Etiological Changes and Prognosis of Hospitalized Patients with Acute Pancreatitis Over a 15-Year Period.

BACKGROUND: The worldwide incidence of acute pancreatitis (AP) is increasing, but the dominant etiology of AP may vary by country. Mixed etiologies are involved in the increase in the number of AP patients. AIMS: This study was to analyze the etiological changes and prognosis of AP patients and explore the prognosis of AP patients with mixed etiologies. METHODS: Using a retrospective analysis method, AP patients hospitalized from January 2007 to December 2021 were selected from a pancreatic center in Nanchang, China. Trends in the main etiologies were analyzed, and the severity and prognosis of different etiologies were compared. RESULTS: A total of 10,071 patients were included. Cholelithiasis (56.0%), hyperlipidemia (25.3%), and alcohol (6.5%) were the top three etiologies. The proportion of acute biliary pancreatitis (ABP) showed a decreasing trend, while the proportion of hypertriglyceridemic pancreatitis (HTGP) and alcoholic AP showed an increasing trend (all ptrend < 0.001). The incidence of organ failure and necrotizing pancreatitis was higher in patients with HTGP than in those with AP induced by other etiologies (all p < 0.05). There was no statistically significant difference in mortality among patients with different etiologies. Patients with AP due to a mixed hypertriglyceridemia-alcoholic etiology had higher ICU admission rates and were more severe than those with AP induced by other mixed etiologies. CONCLUSION: In the past 15 years, the proportion of ABP has trended downward, while those of HTGP and alcoholic AP have risen. Among patients with mixed etiologies, those with a mixed hypertriglyceridemia-alcoholic etiology had a worse prognosis.

Structured alcohol cessation support program versus current practice in acute alcoholic pancreatitis (PANDA): Study protocol for a multicentre cluster randomised controlled trial.

BACKGROUND/OBJECTIVES: The most important risk factor for recurrent pancreatitis after an episode of acute alcoholic pancreatitis is continuation of alcohol use. Current guidelines do not recommend any specific treatment strategy regarding alcohol cessation. The PANDA trial investigates whether implementation of a structured alcohol cessation support program prevents pancreatitis recurrence after a first episode of acute alcoholic pancreatitis. METHODS: PANDA is a nationwide cluster randomised superiority trial. Participating hospitals are randomised for the investigational management, consisting of a structured alcohol cessation support program, or current practice. Patients with a first episode of acute pancreatitis caused by harmful drinking (AUDIT score >7 and < 16 for men and >6 and < 14 for women) will be included. The primary endpoint is recurrence of acute pancreatitis. Secondary endpoints include cessation or reduction of alcohol use, other alcohol-related diseases, mortality, quality of life, quality-adjusted life years (QALYs) and costs. The follow-up period comprises one year after inclusion. DISCUSSION: This is the first multicentre trial with a cluster randomised trial design to investigate whether a structured alcohol cessation support program reduces recurrent acute pancreatitis in patients after a first episode of acute alcoholic pancreatitis, as compared with current practice. TRIAL REGISTRATION: Netherlands Trial Registry (NL8852). Prospectively registered.

Ethanol inhibits pancreatic acinar cell autophagy through upregulation of ATG4B, mediating pathological responses of alcoholic pancreatitis.

Excessive alcohol intake is a major risk factor for pancreatitis, sensitizing the exocrine pancreas to stressors by mechanisms that remain obscure. Impaired autophagy drives nonalcoholic pancreatitis, but the effects of ethanol (EtOH) and alcoholic pancreatitis on autophagy are poorly understood. Here, we find that ethanol reduces autophagosome formation in pancreatic acinar cells, both in a mouse model of alcoholic pancreatitis induced by a combination of EtOH diet and cerulein (a CCK ortholog) and in EtOH+CCK-treated acinar cells (ex vivo model). Ethanol treatments decreased pancreatic level of LC3-II, a key mediator of autophagosome formation. This was caused by ethanol-induced upregulation of ATG4B, a cysteine protease that, cell dependently, regulates the balance between cytosolic LC3-I and membrane-bound LC3-II. We show that ATG4B negatively regulates LC3-II in acinar cells subjected to EtOH treatments. Ethanol raised ATG4B level by inhibiting its degradation, enhanced ATG4B enzymatic activity, and strengthened its interaction with LC3-II. We also found an increase in ATG4B and impaired autophagy in a dissimilar, nonsecretagogue model of alcoholic pancreatitis induced by EtOH plus palmitoleic acid. Adenoviral ATG4B overexpression in acinar cells greatly reduced LC3-II and inhibited autophagy. Furthermore, it aggravated trypsinogen activation and necrosis, mimicking key responses of ex vivo alcoholic pancreatitis. Conversely, shRNA Atg4B knockdown enhanced autophagosome formation and alleviated ethanol-induced acinar cell damage. The results reveal a novel mechanism, whereby ethanol inhibits autophagosome formation and thus sensitizes pancreatitis, and a key role of ATG4B in ethanol's effects on autophagy. Enhancing pancreatic autophagy, particularly by downregulating ATG4B, could be beneficial in mitigating the severity of alcoholic pancreatitis.NEW & NOTEWORTHY Ethanol sensitizes mice and humans to pancreatitis, but the underlying mechanisms remain obscure. Autophagy is important for maintaining pancreatic acinar cell homeostasis, and its impairment drives pancreatitis. This study reveals a novel mechanism, whereby ethanol inhibits autophagosome formation through upregulating ATG4B, a key cysteine protease. ATG4B upregulation inhibits autophagy in acinar cells and aggravates pathological responses of experimental alcoholic pancreatitis. Enhancing pancreatic autophagy, particularly by down-regulating ATG4B, could be beneficial for treatment of alcoholic pancreatitis.

The risk of recurrent pancreatitis after first episode of acute pancreatitis in relation to etiology and severity of disease: A systematic review, meta-analysis and meta-regression analysis.

BACKGROUND AND AIM: The study aims to determine and quantify the stratified risk of recurrent pancreatitis (RP) after the first episode of acute pancreatitis in relation to etiology and severity of disease. METHODS: A systematic review and meta-analysis in compliance with PRISMA statement standards was conducted. A search of electronic information sources was conducted to identify all studies investigating the risk of RP after the first episode of acute pancreatitis. Proportion meta-analysis models using random effects were constructed to calculate the weighted summary risks of RP. Meta-regression was performed to evaluate the effect of different variables on the pooled outcomes. RESULTS: Analysis of 57,815 patients from 42 studies showed that the risk of RP after first episode was 19.8% (95% confidence interval [CI] 17.5-22.1%). The risk of RP was 11.9% (10.2-13.5%) after gallstone pancreatitis, 28.7% (23.5-33.9%) after alcohol-induced pancreatitis, 30.3% (15.5-45.0%) after hyperlipidemia-induced pancreatitis, 38.1% (28.9-47.3%) after autoimmune pancreatitis, 15.1% (11.6-18.6%) after idiopathic pancreatitis, 22.0% (16.9-27.1%) after mild pancreatitis, 23.9% (12.9-34.8%) after moderate pancreatitis, 21.6% (14.6-28.7%) after severe pancreatitis, and 6.6% (4.1-9.2%) after cholecystectomy following gallstone pancreatitis. Meta-regression confirmed that the results were not affected by the year of study (P = 0.541), sample size (P = 0.064), length of follow-up (P = 0.348), and age of patients (P = 0.138) in the included studies. CONCLUSIONS: The risk of RP after the first episode of acute pancreatitis seems to be affected by the etiology of pancreatitis but not the severity of disease. The risks seem to be higher in patients with autoimmune pancreatitis, hyperlipidemia-induced pancreatitis, and alcohol-induced pancreatitis and lower in patients with gallstone pancreatitis and idiopathic pancreatitis.

Mortality Trends, Outcomes, and Predictors of Portal Vein Thrombosis in Acute Pancreatitis Patients: A Propensity-Matched National Study.

BACKGROUND: Portal vein thrombosis (PVT) is a rare complication of acute pancreatitis (AP) and might be associated with worse outcomes. We aimed to study trends, outcomes, and predictors of PVT in AP patients. METHODS: The National Inpatient Sample database was utilized to identify the adult patients (≥ 18 years) with primary diagnosis of AP from 2004 to 2013 using International Classification of Disease, Ninth Revision. Patients with and without PVT were entered into propensity matching model based on baseline variables. Outcomes were compared between both groups and predictors of PVT in AP were identified. RESULTS: Among the total of 2,389,337 AP cases, 7046 (0.3%) had associated PVT. The overall mortality of AP decreased throughout the study period (p trend ≤ 0.0001), whereas mortality of AP with PVT remained stable (1-5.7%, p trend = 0.3). After propensity matching, AP patients with PVT patients had significantly higher in-hospital mortality (3.3% vs. 1.2%), AKI (13.4% vs. 7.7%), shock (6.9% vs. 2.5%), and need for mechanical ventilation (9.2% vs. 2.5%) along with mean higher cost of hospitalization and length of stay (p < 0.001 for all). Lower age (Odd ratio [OR] 0.99), female (OR 0.75), and gallstone pancreatitis (OR 0.79) were negative predictors, whereas alcoholic pancreatitis (OR 1.51), cirrhosis (OR 2.19), CCI > 2 (OR 1.81), and chronic pancreatitis (OR 2.28) were positive predictors of PVT (p < 0.001 for all) in AP patients. CONCLUSION: PVT in AP is associated with significantly higher risk of death, AKI, shock, and need for mechanical ventilation. Chronic and alcoholic pancreatitis is associated with higher risk of PVT in AP.

[Influence of environmental factors and polymorphic loci rs6580502 of the SPINK1 gene, rs10273639 of the PRSS1 gene, rs213950 of the CFTR gene on the risk of developing acute alcoholic-alimentary pancreatitis].

The study of genetic and environmental factors on the risk of acute alcoholic-alimentary pancreatitis (AАAР) is especially relevant to interpret individual links of pathogenesis, to reduce the incidence by eliminating the impact of harmful factors and improve the quality of life of the population through the introduction of optimal nutrition, and a healthy lifestyle, which is especially important for carriers of risk genotypes. The aim of the research was to study the influence of environmental factors and polymorphic loci rs6580502 of the SPINK1 gene, rs10273639 of the PRSS1 gene, rs213950 of the CFTR gene on the risk of АAР. Material and methods. Blood DNA samples obtained from 547 patients with AАAР and 573 healthy individuals were used as the material for the study. The groups were comparable by sex and age. All participants were assessed qualitatively and quantitatively for risk factors, smoking and alcohol consumption, the frequency, quantity and regularity of intake of various types of foods, as well as the size and number of portions eaten. Genomic DNA was isolated by the standard phenol-chloroform extraction method, multiplex genotyping of SNPs was performed on a MALDI-TOF MassARRAY-4 genetic analyzer. Results. It was found that the T/T genotype (p=0.0012) of the rs6580502 SPINK1 was associated with an increased risk of AAAP, and the T allele (p=0.0001) and C/T and T/T genotypes (p=0.0001) of the rs10273639 PRSS1, A allele (p=0.01) and A/G and A/A genotypes (p=0.0006) of the rs213950 CFTR were associated with an decreased risk of the disease. The revealed effects of polymorphic loci of candidate genes were enhanced by the effect of alcohol consumption. The risk of AAAP was reduced by fat intake of less than 89 g per day in carriers of the A/G-A/A CFTR genotypes (rs213950), consumption of fresh vegetables and fruits of more than 27 g per day in carriers of the T/C-T/T PRSS1 genotypes (rs10273639), protein intake of more 84 g per day in carriers of T/C-T/T PRSS1 rs10273639 and A/G-A/A CFTR rs213950. The most significant models of gene-environment interactions included risk factors: deficiency in the diet of protein, fresh vegetables and fruits, smoking, and polymorphic variants of the PRSS1 (rs10273639) and SPINK (rs6580502) genes. Conclusion. In order to prevent the development of AAAP, carriers of risk genotypes of candidate genes need not only to exclude or significantly reduce alcohol consumption (in terms of volume, frequency and duration); but also carriers of the A/G-A/A CFTR genotypes (rs213950) need to balance the diet by reducing fat intake to less than 89 g per day and increasing protein intake to more than 84 g per day; carriers of the T/C-T/T PRSS1 (rs10273639) genotypes should increase their intake of fresh vegetables and fruits over 27 g/day and protein over 84 g/day.

Plasma soluble urokinase-type plasminogen activator receptor (P-suPAR) in the diagnostics between malignant and non-malignant pancreatic lesions.

BACKGROUND: Soluble urokinase-type plasminogen activator receptor (suPAR) is a biomarker elevated in several inflammatory conditions and cancers. It has recently been shown to be elevated in pancreatic ductal adenocarcinoma (PDAC). Plasma suPAR (P-suPAR) predicts the severity of the disease in first acute alcohol-induced pancreatitis (AAP) and ten-year mortality after recovery from first AAP. According to our previous results, P-suPAR is not elevated in chronic pancreatitis (CP) and could possibly be used in distinguishing pancreatic cancer (PC) from CP. When imaging creates a suspicion of a pancreatic lesion, the distinction between malignant and non-malignant disease is crucial. Additional tools are needed, and we still lack a sufficiently sensitive and specific biomarker. Our aim was to further investigate whether preoperatively measured P-suPAR is beneficial in distinguishing between malignant and non-malignant pancreatic lesions. METHODS: One hundred and seventy-six patients evaluated in Tampere University Hospital for pancreatic surgery for suspected malignant pancreatic lesion were recruited for the study. The final study group consisted of 113 patients. P-suPAR and other covariates were measured before the planned operation. RESULTS: P-suPAR was significantly higher in patients with pancreatic cancer (PC) [median 4.1 (IQR 3.3-5.1) ng/mL] than in patients with non-malignant [3.3 (2.9-4.4) ng/mL; p = 0.012] histology. ROC curve analysis resulted in an AUC of 0.65 (95% CI 0.55-0.76); p = 0.007 and a cutoff value of 3.2 ng/mL. Crosstabulation yielded sensitivity of 82% and specificity of 43%. A combination of positive P-suPAR and elevated plasma carbohydrate antigen 19-9 (P-CA19-9) tests did not improve sensitivity but elevated specificity up to 86-88%. CONCLUSIONS: Preoperative P-suPAR is elevated in patients with PC compared to patients with a non-malignant pancreatic lesion. Combining P-suPAR with P-CA19-9 may improve diagnostic accuracy.

Euglycemic Diabetic Ketoacidosis Caused by Alcoholic Pancreatitis and Starvation Ketosis.

Starvation ketosis and pancreatitis are uncommon and underrecognized etiologies of euglycemic diabetic ketoacidosis (DKA). Euglycemic DKA is associated commonly with pregnancy, use of insulin en route to the hospital, and use of sodium-glucose cotransporter-2 (SGLT-2) inhibitors. A 58-year-old male with past medical history of type II diabetes mellitus and alcoholism presented with chief complaint of nausea, vomiting, and poor oral intake for several weeks. Despite extensive history of diabetes and no recent SGLT-2 inhibitor use, his labs were consistent with euglycemic DKA. His imaging and clinical history also confirmed alcoholic pancreatitis. The patient was admitted for euglycemic DKA secondary to starvation ketosis and alcoholic pancreatitis. His anion gap and beta-hydroxybutyrate rapidly cleared with initiation of the DKA protocol. This case teaches us that clinicians should consider early initiation of the DKA protocol even in the setting of euglycemia, when a patient presents with high-anion-gap metabolic acidosis, a high beta-hydroxybutyrate level, and a clinical picture of pancreatitis and starvation.

Ischemic Pancreatitis Is an Important Cause of Acute Pancreatitis in the Intensive Care Unit.

BACKGROUND: Ischemic pancreatitis (IP) has mainly been described in case reports. The aims of the study were to assess the frequency, clinical characteristics and outcomes in patients with IP among patients hospitalized in the intensive care unit (ICU) for acute pancreatitis (AP). METHODS: All patients with first time AP between 2011 and 2018 in the ICU of Landspitali Hospital, Iceland were retrospectively included. IP as an etiology required a clinical setting of circulatory shock, arterial hypotension, hypovolemia and/or arterial hypoxemia [PaO 2 of 60 mm Hg (8.0 kPa), or less] before the diagnosis of AP without prior history of abdominal pain to this episode. Other causes of AP were ruled out. IP patients were compared with patients with AP of other etiologies, also hospitalized in the ICU. RESULTS: Overall 67 patients with AP were identified (median age 60 y, 37% females), 31% idiopathic, 24% alcoholic, 22% IP, 15% biliary, and 8% other causes. Overall, 15 (22%) fulfilled the predetermined criteria for IP, 9 males (64%), median age 62 years (interquartile range: 46 to 65). IP was preceded mainly by systemic shock (73%). Other causes included dehydration, hypoxia, or vessel occlusion to the pancreas. Necrosis of the pancreas was rare with one patient requiring pancreatic necrosectomy. Inpatient mortality was higher among patients with IP than in other patients with AP (33% vs. 14%, P =0.12). CONCLUSIONS: IP was found in a significant proportion of AP patients hospitalized in the ICU. The main causes of IP were systemic shock and hypoxia. IP was associated with ∼30% mortality.

Increasing Prevalence and Racial Disparity of Alcohol-Related Gastrointestinal and Liver Disease During the COVID-19 Pandemic: A Population-Based National Study.

OBJECTIVES: One consequence of social distancing during the coronavirus disease 2019 (COVID-19) pandemic was an increase in alcohol use disorders. We postulated that this would be associated with a rise in alcohol-related gastrointestinal and liver disease. METHODS: Using Explorys Inc., an aggregate of electronic health records from US health care systems from 1999 to June 2021, we identified patients with "alcoholic hepatitis," "inflammation of pancreas caused by alcohol," and "alcoholic gastritis," based on Systematized Nomenclature of Medicine-Clinical Terms (SNOMED-CT). We compared patients utilizing health care during the pandemic to those before it. RESULTS: We identified 8,445,720 patients treated from June 21, 2020 to June 20, 2021 ("COVID cohort") and 65,587,860 patients treated before this ("pre-COVID cohort"). African American patients were more likely to be treated for all causes during COVID-19 [odds ratio (OR): 1.65; P <0.0001]. Alcoholic hepatitis (OR: 2.77), alcoholic pancreatitis (OR: 3.67), and alcoholic gastritis (OR: 1.70) (for each, P <0.0001) were more likely in all patients in the COVID cohort. African Americans in the COVID cohort were more likely to be diagnosed with alcoholic hepatitis (OR: 2.63), alcoholic pancreatitis (OR: 2.17), and alcoholic gastritis (OR: 3.09) [for each, P <0.0001]. CONCLUSIONS: The prevalence of alcohol-related liver and gastrointestinal disease increased during COVID-19. We suspect these increases are associated with increased alcohol use disorder resulting from the stress of social isolation. These data suggest COVID-19 disproportionately affected African Americans in overall health care utilization and increased burden of alcoholic gastrointestinal and liver disease.

Incidence, Burden, and Predictors of Readmission for Acute Alcoholic Pancreatitis: A National Analysis over 11 Months.

BACKGROUND/OBJECTIVES: Data regarding incidence, health-care burden, and predictors for readmission in patients with acute alcoholic pancreatitis (AAP) is scarce. We aim to identify incidence, health-care burden, and predictors of readmission over an 11-month period. METHODS: Retrospective cohort study using the 2016 National Readmission Database of adult patients admitted with a principal diagnosis of AAP in January and 11-month readmission follow up for all-cause readmission. Incidence of all-cause readmission, mortality rate, morbidity, length of stay (LOS), total hospitalization charges and costs were evaluated. Independent risk factors for all-cause readmission were identified using a Cox multivariate logistic regression analysis. RESULTS: A total of 6633 patients were included in the study. The mean age was 45.7 years and 28.9% of patients were female. 73.1% of patients had a modified BISAP score of 0. The 11-month readmission rate was 43.1%. The main cause of readmission was another episode of AAP. The mortality rate of readmission was 0.5% and the mortality rate during the index admission (IA) was 1.1% (P = 0.03). The mean LOS, total hospitalization charges and costs for readmission were 4.5 days, $34,307 and $8958, respectively. Independent predictors of readmission were Charlson Comorbidity Index score of ≥ 3, associated chronic alcoholic pancreatitis, and chronic pancreatitis (CP) from other causes. CONCLUSION: Among patients admitted with AAP, the 11-month readmission rate was 43.1%. Over one-third of readmissions were due to another episode of AAP. Readmission associated with significant resource utilization. Special attention should be placed in patients with underlying CP due to the increased risk of readmission.

Acute and Chronic Alcoholic Pancreatitis, Including Paraduodenal Pancreatitis.

CONTEXT.­: In the last 2 decades there has been significant progress in typing and recognition of pancreatitis, a necroinflammatory and fibroinflammatory process of multifactorial origin. OBJECTIVE.­: To present the current state of pathology and pathogenesis of alcohol-associated pancreatitis, including paraduodenal pancreatitis. In the context of the most important epidemiologic, clinical, and radiologic features, the related macroscopic changes and histopathologic characteristics are addressed. DATA SOURCES.­: In acute pancreatitis we discuss the pathologic findings that distinguish mild from severe pancreatitis and highlight autodigestive fat necrosis as the initial morphologic damage. In chronic pancreatitis we present a histologic staging system that describes the damage patterns as a necrosis-fibrosis sequence that takes place during the development of early to advanced and end-stage chronic pancreatitis. In paraduodenal pancreatitis the anatomic peculiarities are related to the sequence of morphologic changes that are correlated to the most important imaging findings. Pathogenetically, we discuss the role of alcohol overconsumption in triggering autodigestive fat necrosis in the pancreas, the repair of which results in a pancreas-transforming fibroinflammatory process. CONCLUSIONS­: Whereas in acute pancreatitis there are no lesions that are diagnostic for alcohol overconsumption and that exclude other etiologies such as gallstone disease or drugs, the sequence of damage patterns in chronic pancreatitis are strongly related to the effect of alcohol overconsumption and allow in many cases the distinction from hereditary, autoimmune, or obstructive pancreatitis. Paraduodenal pancreatitis can be considered a special manifestation of alcoholic pancreatitis.

The Quick Sepsis-Related Organ Failure Assessment Score Is Prognostic of Pancreatitis Severity in Patients With Alcohol-Induced Pancreatitis.

OBJECTIVES: The aim of this study was to determine if the quick Sepsis-Related Organ Failure Assessment (qSOFA) score assessed at and 48 hours after admission is prognostic for alcohol-induced acute pancreatitis (AAP) severity. METHODS: This is a retrospective cohort review study of 161 patients admitted to a single academic hospital in Houston, TX, with the diagnosis of AAP. Receiver operator characteristics analysis and logistic regression were used to assess the diagnostic accuracy and prognostic ability of the qSOFA score. RESULTS: A qSOFA score of 2 or higher at and 48 hours after admission had a specificity of 94% or greater and sensitivity of 33% or higher for pancreatitis severity and need for intensive care admission, intubation, or vasopressors. The qSOFA score at and 48 hours after admission was prognostic of intensive care unit admission by an adjusted odds ratio of 48.5 (95% confidence interval [CI], 6.4-1013.3; P < 0.001) and 18.8 (95% CI, 2.2-467.3; P < 0.05), respectively. The qSOFA score at admission was prognostic of severe pancreatitis by an adjusted odds ratio of 35.3 (95% CI, 7.2-224.3; P < 0.001). CONCLUSIONS: A qSOFA score of 2 or higher is highly specific and prognostic of multiple clinical outcomes both at and 48 hours after admission in patients with AAP.

Urolithin A attenuates severity of chronic pancreatitis associated with continued alcohol intake by inhibiting PI3K/AKT/mTOR signaling.

Heavy alcohol consumption is the dominant risk factor for chronic pancreatitis (CP); however, treatment and prevention strategies for alcoholic chronic pancreatitis (ACP) remains limited. The present study demonstrates that ACP induction in C57BL/6 mice causes significant acinar cell injury, pancreatic stellate cell (PSC) activation, exocrine function insufficiency, and an increased fibroinflammatory response when compared with alcohol or CP alone. Although the withdrawal of alcohol during ACP recovery led to reversion of pancreatic damage, continued alcohol consumption with established ACP perpetuated pancreatic injury. In addition, phosphokinase array and Western blot analysis of ACP-induced mice pancreata revealed activation of the phosphatidylinositol 3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) and cyclic AMP response element binding protein (CREB) signaling pathways possibly orchestrating the fibroinflammatory program of ACP pathogenesis. Mice treated with urolithin A (Uro A, a gut-derived microbial metabolite) in the setting of ACP with continued alcohol intake (during the recovery period) showed suppression of AKT and P70S6K activation, and acinar damage was significantly reduced with a parallel reduction in pancreas-infiltrating macrophages and proinflammatory cytokine accumulation. These results collectively provide mechanistic insight into the impact of Uro A on attenuation of ACP severity through suppression of PI3K/AKT/mTOR signaling pathways and can be a useful therapeutic approach in patients with ACP with continuous alcohol intake.NEW & NOTEWORTHY Our novel findings presented here demonstrate the utility of Uro A as an effective therapeutic agent in attenuating alcoholic chronic pancreatitis (ACP) severity with alcohol continuation after established disease, through suppression of the PI3K/AKT/mTOR signaling pathway.

Activation of pancreatic stellate cells attenuates intracellular Ca2+ signals due to downregulation of TRPA1 and protects against cell death induced by alcohol metabolites.

Alcohol abuse, an increasing problem in developed societies, is one of the leading causes of acute and chronic pancreatitis. Alcoholic pancreatitis is often associated with fibrosis mediated by activated pancreatic stellate cells (PSCs). Alcohol toxicity predominantly depends on its non-oxidative metabolites, fatty acid ethyl esters, generated from ethanol and fatty acids. Although the role of non-oxidative alcohol metabolites and dysregulated Ca2+ signalling in enzyme-storing pancreatic acinar cells is well established as the core mechanism of pancreatitis, signals in PSCs that trigger fibrogenesis are less clear. Here, we investigate real-time Ca2+ signalling, changes in mitochondrial potential and cell death induced by ethanol metabolites in quiescent vs TGF-ß-activated PSCs, compare the expression of Ca2+ channels and pumps between the two phenotypes and the consequences these differences have on the pathogenesis of alcoholic pancreatitis. The extent of PSC activation in the pancreatitis of different aetiologies has been investigated in three animal models. Unlike biliary pancreatitis, alcohol-induced pancreatitis results in the activation of PSCs throughout the entire tissue. Ethanol and palmitoleic acid (POA) or palmitoleic acid ethyl ester (POAEE) act directly on quiescent PSCs, inducing cytosolic Ca2+ overload, disrupting mitochondrial functions, and inducing cell death. However, activated PSCs acquire remarkable resistance against ethanol metabolites via enhanced Ca2+-handling capacity, predominantly due to the downregulation of the TRPA1 channel. Inhibition or knockdown of TRPA1 reduces EtOH/POA-induced cytosolic Ca2+ overload and protects quiescent PSCs from cell death, similarly to the activated phenotype. Our results lead us to review current dogmas on alcoholic pancreatitis. While acinar cells and quiescent PSCs are prone to cell death caused by ethanol metabolites, activated PSCs can withstand noxious signals and, despite ongoing inflammation, deposit extracellular matrix components. Modulation of Ca2+ signals in PSCs by TRPA1 agonists/antagonists could become a strategy to shift the balance of tissue PSCs towards quiescent cells, thus limiting pancreatic fibrosis.

Protein kinase D: A therapeutic target in experimental alcoholic pancreatitis.

BACKGROUND: Alcohol abuse, a main cause of pancreatitis, has been known to augment NF-κB activation and cell necrosis in pancreatitis. However, the underlying mechanisms are unclear. We recently reported that inhibition of protein kinase D (PKD) alleviated NF-κB activation and severity of experimental pancreatitis. Here we investigated whether PKD signaling mediated the modulatory effects of alcohol abuse on pathological responses in alcoholic pancreatitis. METHODS: Alcoholic pancreatitis was provoked in two rodent models with pair-feeding control and ethanol-containing Lieber-DeCarli diets for up to 8 weeks followed by up to 7 hourly intraperitoneal injections of cerulein at 1 µg/kg (rats) or 3 µg/kg (mice). Effects of PKD inhibition by PKD inhibitors or genetic deletion of pancreatic PKD isoform (PKD3Δpanc mice) on alcoholic pancreatitis parameters were determined. RESULTS: Ethanol administration amplified PKD signaling by promoting expression and activation of pancreatic PKD, resulted in augmented/promoted pancreatitis responses. Pharmacological inhibition of PKD or with PKD3Δpanc mice prevented the augmenting/sensitizing effect of ethanol on NF-κB activation and inflammatory responses, cell necrotic death and the severity of disease in alcoholic pancreatitis. PKD inhibition prevented alcohol-enhanced trypsinogen activation, mRNA expression of multiple inflammatory molecules, the receptor-interacting protein kinase activation, ATP depletion, and downregulation of pro-survival Bcl-2 protein in alcoholic pancreatitis. Furthermore, PKD inhibitor CID755673 or CRT0066101, administrated after the induction of pancreatitis in mouse and rat alcoholic pancreatitis models, significantly mitigated the severity of pancreatitis. CONCLUSION: PKD mediates effect of alcohol abuse on pathological process of pancreatitis and constitutes a novel therapeutic target to treat this disease.