007

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Abstract. Extracellular nucleotides and nucleosides act as signaling molecules involved in a wide spectrum of biological effects. Their levels are controlled by a complex cell surface-located group of enzymes called ectonucleotidases. There are four major families of ectonucleotidases, nucleoside triphosphate diphosphohydrolases (NTPDases/CD39), ectonucleotide pyrophosphatase/phosphodiesterases (E-NPPs), alkaline phosphatases and ecto-5'-nucleotidase. In the last few years, substantial progress has been made toward the molecular identification of members of the ectonucleotidase families and their enzyme structures and functions. In this review, there is an emphasis on the involvement of NTPDase and 5'-nucleotidase activities in disease processes in several tissues and cell types. Brief background information is given about the general characteristics of these enzymes, followed by a discussion of their roles in thromboregulatory events in diabetes, hypertension, hypercholesterolemia and cancer, as well as in pathological conditions where platelets are less responsive, such as in chronic renal failure. In addition, immunomodulation and cell-cell interactions involving these enzymes are considered, as well as ATP and ADP hydrolysis under different clinical conditions related with alterations in the immune system, such as acute lymphoblastic leukemia (ALL), Bchronic lymphocytic leukemia (B-CLL) and infections associated with human immunodeficiency virus (HIV). Finally, changes in ATP, ADP and AMP hydrolysis induced by inborn errors of metabolism, seizures and epilepsy are discussed in order to highlight the importance of these enzymes in the control of neuronal activity in pathological conditions. Despite advances made toward understanding the molecular structure of ectonucleotidases, much more investigation will be necessary to entirely grasp their role in physiological and pathological conditions.

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Disordered Pancreatic Inflammatory Responses and Inhibition of Fibrosis in CD39-Null Mice

Cited by 42 publications

References 27 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

The role of P2X7 receptors in tissue fibrosis: a brief review

NTPDase and 5'‐nucleotidase activities in physiological and disease conditions: New perspectives for human health

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