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Acute pancreatitis (AP) is often accompanied by alterations in the acid-base balance, but how blood pH influences the outcome of AP is largely unknown. We studied the association between blood pH and the outcome of AP with meta-analysis of clinical trials, and aimed to discover the causative relationship between blood pH and AP in animal models. PubMed, EMBASE, and Cochrane Controlled Trials Registry databases were searched from inception to January 2017. Human studies reporting systemic pH status and outcomes (mortality rate, severity scores, and length of hospital stay) of patient groups with AP were included in the analyses. We developed a new mouse model of chronic metabolic acidosis (MA) and induced mild or severe AP in the mice. Besides laboratory blood testing, the extent of pancreatic edema, necrosis, and leukocyte infiltration were assessed in tissue sections of the mice. Thirteen studies reported sufficient data in patient groups with AP (n = 2,311). Meta-analysis revealed markedly higher mortality, elevated severity scores, and longer hospital stay in AP patients with lower blood pH or base excess (P < 0.001 for all studied outcomes). Meta-regression analysis showed significant negative correlation between blood pH and mortality in severe AP. In our mouse model, pre-existing MA deteriorated the pancreatic damage in mild and severe AP and, vice versa, severe AP further decreased the blood pH of mice with MA. In conclusion, MA worsens the outcome of AP, while severe AP augments the decrease of blood pH. The discovery of this vicious metabolic cycle opens up new therapeutic possibilities in AP.

Objective: Defective mucus production in the pancreas may be an important factor in the initiation and progression of chronic pancreatitis (CP), therefore we aimed to (i) investigate the qualitative and quantitative changes of mucus both in human CP and in an experimental pancreatitis model and (ii) to correlate the mucus phenotype with epithelial ion transport function. Design: Utilizing human tissue samples and a murine model of cerulein induced CP we measured pancreatic ductal mucus content by morphometric analysis and the relative expression of different mucins in health and disease. Pancreatic fluid secretion in CP model was measured in vivo by magnetic resonance cholangiopancreatography (MRCP) and in vitro on cultured pancreatic ducts. Time-changes of ductal secretory function were correlated to those of the mucin production. Results: We demonstrate increased mucus content in the small pancreatic ducts in CP. Secretory mucins MUC6 and MUC5B were upregulated in human, Muc6 in mouse CP. In vivo and in vitro fluid secretion was decreased in cerulein-induced CP. Analysis of time-course changes showed that impaired ductal ion transport is paralleled by increased Muc6 expression. Conclusion: Mucus accumulation in the small ducts is a combined effect of mucus hypersecretion and epithelial fluid secretion defect, which may lead to ductal obstruction. These results suggest that imbalance of mucus homeostasis may have an important role in the early-phase development of CP, which may have novel diagnostic and therapeutic implications.

Acute pancreatitis (AP) is the inflammation of pancreas, usually a mild and self-limited process but not uncommonly complicated and severe, which leads to multiple organ dysfunctions. The reported annual incidence of AP has ranged from 4.9 to 73.5 per 100,000 worldwide.1 Severe AP (SAP) occurs in 15% to 20% of these patients and requires intensive approaches in critical care units with mortality rates as high as 30%.2–4 Cytokines and inflammatory mediators were accused for systemic manifestations of the disease; on the other hand, translocation of enteric bacteria is the most important cause of subsequent systemic events such as sepsis and related complications.5,6 Thus, preventive and therapeutic strategies on deteriorating AP should target both protection of mucosal integrity and modulation of inflammatory mediators. Poly(ADP-ribose) polymerase (PARP) enzyme system, which was one of the targets of this study, is responsible for the control of cellular processes, such as DNA repair, mitochondrial functions, and programmed cell death. 3-Aminobenzamide (3-AB) is an inhibitor of PARP. Previous studies on experimental AP models by PARP inhibition (PARPi) showed significant decrease in pancreatic injury scores7 and disease severity index.8 Recent studies also showed that significant improvements achieved by PARPi at respect of pancreatic tissue histopathology scores (THSc),9 tissue oxidative stress parameter (TOSp) status,10 and bacterial translocation (Bact-Trans) rates.11 Hyperbaric oxygen (HBO) therapy also has been investigated in previous experimental studies that have significantly improved TOSp12 and apoptosis in SAP.13,14 Thereafter, more recent studies by HBO in AP indicated that enhanced inflammatory response,15 cytokines levels,16 TOSp, and THSc.17,18 In consideration of previous studies, that PARPi or HBO has showed favorable effects, the objective of the present study was to evaluate effects of HBO and 3-AB cotreatment in SAP, at respect of Bact-Trans, THSc, and TOSp.

The field of pancreatic stellate cell (PSC) biology is very young, as the essential in-vitro tools to study these cells (ie, methods to isolate and culture PSC) were only developed as recently as in 1998. Nonetheless, there has been an exponential increase in research output in this field over the past decade, with numerous research groups around the world focusing their energies into elucidating the biology and function of these cells. It is now well established that PSC are responsible for producing the stromal reaction (fibrosis) of two major diseases of the pancreas—chronic pancreatitis and pancreatic cancer. Despite exponentially increasing data, the methods for studying PSC remain variable. Although within individual laboratories methods are consistent, different methodologies used by various research groups make it difficult to compare results and conclusions. This article is not a review article on the functions of PSC. Instead, members of the Pancreatic Star Alliance (http://www.pancreaticstaralliance.com) discuss here and consolidate current knowledge, to outline and delineate areas of consensus or otherwise (eg, with regard to methodological approaches) and, more importantly, to identify essential directions for future research. Hepatic stellate cells (HSC) were first described by Karl von Kupffer in 1876; however, similar cells in the pancreas were first observed in the 1980s.1–3 In 1998, Apte et al 4 and Bachem et al 5 isolated and cultured PSC.4 5 In the normal pancreas, PSC are located in close proximity to the basal aspect of pancreatic acinar cells. In sections immunostained for the marker desmin (a cytoskeletal protein), quiescent PSC can be seen as cells with a central cell body and long cytoplasmic projections extending along the base of adjacent acinar cells similar to that of pericytes in the mammary gland. …

Premature activation of digestive enzymes within the pancreas which leads to autodigestion of the gland is an early step in the pathogenesis of pancreatitis. Pancreatic injury is followed by other manifestations of inflammation including plasma extravasation, edema, and neutrophil infiltration which constitute the features of pancreatitis. Recent studies indicate that neural innervation of the pancreas may play an important role in the initiation and maintenance of the inflammatory response to injury. The pancreas is innervated by vagal, sympathetic and parasympathetic neurons, as well as sensory neurons. Activation of pancreatic primary sensory neurons causes the release of inflammatory neuropeptides both in the spinal cord to signal pain and in the pancreas itself where they produce plasma extravasation and neutrophil infiltration. Recent studies indicate that primary sensory neurons of the pancreas express transient receptor potential V1 (TRPV1) channels whose activation induces pancreatic inflammation. Moreover, blockade of these TRP channels significantly ameliorates experimental pancreatitis. This review describes our current understanding of the role of TRPV1 channels in pancreatitis and illustrates how this mechanism might be used to direct future treatments of pancreatic diseases.

WOS: 000184240800008, PubMed ID: 12845374, The literature indicates that acute pancreatitis is a complication of massive hemolysis with a prevalence of about 20%. We describe an experimental model of hemolysis-induced acute pancreatitis. Hemolytic anemia was induced in rats by a single ip injection of 60 mg/kg of 20 mg/ml acetylphenylhydrazine (APH) in 20% (v/v) ethanol on the first experimental day (day 0). One hundred and fifty Wistar albino rats weighing 180-200 g were divided into three groups of 50 animals each: groups 1, 2 and 3 were injected ip with APH, 20% ethanol, and physiological saline, respectively. Ten rats from each group were sacrificed on study days 1, 2, 3, 4 and 5. Serum amylase, lipase levels and pancreatic tissue tumor necrosis factor-alpha (TNF-alpha) and platelet-activating factor (PAF) contents were determined and a histological examination of the pancreas was performed. No hemolysis or pancreatitis was observed in any of the rats in groups 2 and 3. In group 1, massive hemolysis was observed in 35 (70%) of 50 rats, moderate hemolysis in seven (14%), and no hemolysis in eight (16%). Thirty-three of 35 (94.2%) rats with massive hemolysis had hyperamylasemia, and 29 of these rats (82.8%) had histologically proven pancreatitis. The most severe pancreatitis occurred on day 3, as demonstrated by histology. Tissue TNF-alpha and PAF levels were statistically higher in group 1 than in groups 2 and 3. Acute massive hemolysis induced acute pancreatitis, as indicated by histology, in almost 80% of cases. Hemolysis may induce acute pancreatitis by triggering the release of proinflammatory and immunoregulatory cytokines.

Choline-esterase inhibitor (Cl-INH), a regulatory alpha-glycoprotein, was administered at different dosages and intervals to rats with induced acute pancreatitis. When compared to controls, treated rats showed no significant differences in the severity of histopathological lesions, such as edema and single cell necrosis. On the other hand, both mortality and extent of massive necrosis were significantly affected by Cl-INH administration regardless of the dosages.