L. Antonioli

CD39 and CD73 in immunity and inflammation

The enzymatic activities of CD39 and CD73 play strategic roles in calibrating the duration, magnitude, and chemical nature of purinergic signals delivered to immune cells through the conversion of ADP/ATP to AMP and AMP to adenosine, respectively. This drives a shift from an ATP-driven proinflammatory environment to an anti-inflammatory milieu induced by adenosine. The CD39/CD73 pathway changes dynamically with the pathophysiological context in which it is embedded. It is becoming increasingly appreciated that altering this catabolic machinery can change the course or dictate the outcome of several pathophysiological events, such as AIDS, autoimmune diseases, infections, atherosclerosis, ischemia-reperfusion injury, and cancer, suggesting these ectoenzymes are novel therapeutic targets for managing a variety of disorders.

Adenosine signaling and the immune system: When a lot could be too much

Adenosine is increasingly recognized as a key mediator of the immune response. Signals delivered by extracellular adenosine are detected and transduced by G-protein-coupled cell-surface receptors, classified into four subtypes: A1, A2A, A2B and A3. These receptors, expressed virtually on all immune cells, modulate all aspects of immune/inflammatory responses. These immunoregulatory effects, which are mostly anti-inflammatory, contribute to the general tissue protective effects of adenosine and its receptors. In some instances, however, the effect of adenosine on the immune system is deleterious, as prolonged adenosine signaling can hinder anti-tumor and antibacterial immunity, thereby promoting cancer development and progression and sepsis, respectively.

SACCHAROMYCES BOULARDIIREDUCES THE SEVERITY OF HERPES SIMPLEX VIRUS TYPE 1- INDUCED GASTROINTESTINAL DYSFUNCTION

INTRODUCTION: WOPN is a frequent sequel of acute necrotizing pancreatitis. The best approach for drainage of these collections is still controversial. We present our retrospective data comparing the two endoscopic methods for drainage of WOPN. AIMS & METHODS: Outcomes of patients undergoing EUS guided transmural drainage (EUTMD) using a newly designed fully covered large-bore wide-flare metal stent (Nagi stent) (Gr I) were compared to the outcomes of patients who underwent placement of multiple plastic stents (Gr II). The pre-op CECT confirmed suitability of endoscopic drainage based on location, wall thickness & contents. Visual quantification of necrosis (450% solid debris) by EUS excluded 8 patients (3 in Gr I and 5 in Gr. II). The procedure in both groups is done by standard technique by a single endoscopist. The difference between the two groups was tract dilatation (6 mm in Gr I vs. 18 mm in Gr II). Placement of NCT and subsequent necrosectomy was done whenever necessary. Follow-up imaging was done at 72 hrs and thereafter at 2, 4, & 6 weeks. The outcomes were compared in terms of clinical success, need for surgery, complications, hospital stay and mortality. RESULTS:N: 21(Gr. I), 61(Gr. II). The two groups were comparable in terms of demographics, etiology of pancreatitis, cyst location, size and amount of debris. Placement of NCT, need of necrosectomy and no of sessions required were also not different between the two groups. Clinical success defined as resolution of symptoms was seen in 100% of Gr. I patients vs. 73% in Gr. II (p1⁄4 0.048). None of the patients in Gr I required subsequent surgery vs 20/61 (32.7%) in Gr. II (p1⁄4 0.025). Complications: 15% in Gr. I vs 37% in Gr. II (p1⁄4 0.016) Mean hospital stay was 4 days (1-33) in Gr. I vs 8 (4-65) in Gr II (p1⁄4 0.012). Mortality was none in Gr. I vs. 6.5% (4/61) in Gr. II (p1⁄4 0.22) CONCLUSION: The Nagi stent is effective and safe for EUTMD of WOPN. It permits rapid clinical resolution with 100% technical and clinical success rates. It offers distinct advantage over plastic stents although further prospective studies are warranted. Disclosure of Interest: None declared

Cyclooxygenase inhibitors modulate pro-fibrotic signalling mediated by transforming growth factor beta in experimental colitis

Objective: In gastrointestinal diseases, drug discovery targeting 5-HT receptors has been developed focusing on antiemetic and treatment for irritable bowel syndrome targeting 5-HT3 receptors and on gastrointestinal motility activation targeting 5-HT4 receptors. Recently, we found a new pharmacological activity mediated 5-HT receptors showing actions of neural regeneration and neurogenesis. Methods: In this study, we are focusing on promoting effect of 5-HT4 receptor-activation on in vivo neural regeneration and neurogenesis in rodent rectal transection and anastomosis (RTA) and intestinal transection and anastomosis (ITA) models. Results: In rat and guinea-pig RTA models, local and oral treatment with mosapride citrate (10–100 l mol L) promoted enteric neural regeneration and neurogenesis at the anastomotic site from neural stem cells for 2 weeks after the surgery. In mouse ITA model, oral treatment with mosapride citrate (100 l mol L) promoted enteric neural regeneration and neurogenesis at the anastomotic site for 1 week after the surgery. Especially, in guinea pig model, the recovery of rectal distension-induced internal anal sphincter (IAS) relaxation reflex response was found for 2 weeks after the surgery. 5-HT4 receptor antagonists, GR113808 (10 l mol L) and SB 207266 (10–50 l mol L) suppressed 5-HT4 receptor activation induced neural regeneration and neurogenesis, and the recovery of IAS relaxation reflex response. In addition, we found mosapride citrate enhanced mobilization of neural stem cells by subcutaneous transplantation of gel sponge experiments in rats. This effect contributes to in vivo neural regeneration and neurogenesis. Furthermore, we confirmed transplanted embryonic neural stem cells of central nervous system from tail vein mobilized at the anastomotic site in mouse ITA model with oral application of mosapride for 1 week. Conclusion: Drug discovery based on the evidence of the present study will propose the possibility contributing to pharmacotherapy for defecation dysfunction after surgery and gastrointestinal motility dysfunction due to decreased enteric neurons in diabetic patients, pseudo-Hirschsprung’s disease patients and elders. 002 Mechanosensitive myenteric neurons in the guinea pig gastric corpus G. MAZZUOLI and M. SCHEMANN Techn. Universität München, Inst. für Human Biologie, Freising, Germany, and TU Munich, Human Biology, Freising, Germany

Interplay between colonic inflammation and tachykininergic pathways in the onset of colonic dysmotility in a mouse model of diet-induced obesity

BackgroundThe murine model of high fat diet (HFD)-induced obesity is characterized by an increment of intestinal permeability, secondary to an impairment of mucosal epithelial barrier and enteric inflammation, followed by morphofunctional rearrangement of the enteric nervous system. The present study investigated the involvement of abdominal macrophages in the mechanisms underlying the development of enteric dysmotility associated with obesity.MethodsWild type C57BL/6J mice were fed with HFD (60% kcal from fat) or normocaloric diet (NCD, 18% kcal from fat) for 8 weeks. Groups of mice fed with NCD or HFD were treated with clodronate encapsulated into liposomes to deplete abdominal macrophages. Tachykininergic contractions, elicited by electrical stimulation or exogenous substance P (SP), were recorded in vitro from longitudinal muscle colonic preparations. Substance P distribution was examined by confocal immunohistochemistry. The density of macrophages in the colonic wall was examined by immunohistochemical analysis. Malondialdehyde (MDA, colorimetric assay) and IL-1β (ELISA assay) levels were also evaluated.ResultsMDA and IL-1β levels were increased in colonic tissues from HFD-treated animals. In colonic preparations, electrically evoked tachykininergic contractions were enhanced in HFD mice. Immunohistochemistry displayed an increase in substance P immunoreactivity in myenteric ganglia, as well as in the muscular layers of colonic cryosections from obese mice. Macrophage depletion in HFD mice was associated with a significant reduction of colonic inflammation. In addition, the decrease in macrophage density attenuated the morphofunctional alterations of tachykininergic pathways observed in obese mice.ConclusionObesity elicited by HFD determines a condition of colonic inflammation, followed by a marked rearrangement of motor excitatory tachykininergic enteric nerves. Macrophage depletion counteracted the morphofunctional changes of colonic neuromuscular compartment, suggesting a critical role for these immune cells in the onset of enteric dysmotility associated with obesity.

Modulatory role of adenosine A2B receptors in fibrotic gut wall remodeling associated with experimental colitis

s from Purines 2014, an International Conference on Nucleotides, Nucleosides and Nucleobases, held in Bonn, Germany, from July 23–27, 2014 Published online: 3 December 2014 # Springer Science+Business Media Dordrecht 2014 Abstracts—Plenary Lecturess—Plenary Lectures

Role of adenosine receptors in the control of enteric neuromuscular functions under normal conditions and in the presence of bowel inflammation

s from Purines 2014, an International Conference on Nucleotides, Nucleosides and Nucleobases, held in Bonn, Germany, from July 23–27, 2014 Published online: 3 December 2014 # Springer Science+Business Media Dordrecht 2014 Abstracts—Plenary Lecturess—Plenary Lectures

Alterations of colonic cholinergic and tachykininergic motility in a rat model of Parkinson’s Disease

Objective: In gastrointestinal diseases, drug discovery targeting 5-HT receptors has been developed focusing on antiemetic and treatment for irritable bowel syndrome targeting 5-HT3 receptors and on gastrointestinal motility activation targeting 5-HT4 receptors. Recently, we found a new pharmacological activity mediated 5-HT receptors showing actions of neural regeneration and neurogenesis. Methods: In this study, we are focusing on promoting effect of 5-HT4 receptor-activation on in vivo neural regeneration and neurogenesis in rodent rectal transection and anastomosis (RTA) and intestinal transection and anastomosis (ITA) models. Results: In rat and guinea-pig RTA models, local and oral treatment with mosapride citrate (10–100 l mol L) promoted enteric neural regeneration and neurogenesis at the anastomotic site from neural stem cells for 2 weeks after the surgery. In mouse ITA model, oral treatment with mosapride citrate (100 l mol L) promoted enteric neural regeneration and neurogenesis at the anastomotic site for 1 week after the surgery. Especially, in guinea pig model, the recovery of rectal distension-induced internal anal sphincter (IAS) relaxation reflex response was found for 2 weeks after the surgery. 5-HT4 receptor antagonists, GR113808 (10 l mol L) and SB 207266 (10–50 l mol L) suppressed 5-HT4 receptor activation induced neural regeneration and neurogenesis, and the recovery of IAS relaxation reflex response. In addition, we found mosapride citrate enhanced mobilization of neural stem cells by subcutaneous transplantation of gel sponge experiments in rats. This effect contributes to in vivo neural regeneration and neurogenesis. Furthermore, we confirmed transplanted embryonic neural stem cells of central nervous system from tail vein mobilized at the anastomotic site in mouse ITA model with oral application of mosapride for 1 week. Conclusion: Drug discovery based on the evidence of the present study will propose the possibility contributing to pharmacotherapy for defecation dysfunction after surgery and gastrointestinal motility dysfunction due to decreased enteric neurons in diabetic patients, pseudo-Hirschsprung’s disease patients and elders. 002 Mechanosensitive myenteric neurons in the guinea pig gastric corpus G. MAZZUOLI and M. SCHEMANN Techn. Universität München, Inst. für Human Biologie, Freising, Germany, and TU Munich, Human Biology, Freising, Germany

Role of A2B receptors in the control of colonic cholinergic motility in the presence of bowel inflammation

Objective: In gastrointestinal diseases, drug discovery targeting 5-HT receptors has been developed focusing on antiemetic and treatment for irritable bowel syndrome targeting 5-HT3 receptors and on gastrointestinal motility activation targeting 5-HT4 receptors. Recently, we found a new pharmacological activity mediated 5-HT receptors showing actions of neural regeneration and neurogenesis. Methods: In this study, we are focusing on promoting effect of 5-HT4 receptor-activation on in vivo neural regeneration and neurogenesis in rodent rectal transection and anastomosis (RTA) and intestinal transection and anastomosis (ITA) models. Results: In rat and guinea-pig RTA models, local and oral treatment with mosapride citrate (10–100 l mol L) promoted enteric neural regeneration and neurogenesis at the anastomotic site from neural stem cells for 2 weeks after the surgery. In mouse ITA model, oral treatment with mosapride citrate (100 l mol L) promoted enteric neural regeneration and neurogenesis at the anastomotic site for 1 week after the surgery. Especially, in guinea pig model, the recovery of rectal distension-induced internal anal sphincter (IAS) relaxation reflex response was found for 2 weeks after the surgery. 5-HT4 receptor antagonists, GR113808 (10 l mol L) and SB 207266 (10–50 l mol L) suppressed 5-HT4 receptor activation induced neural regeneration and neurogenesis, and the recovery of IAS relaxation reflex response. In addition, we found mosapride citrate enhanced mobilization of neural stem cells by subcutaneous transplantation of gel sponge experiments in rats. This effect contributes to in vivo neural regeneration and neurogenesis. Furthermore, we confirmed transplanted embryonic neural stem cells of central nervous system from tail vein mobilized at the anastomotic site in mouse ITA model with oral application of mosapride for 1 week. Conclusion: Drug discovery based on the evidence of the present study will propose the possibility contributing to pharmacotherapy for defecation dysfunction after surgery and gastrointestinal motility dysfunction due to decreased enteric neurons in diabetic patients, pseudo-Hirschsprung’s disease patients and elders. 002 Mechanosensitive myenteric neurons in the guinea pig gastric corpus G. MAZZUOLI and M. SCHEMANN Techn. Universität München, Inst. für Human Biologie, Freising, Germany, and TU Munich, Human Biology, Freising, Germany