Substance P, acting via the neurokinin 1 receptor (NK1R), plays an important role in mediating a variety of inf lammatory processes. However, its role in acute pancreatitis has not been previously described. We have found that, in normal mice, substance P levels in the pancreas and pancreatic acinar cell expression of NK1R are both increased during secretagogue-induced experimental pancreatitis. To evaluate the role of substance P, pancreatitis was induced in mice that genetically lack NK1R by administration of 12 hourly injections of a supramaximally stimulating dose of the secretagogue caerulein. During pancreatitis, the magnitude of hyperamylasemia, hyperlipasemia, neutrophil sequestration in the pancreas, and pancreatic acinar cell necrosis were significantly reduced in NK1R؊͞؊ mice when compared with wild-type NK1R؉͞؉ animals. Similarly, pancreatitisassociated lung injury, as characterized by intrapulmonary sequestration of neutrophils and increased pulmonary microvascular permeability, was reduced in NK1R؊͞؊ animals. These effects of NK1R deletion indicate that substance P, acting via NK1R, plays an important proinf lammatory role in regulating the severity of acute pancreatitis and pancreatitisassociated lung injury.The neuropeptide substance P has been shown to play an important role in asthma, inflammatory bowel disease, arthritis, and other inflammatory processes (1, 2). Subsequent to its release from nerve endings, substance P binds to neurokinin 1 receptors (NK1R) on effector cells, increases microvascular permeability, and promotes plasma extravasation from the intravascular to the extravascular space. Although pancreatic acinar cells are known to express NK1R and substance P has been detected within the pancreas (3-5), apparently no studies have been reported that have examined the possibility that this neuropeptide might play a role in the evolution of a pancreatic inflammatory disease such as acute pancreatitis. We have found that pancreatic levels of substance P and the expression of NK1R on pancreatic acinar cells are increased during experimental acute pancreatitis. We have also found that genetic deletion of NK1R reduces the severity of pancreatitis and pancreatitis-associated lung injury. These observations indicate that substance P, acting through NK1R, plays an important proinflammatory role in regulating the severity of acute pancreatitis and associated lung injury. MATERIALS AND METHODSAll experiments were performed according to protocols approved by the Institutional Animal Care and Use Committee of the Beth Israel Hospital. Breeding pairs of NK1R-deficient mice were generated as described (6), and the identity of their offspring as NK1R-deficient (Ϫ͞Ϫ) homozygotes was confirmed by Southern blotting (6). Animals were bred and housed in standard shoe box cages in a climate-controlled room with an ambient temperature of 23 Ϯ 2°C and a 12-h light͞12-h dark cycle. They were fed standard laboratory chow, given water ad libitum, randomly assigned to control or experimental groups, and...

Supramaximal stimulation of the pancreas with the CCK analog caerulein causes acute edematous pancreatitis. In this model, active trypsin can be detected in the pancreas shortly after the start of supramaximal stimulation. Incubation of pancreatic acini in vitro with a supramaximally stimulating caerulein concentration also results in rapid activation of trypsinogen. In the current study, we have used the techniques of subcellular fractionation and both light and electron microscopy immunolocalization to identify the site of trypsinogen activation and the subsequent fate of trypsin during caerulein-induced pancreatitis. We report that trypsin activity and trypsinogen-activation peptide (TAP), which is released on activation of trypsinogen, are first detectable in a heavy subcellular fraction. This fraction is enriched in digestive enzyme zymogens and lysosomal hydrolases. Subsequent to trypsinogen activation, both trypsin activity and TAP move to a soluble compartment. Immunolocalization studies indicate that trypsinogen activation occurs in cytoplasmic vacuoles that contain the lysosomal hydrolase cathepsin B. These observations suggest that, during the early stages of pancreatitis, trypsinogen is activated in subcellular organelles containing colocalized digestive enzyme zymogens and lysosomal hydrolases and that, subsequent to its activation, trypsin is released into the cytosol.

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This Guideline is a joint official statement of the Asian Pacific Association of Gastroenterology (APAGE) and the Asian Pacific Society for Digestive Endoscopy (APSDE). It was developed in response to the increasing use of antithrombotic agents (antiplatelet agents and anticoagulants) in patients undergoing gastrointestinal (GI) endoscopy in Asia. After reviewing current practice guidelines in Europe and the USA, the joint committee identified unmet needs, noticed inconsistencies, raised doubts about certain recommendations and recognised significant discrepancies in clinical practice between different regions. We developed this joint official statement based on a systematic review of the literature, critical appraisal of existing guidelines and expert consensus using a two-stage modified Delphi process. This joint APAGE-APSDE Practice Guideline is intended to be an educational tool that assists clinicians in improving care for patients on antithrombotics who require emergency or elective GI endoscopy in the Asian Pacific region.

The mechanisms responsible for intrapancreatic digestive enzyme activation as well as the relationship between that activation and cell injury during pancreatitis are not understood. We have employed an in vitro system in which freshly prepared pancreatic acini are exposed to a supramaximally stimulating concentration of the CCK analog caerulein to explore these issues. We find that in vitro trypsinogen activation depends on the continued presence of Ca2+ in the suspending medium and that it is half-maximal in the presence of 0.3 mM Ca2+. Caerulein-induced trypsinogen activation can be halted by removal of Ca2+ from the suspending medium or by chelation of intracellular Ca2+. Increasing intracellular Ca2+ with either ionomycin or thapsigargin does not induce trypsinogen activation. We have monitored cell injury by measuring the leakage of lactate dehydrogenase (LDH) from acini and by quantitating intercalation of propidium iodide (PI) into DNA. Leakage of LDH and intercalation of PI in response to supramaximal stimulation with caerulein can be detected only after caerulein-induced trypsinogen activation has already occurred, and these indications of cell injury can be prevented by addition of a cell-permeant protease inhibitor. Our findings indicate that caerulein-induced intra-acinar cell activation of trypsinogen depends on a rise in intracellular Ca2+, which reflects entry of Ca2+ from the suspending medium. Intra-acinar cell activation of trypsinogen is an early as well as a critical event in pancreatitis. The subsequent cell injury in this model is mediated by activated proteases.

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Background and Aim:Low-volume polyethylene glycol with ascorbic acid (PEG-Asc) use is reported to be as safe and effective as traditional 4-L polyethylene glycol use. However, PEG-Asc produces bubbles, which cause problems during colonoscopy. Data on the effects of using antifoaming agents such as simethicone with PEG-Asc are lacking. The aim of this CONSORT-prospective, randomized, observer-blinded, controlled trial is to compare the quality of bowel preparation and compliance between PEG-Asc users and PEG-Asc plus simethicone users.Methods:Adult outpatients aged 18 to 80 years undergoing colonoscopy were recruited to the study. Two hundred sixty patients were randomly assigned to 1 of 2 treatment arms, PEG-Asc or PEG-Asc plus simethicone. The primary outcome measure was the bowel cleansing quality using Boston bowel preparation scale and bubble scores. The secondary outcome measures were patient tolerability and doctor tolerability.Results:The simethicone group showed superior cleansing results (6–9 Boston scale scores: 99% vs. 84%, <5% bubble scores: 96% vs. 49%, P < 0.001) and fewer gastrointestinal symptoms (abdominal fullness: 24% vs. 55%, colicky pain: 5% vs. 24%, P < 0.001) than the non-simethicone group. Moreover, endoscopist fatigue during colonoscopy was lower in the simethicone group than in the non-simethicone group (1.31 ± 0.75 vs. 2.97 ± 2.14, P < 0.001).Conclusion:PEG-Asc plus simethicone use was more effective and associated with better patient and endoscopist tolerance than PEG-Asc use. Therefore, this combination is recommended as one of the promising methods for bowel preparation before colonoscopy.

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