Generation of Hydrogen Peroxide and Downstream Protein Kinase D1 Signaling Is a Common Feature of Inducers of Pancreatic Acinar-to-Ductal Metaplasia

Pancreatic acinar-to-ductal metaplasia (ADM) is a reversible process that occurs after pancreatic injury, but becomes permanent and leads to pancreatic lesions in the presence of an oncogenic mutation in KRAS. While inflammatory macrophage-secreted chemokines, growth factors that activate epidermal growth factor receptor (EGFR) and oncogenic KRAS have been implicated in the induction of ADM, it is currently unclear whether a common underlying signaling mechanism exists that drives this process. In this study, we show that different inducers of ADM increase levels of hydrogen peroxide, most likely generated at the mitochondria, and upregulate the expression of Protein Kinase D1 (PKD1), a kinase that can be activated by hydrogen peroxide. PKD1 expression in acinar cells affects their survival and mediates ADM, which is in part due to the PKD1 target NF-κB. Overall, our data implicate ROS-PKD1 signaling as a common feature of different inducers of pancreatic ADM.

Exposure to binge ethanol and fatty acid ethyl esters exacerbates chronic ethanol-induced pancreatic injury in hepatic alcohol dehydrogenase deficient deer mice

Alcoholic chronic pancreatitis (ACP) is a fibroinflammatory disease of the pancreas. However, metabolic basis of ACP is not clearly understood. In this study, we evaluated differential pancreatic injury in hepatic alcohol dehydrogenase deficient (ADH-) deer mice fed chronic ethanol (EtOH), chronic plus binge EtOH, and chronic plus binge EtOH and fatty acid ethyl esters (FAEEs, nonoxidative metabolites of EtOH) to understand the metabolic basis of ACP. Hepatic ADH- and ADH normal (ADH+) deer mice were fed Lieber-DeCarli liquid diet containing 3% (w/v) EtOH for three months. One week before the euthanization, chronic EtOH fed mice were further administered with an oral gavage of binge EtOH with/without FAEEs. Blood alcohol concentration (BAC), pancreatic injury and inflammatory markers were measured. Pancreatic morphology, ultrastructural changes, endoplasmic reticulum (ER)/oxidative stress were examined using H & E staining, electron microscopy, immunostaining, and/or Western blot, respectively. Overall, BAC was substantially increased in chronic EtOH fed groups of ADH- vs. ADH+ deer mice. A significant change in pancreatic acinar cell morphology, with mild to moderate fibrosis and ultrastructural changes evident by dilatations and disruption of ER cisternae, ER/oxidative stress along with increased levels of inflammatory markers were observed in the pancreas of chronic EtOH fed groups of ADH- vs. ADH+ deer mice. Furthermore, chronic plus binge EtOH and FAEEs exposure elevated BAC, enhanced ER/oxidative stress and exacerbated chronic EtOH-induced pancreatic injury in ADH- deer mice suggesting a role of increased body burden of EtOH and its metabolism under reduced hepatic ADH in initiation and progression of ACP.

Management of pediatric blunt abdominal trauma: تدبير رضوح البطن الكليلة عند الأطفال

Aim of study: Evaluating a non- operative treatment of pediatric blunt abdominal trauma and avoiding unnecessary surgical intervention in Tishreen University Hospital. Methods: During years (2016- 2020) a retroprospective study was conducted on 62 children who had isolated blunt abdominal trauma or associated with other injuries, most of them were managed by non- operative treatment but some required surgical management. Results: Non- operative management of pediatric blunt abdominal injuries was applied for 59 patients, three patients required a surgical procedure, the spleen was the most organ exposed to injury (40) child, followed by liver (26) child, kidney (4) and (1) pancreatic injury. Non- operative management was successful in most solid organs injuries with grades 1, 2 and 3, but it failed in 5 grade splenic injury. one out of two hollow viscus injuries required surgical intervention. There were no statistical differences between the study groups in age, gender and injury mechanism. Hospital length of stay was significantly longer in patients who underwent a laparotomy (6) days compared to other non- operative patients (3) days, one complication occurred during non- operative management as pseudocyst after pancreatic injury, (4) patient died in the non- operative group due to hemodynamic instability and associated severe cerebral injuries. Conclusion: It is safe to treat most children with blunt abdominal injuries non- operatively if monitoring is adequate with hemodynamic stability.

Cell Type of Pancreatic Ductal Adenocarcinoma Origin: Implications for Prognosis and Clinical Outcomes

<b><i>Background:</i></b> Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease that has no effective early detection method or treatment to date. <b><i>Summary:</i></b> The normal cell type that initiates PDAC, or its cellular origin, is still unknown. To investigate the contribution of distinct normal epithelial cell types to PDAC tumorigenesis, genetically engineered mouse models were used to show that both acinar and ductal cells are capable of giving rise to PDAC. These studies indicated that genetic mutations and pancreatic injury interact differently with each cellular origin to affect their predilection and process for forming PDAC. In this review, we summarize recent findings using various genetically engineered mouse models in the identification and characterization of the PDAC cell of origin. We also discuss potential implications for cellular origin on tumor development, PDAC transcriptional subtype, and disease prognosis of patients. <b><i>Key Message:</i></b> Although it is clear that both ductal and acinar cells have the potential to form PDAC, whether cellular origin can indeed influence patient prognosis and whether knowledge of cellular origin will aid in the diagnosis or treatment of patients in the future will need further study.

Construction of an lncRNA–mRNA Co-Expression Regulatory Network Mediating Inflammation and Regeneration Following Acute Pancreatitis Injury

Long noncoding RNAs (lncRNAs) play important roles in the occurrence and development of many diseases and can be used as targets for diagnosis and treatment. However, the expression and function of lncRNAs in the injury and repair of acute pancreatitis (AP) are unclear. To decipher lncRNAs’ regulatory roles in AP, we reanalyzed an RNA-seq dataset of 24 pancreatic tissues, including those of normal control mice (BL), those 7 days after mild AP (D7), and those 14 days after mild AP (D14). The results showed significant differences in lncRNA and mRNA expression of D7/D14 groups compared with the control group. Co-expression analysis showed that differentially expressed (DE) lncRNAs were closely related to immunity- and inflammation-related pathways by trans-regulating mRNA expression. The lncRNA–mRNA network showed that the lncRNAs Dancer, Gmm20488, Terc, Snhg3, and Snhg20 were significantly correlated with AP pathogenesis. WGCNA and cis regulation analysis also showed that AP repair-associated lncRNAs were correlated with extracellular and inflammation-related genes, which affect the repair and regeneration of pancreatic injury after AP. In conclusion, the systemic dysregulation of lncRNAs is strongly involved in remodeling AP’s gene expression regulatory network, and the lncRNA–mRNA expression network could identify targets for AP treatment and damage repair.

Insights into Acute Pancreatitis Associated COVID-19: Literature Review

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) primarily affects the lungs, causing respiratory symptoms. However, the infection clearly affects all organ systems including the gastrointestinal system. Acute pancreatitis associated with coronavirus disease 2019 (COVID-19) has been widely reported Recent studies have discussed pancreatic compromise incidentally in asymptomatic patients, or in a form of clinical symptoms such as abdominal pain, nausea, or vomiting, which is further reflected in some cases with abnormal serum lipase and amylase levels It was suggested that upregulation of angiotensin-converting enzyme II cell receptors or inflammatory cytokines play a major role in predisposing pancreatic injury in SARS-CoV-2 positive patients To date, there is insufficient data to establish the causality of acute pancreatitis in SARS-CoV-2 infected cases. In this paper, we organize recent studies conducted to observe the frequency of acute pancreatitis associated with COVID-19 cases while highlighting present hypotheses, predisposing factors, and their effect on the outcome, and point to gaps in our knowledge.

Early pancreaticogastrostomy: a better and novel approach for high grade traumatic pancreatic injuries - case report from tertiary care centre in India

Traumatic pancreatic injury is a rare entity which is associated with severe morbidity and mortality. The management varies according to the American association for the surgery of trauma-organ injury scale (AAST-OIS) grading of injury, hemodynamic status and time of definitive diagnosis. Non-operative versus operative management has potential risks and benefits and long term debate on the ideal management is still ongoing. A 19-year boy, with severe, generalised pain abdomen was admitted after road traffic accident. Upon admission, the investigations: ultrasonography (USG) and computed tomography (CT) scan abdomen, showed traumatic pancreatic injury (AAST-OIS, grade V), was taken for exploratory laparotomy which revealed lacerated head of pancreas along with normal distal segment of pancreas with no associated injury to nearby hollow viscera, vascular structures. He underwent primary closure of head of pancreas with distal segment pancreaticogastrostomy. Postoperatively he recovered well with no complications. In the present case, as he had traumatic pancreatic injury (AAST-OIS, grade V) and there was no involvement of hollow viscera and vascular structures, the operative intervention can decrease morbidity as by pancreaticogastrostomy we have diverted the pancreatic fluid into stomach, subsequently decreasing the chances of pseudocyst, fistula, necrosis of pancreas. Thus we conclude, high grade blunt traumatic abdomen injuries should be managed with adequate resection and subsequent reconstruction and/or drainage procedure. Pancreaticoduodenectomy, distal pancreatectomy, pancreaticogastrostomy, pancreaticojejunostomy are the available options to be used according to the grading of injury and associated injuries.

Management of Pancreatic Trauma In Urban India: A Multicenter Study

Background: Pancreatic trauma occurs in 0.2-2% of patients with blunt trauma and 1–12% of patients with penetrating trauma. The mortality and morbidity rates range from 9-34% and 30-60% respectively. We aimed to review the management of pancreatic trauma in a multicenter database from India.Methods: We analyzed all patients who suffered a pancreatic injury and who were included in the multicenter prospective observational study ‘Towards Improved Trauma Care Outcomes (TITCO)’.Results: Of the 16047 trauma cases, 1134 (7.1%) patients suffered abdominal trauma. Of all those with abdominal trauma 55 patients (4.9%) had injury to the pancreas. 28 patients (50.9%) with pancreatic trauma were managed conservatively. 27 patients (49.1%) underwent surgical exploration in the form of laparotomies. 11 procedures were undertaken for pancreas. A total of 45 (82%) patients had associated injuries along with pancreatic injury. Thorax (19) (including injuries to lung, pleura and ribs), liver (17), bowel (14) and spleen (13) were the most common associated injuries.Conclusion: Conservative management was as common as operative management in patients with pancreatic injuries. Most (80%) grade III/IV underwent operative treatment. Many patients (82%) had associated injuries. Level of evidence: III

Trimethylamine N-oxide promotes hyperlipidemia acute pancreatitis via inflammatory response

Trimethylamine N-oxide (TMAO), a metabolite of gut microbiota, is involved in the regulation of lipid metabolism and inflammatory response; however, the role of TMAO in hyperlipidemia acute pancreatitis (HAP) is not clear. In this study, HAP mice were used as an animal model to explore the effects and possible mechanism of TMAO on HAP, which may provide new ideas for the treatment of HAP. Results found that the levels of triglycerides, total cholesterol, low-density lipoprotein cholesterol, nonestesterified fatty acid, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, α-amylase, TMAO, and flavin-containing monooxygenase 3 were significantly increased, the levels of high-density lipoprotein cholesterol and insulin were significantly decreased, and there was an obvious pancreatic injury and inflammatory response in the model group. The choline analogue 3,3-dimethyl-1-butanol (DMB) treatment reversed the changes of serum biochemical parameters, alleviated the pancreatic tissue injury, and reduced the levels of inflammatory cytokines. Further studies of toll-like receptor (TLR)/p-glycoprotein 65 (p65) pathway found that the expressions of TLR2, TLR4, and p-p65/p65 in the model group were significantly increased, which was more obvious after Escherichia coli (Migula) Castellani & Chalmers treatment, while activation of the TLR/p65 pathway was inhibited by DMB. The results indicated that TMAO promotes HAP by promoting inflammatory response through TLR/p65 signaling pathway, suggesting that TMAO may be a potential target of HAP.

Prevalence of hepatopancreatic injury and clinical outcomes in patients with COVID-19 in USA

Background (1) To determine the prevalence of hepatopancreatic injury in coronavirus disease 2019 (COVID-19) patients. (2) To correlate hepatopancreatic injury in COVID-19 with mortality, disease severity, and length of stay in this cohort. Results Forty-five thousand three hundred sixty patients were included in the analysis, 62.82% of which had either hepatic or pancreatic injury. There was a significant upward trend in transaminases, alkaline phosphatase, prothrombin time, bilirubin, lactate dehydrogenase, and lipase and a downward trend in albumin with an increase in disease severity. COVID-19-positive patients with hepato-pancreatic injury have a significantly higher mortality (OR 3.39, 95%CI 3.15–3.65) after controlling for the differences in age, sex, race/ethnicity, liver cirrhosis, and medication exposures. They also have increased disease severity (OR 2.7, 95%CI 2.5–2.9 critical vs mild/moderate; OR 1.4, 95% CI 1.3–1.5 severe vs mild/moderate) and longer hospital length of stay (2 days). Conclusion COVID-19 can cause liver injury. Mortality, disease severity, and hospital length of stay are increased in COVID-19 patients with hepatopancreatic injury. Graphical Abstract