Impaired Regulation of PMCA Activity by Defective CFTR Expression Promotes Epithelial Cell Damage in Alcoholic Pancreatitis and Hepatitis

Background and aims. Alcoholic pancreatitis and hepatitis are frequent, potentially lethal diseases with limited treatment options. Our previous study reported that the expression of CFTR Cl- channel is impaired by ethanol in pancreatic ductal cells leading to more severe alcohol-induced pancreatitis. In addition to determining epithelial ion secretion, CFTR has multiple interactions with other proteins, which may influence intracellular Ca2+ signaling. Thus, we aimed to investigate the impact of ethanol-mediated CFTR damage on intracellular Ca2+ homeostasis in pancreatic ductal epithelial cells and cholangiocytes.Methods. Human and mouse pancreas and liver samples and ex vivo organoids were used to study ion secretion, intracellular signaling and protein expression and interaction. The effect of PMCA4 inhibition was analysed in a mouse model of alcohol-induced pancreatitis.Results. The decreased CFTR expression impaired PMCA function and resulted in sustained intracellular Ca2+ elevation in ethanol-treated and mouse and human pancreatic organoids. Liver samples derived from alcoholic hepatitis patients and ethanol-treated mouse liver organoids showed decreased CFTR expression and function, and impaired PMCA4 activity. PMCA4 co-localizes and physically interacts with CFTR on the apical membrane of polarized epithelial cells, where CFTR-dependent calmodulin recruitment determines PMCA4 activity. The sustained intracellular Ca2+ elevation in the absence of CFTR inhibited mitochondrial function and was accompanied with increased apoptosis in pancreatic epithelial cells and PMCA4 inhibition increased the severity of alcohol-induced AP in mice.Conclusion. Our results suggest that improving Ca2+ extrusion in epithelial cells may be a potential novel therapeutic approach to protect the exocrine pancreatic function in alcoholic pancreatitis and prevent the development of cholestasis in alcoholic hepatitis.

Targeting Endoplasmic Reticulum Stress as an Effective Treatment for Alcoholic Pancreatitis

Pancreatitis and alcoholic pancreatitis are serious health concerns with an urgent need for effective treatment strategies. Alcohol is a known etiological factor for pancreatitis, including acute pancreatitis (AP) and chronic pancreatitis (CP). Excessive alcohol consumption induces many pathological stress responses; of particular note is endoplasmic reticulum (ER) stress and adaptive unfolded protein response (UPR). ER stress results from the accumulation of unfolded/misfolded protein in the ER and is implicated in the pathogenesis of alcoholic pancreatitis. Here, we summarize the possible mechanisms by which ER stress contributes to alcoholic pancreatitis. We also discuss potential approaches targeting ER stress and UPR in developing novel therapeutic strategies for the disease.

Exogenous and endogenous mortality parameters as indicators of the sanitary and epidemiological status of the population of the region

Introduction. The concepts of the epidemiological transition and types of population health are applied to analyzing and evaluating the sanitary and epidemiological status of the population. Materials and methods. For many years of mortality, the dynamics of the male population of the Irkutsk region standardized indicators were used (European age standard). For identifying trends of changing mortality rates, an analytical alignment of the time series was used. It was a linear model by EXCEL’s standard tools (Microsoft Office 2007). The significance of the trend equation was calculated using F-test in IBM SPSS Statistics 23 (p < 0,05). Results. It has been established that the formation of various types of pathology and caused by this pathology mortality occurred under the influence of factors of different nature in the process of changes in social, environmental, epidemiological situations in the region. In the 1990 th and the first half of the 2000 th, high mortality rates in the class of diseases of the circulatory system and the class of external causes of morbidity and mortality were determined mainly by psychosocial disadvantage factors. By the class of Diseases of the respiratory system, there was noted a steady decrease in mortality rate from chronic diseases of the lower respiratory tract and pneumonia. It was probably due to an increase in the level and quality of medical care. A steady tendency to increase intensive and extensive mortality rates by class of Certain infectious and parasitic diseases was seen. That was caused by negative changes in infectious and epidemic processes under the influence of man-made pollution was noted. During 2005 - 2015 the digestive system’s share of the class of Diseases in the mortality structure increased. That is due to the prevalence of alcoholic liver disease, chronic alcoholic pancreatitis, complications of the ulcer of the stomach and duodenum. Conclusion. The combination of the identified patterns of the formation of intensive and extensive mortality rates determined by exogenous and endogenous factors made it possible to characterize the situation in the Irkutsk region as a relative sanitary and epidemiological disadvantage of the population.

Cytolysin-positive Enterococcus faecalis is elevated in patients with chronic alcoholic pancreatitis

Introduction: Patients with alcoholic hepatitis have an increase in cytolysin-producing Enterococcus faecalis that correlates with disease severity and mortality. Aim: To determine whether patients with chronic alcoholic pancreatitis have an elevated abundance of cytolysin-producing E. faecalis. Methods: Quantification by qPCR of cytolysin-producing E. faecalis in controls and patients with alcoholic hepatitis or pancreatitis. Results: Patients with alcoholic pancreatitis had a higher proportion of intestinal cytolysin-positive E. faecalis than healthy controls and patients with alcoholic hepatitis. Conclusion: Cytolytic E. faecalis may also be involved in this other alcohol-related complication and benefit from targeted microbiota editing strategies.

Targeting Endoplasmic Reticulum Stress as an Effective Treatment for Alcoholic Pancreatitis

Pancreatitis and alcoholic pancreatitis are serious health concerns, and there is an urgent need for effective treatment strategies. Alcohol is a known etiological factor for pancreatitis, including acute pancreatitis (AP) and chronic pancreatitis (CP). Excessive alcohol consumption induces many pathological stress responses; of particular note is endoplasmic reticulum (ER) stress and adaptive unfolded protein response (UPR). ER stress results from the accumulation of unfolded/misfolded protein in the ER and is implicated in the pathogenesis of alcoholic pancreatitis. Here we summarize the possible mechanisms by which ER stress contributes to alcoholic pancreatitis. We also discuss potential approaches targeting ER stress and UPR for developing novel therapeutic strategies for the disease.

P103 IS BOTULINUM TOXIN PRE-CONDITIONING & 3D PLANNING USEFUL IN A BILATERAL SUBCOSTAL EVENTRATION WITH LAPAROSTOME AND COLOSTOMY?

Aim To assess the usefulness of 3D Planning and preconditioning with botulinum toxin in a complex abdominal wall hernia. Material and Methods A 54-year-old man with sever alcoholic pancreatitis required surgery due to poor evolution, performing subtotal colectomy with a right colon colostomy and necrosectomy by bilateral subcostal laparotomy. After several operations and not being able to close the wall, the use of negative pressure therapy and subsequently skin grafting was required. Abdominal wall 3D Planning was performed and botulinum toxin injection was administered before definite surgery. During surgery, after digestive reconstruction, it was observed that wound’s edges did not approximate due to retraction of rectus in the cranial and caudal pole. Posterior layer was closed with running suture and double polypropylene mesh was placed. One year after surgery, patient remains without recurrences with a firm abdominal wall and recovery of life’s quality with radiologic confirmation images. Results Intestinal and Wall reconstruction in one step was feasible, although botulinum toxin injection did not provide benefits due a bilateral subcostal incision with significant muscle retraction. The 3D Planning allowed us to assess the degree of retraction of the musculature, much greater than what was appreciated in the physical examination. Conclusions The subcostal incision should be avoided in severe pancreatitis. Surgical planning with 3D technology is developing, allowing the entire anatomy to be assessed globally. 3D, useful tool for teaching, suggests that in subcostal laparotomies, it could help predicting that botulinum toxin would not be useful due to muscular retraction.

EP.WE.351Changes in social behaviour during the COVID-19 pandemic and consequences on hospital admissions from acute alcoholic related pancreatitis

Background Shifts in social behaviours as a consequence of the COVID-19 pandemic may make people more prone to alcohol use as a coping mechanism. This study aims to investigate whether there was an impact on acute alcohol-related pancreatitis cases given potential changes in alcohol consumption during the first COVID-19 lockdown period in the United Kingdom. It considers the time period since social establishments re-opened in July 2020, to evaluate whether increase alcoholic pancreatitis cases, as a proxy for altered drinking habits, persisted. Methods All codes relating to pancreatitis were used to identify cases between March to September (2016 to 2020). Inclusion criteria: acute alcohol-related pancreatitis only. These cases were screened by a group of independent medical juniors and analysed using Excel. Results A total of 1905 patients with pancreatitis were identified in the initial search, of which 136 were admitted with acute alcoholic pancreatitis. There was an increase in absolute number of new cases in 2020 compared to previous years (27 compared to a mean of 16 in the previous 4 years). When shops and pubs reopened, cases reduced by 37.5%. Conclusion This study highlights the issue of increased admission with acute pancreatitis relating to alcohol in the COVID-19 lock down period. During which, this group of patients are likely socially isolated with a lack of support. This calls for an increase in community support for such patients with emphasis on admission avoidance. This is especially important in an era when there is increased hospital admission due to COVID-19.