Pathogenesis Of Acute Pancreatitis Research Articles

PFKFB3 controls acinar IP3R-mediated Ca2+ overload to regulate acute pancreatitis severity.

Acute Pancreatitis (AP) is among the most common hospital gastrointestinal diagnosis; understanding the mechanisms underlying the severity of AP are critical for development of new treatment options for this disease. Here, we evaluate the biological function of phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) in AP pathogenesis in two independent genetically engineered mouse models of AP. PFKFB3 is elevated in AP and severe AP (SAP) and knockout of Pfkfb3 abrogates the severity of alcoholic SAP (FAEE-SAP). Using a combination of genetic, pharmacological, and molecular studies we define the interaction of PFKFB3 with inositol 1,4,5-trisphosphate receptor (IP3R) as a key event mediating this phenomenon. Further analysis demonstrated that the interaction between PFKFB3 and IP3R promotes FAEE-SAP severity by altering intracellular calcium homeostasis in acinar cells. Together our results support a PFKFB3-driven mechanism controlling AP pathobiology and define this enzyme as a therapeutic target to ameliorate the severity of this dismal condition.

Adipose Triglyceride Lipase–Mediated Adipocyte Lipolysis Exacerbates Acute Pancreatitis Severity in Mouse Models and Patients

Dyslipolysis of adipocytes has played a critical role in various diseases. Adipose triglyceride lipase (ATGL) is a rate-limiting enzyme in adipocyte autonomous lipolysis. However, whether the degree of adipocyte lipolysis relates to the prognoses in acute pancreatitis (AP) and the role of ATGL mediated lipolysis in the pathogenesis of AP remains elusive. The visceral adipose tissue (VAT) consumption rate (VATR) in the acute stage was measured in both AP patients and mouse models. Lipolysis levels and ATGL expression were detected in caerulein (CER)-induced AP models. CL316,243, a lipolysis stimulator, and adipose tissue-specific ATGL knockout (AAKO) mice were used to further investigate the role of lipolysis in AP. The ATGL-specific inhibitor, Atglistatin, was performed in C57Bl/6N and ob/ob AP models. This study found that increased VATR in the acute phase was independently associated with adverse prognoses in AP patients, which was validated in mice AP models. Lipolysis of adipocytes was elevated in AP mice. Stimulation of lipolysis could aggravate AP. Genetic blockage of ATGL specifically in adipocytes was able to alleviate the damage to AP. The application of Atglistatin could effectively protect against AP in both lean and obese mice. These findings demonstrated that ATGL-mediated adipocyte lipolysis exacerbates AP and highlighted the therapeutic potential of ATGL as a drug target for AP.

Cytokine Dynamics in Acute Pancreatitis: The Quest for Biomarkers from Acute Disease to Disease Resolution.

Background: Acute pancreatitis (AP) is an inflammatory disease of the pancreas with incompletely known pathogenic mechanisms. This study aimed to explore the temporal changes in serum cytokines in patients with AP and to assess the association of these changes with disease severity. Methods: Fifty patients hospitalized with AP were enrolled, and their serum cytokine levels were analyzed at four different time points. A healthy control (HC) group of 30 outpatients was included. Results: AP patients showed increased levels of interleukin (IL)-6, IL-8, IL-10, vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-alpha, and monocyte chemoattractant protein (MCP)-1 at admission when compared with HC. IL-6, VEGF, and EGF remained elevated 1 month after hospitalization and 6 months after discharge. Conclusions the Bedside Index of Severity in Acute Pancreatitis (BISAP) and severity classification of the revised Atlanta classification system, IL-6 and VEGF, determined 48 h after hospitalization, were the two cytokines consistently elevated in the most severe patients. Increased levels of IL-4, IL-6, IL-10, and TNF-alpha at admission and MCP-1 48 h after admission are also related to the length of hospital stay. Conclusions: Our study highlights the role cytokines play in the pathogenesis of AP and can be useful in the development of future drug trials for AP.

Triglycerides: A Sensitizer but Not a Trigger for Hypertriglyceridemic Acute Pancreatitis.

The incidence of hypertriglyceridemic acute pancreatitis (HTG-AP) is increasing. Although the guideline defines the diagnostic criteria as triglyceride (TG) greater than 11.3 mmol/L, there is actually no specific threshold. Many people with hypertriglyceridemia (HTG) or obvious chyloid blood do not develop acute pancreatitis (AP). To explore the role of HTG in the pathogenesis of AP. Thirty-six male SD rats were randomly assigned into normal control, AP, HTG, HTG-AP, low-dose fenofibrate andhigh-dose fenofibrate groups. Serum indices and cytokine levels in serum, and pathological changes in pancreatic tissues were observed. The expression levels of TLR4 and NF-κBp65 in pancreatic tissues were detected by immunohistochemistry and Western blot. In normal rats, HTG alone did not induce AP. However, after establishing the HTG-AP model with Poloxam 407 and L-arginine, serum-free fatty acid and TG levels were positively correlated with the levels of lipase, amylase, IL-1β, IL-6, pancreatic inflammation scores, and the expressions of TLR4 and NF-κBp65 (all P < 0.001). Expressions of TLR4 and NF-κBp65 were significantly increased in the pancreatic tissues of HTG-AP rats. Fenofibrate effectively decreased TG levels in HTG-AP rats and reduced the expression of TLR4 and NF-κBp65 (all P < 0.001). HTG does not directly cause AP, but rather increases the susceptibility to AP or aggravates the inflammatory response. It is more like a sensitizer of inflammation rather than an activator.

Exosomes Derived from Caerulein-Stimulated Pancreatic Acinar Cells Mediate Peritoneal Macrophage M1 Polarization and Pyroptosis via an miR-24-3p/MARCH3/NLRP3 Axis in Acute Pancreatitis.

Acute pancreatitis (AP) has a high incidence of hospitalizations, morbidity, and mortality worldwide. A growing number of studies on AP pathogenesis are based on caerulein-induced experimental model, which simulates human AP in vivo. It has been demonstrated that both pancreatic acinar cells and peritoneal macrophages are involved in pancreatic inflammation and damage. However, their connection has not been well understood. A caerulein-induced AP model was established on the pancreatic acinar cell line AR42J. Rat macrophages were isolated from the peritoneal cavity. The effects of caerulein-induced pancreatic exosomes on the peritoneal macrophage and pancreas in vivo and in vitro were examined. The underlying molecular mechanism was investigated by exploring the regulatory role of downstream molecules. We found that exosomes derived from caerulein-treated AR42J cells induced rat peritoneal macrophage M1 polarization and pyroptosis. miR-24-3p was upregulated in caerulein-stimulated exosomes, whereas the miR-24-3p inhibitor counteracted the effect of pancreatic exosomes on peritoneal macrophage M1 polarization and pyroptosis. Furthermore, miR-24-3p inhibited March3 expression, whereas MARCH3 mediated NLRP3 ubiquitination in rat peritoneal macrophages, which, in turn, contributed to the apoptosis, reactive oxygen species production, and inflammation in AR42J cells. Exosomes derived from caerulein-stimulated pancreatic acinar cells mediate peritoneal macrophage M1 polarization and pyroptosis via an miR-24-3p/MARCH3/NLRP3 axis in AP.

Soat2 inhibitor avasimibe alleviates acute pancreatitis by suppressing acinar cell ferroptosis.

Ferroptosis, characterized by lipid peroxidation, plays a significant role in the pathogenesis of acute pancreatitis (AP). While sterol O-acyltransferase 2 (Soat2) is known for its crucial regulatory role in cholesterol homeostasis, its involvement in the development of AP remains unreported. We conducted this study to identify the pivotal role of Soat2 in AP using transcriptomic databases. Subsequently, we confirmed its alterations through both in vitro and in vivo experimental models. Furthermore, we performed intervention with the Soat2 inhibitor avasimibe to evaluate pancreatic tissue pathology and serum enzymatic levels and observe inflammatory cell infiltration through immunohistochemistry. Additionally, changes in indicators related to ferroptosis were also observed. The results showed that in the AP mouse model, the protein and mRNA levels of Soat2 were significantly increased. Following avasimibe administration, there was a decrease in serum amylase levels, reduction in pancreatic tissue pathological damage, and attenuation of inflammatory cell infiltration. Furthermore, avasimibe administration resulted in downregulation of ferroptosis-related indicators. In conclusion, our findings suggest that the Soat2 inhibitor avasimibe protects against AP in mice through inhibition of the ferroptosis.

Discoveries of GPR39 as an evolutionarily conserved receptor for bile acids and of its involvement in biliary acute pancreatitis.

Acute pancreatitis (AP) is one of the most common gastrointestinal diseases. Bile acids (BAs) were proposed to be a cause of AP nearly 170 years ago, though the underlying mechanisms remain unclear. Here, we report that two G protein-coupled receptors, GPR39 and GHSR, mediated cellular responses to BAs. Our results revealed GPR39 as an evolutionarily conserved receptor for BAs, particularly 3-O-sulfated lithocholic acids. In cultured cell lines, GPR39 is sufficient for BA-induced Ca2+ elevation. In pancreatic acinar cells, GPR39 mediated BA-induced Ca2+ elevation and necrosis. Furthermore, AP induced by BAs was significantly reduced in GPR39 knockout mice. Our findings provide in vitro and in vivo evidence demonstrating that GPR39 is necessary and sufficient to mediate BA signaling, highlighting its involvement in biliary AP pathogenesis, and suggesting it as a promising therapeutic target for biliary AP.

MiR-148a and miR-551b-5p regulate inflammatory responses via regulating autophagy in acute pancreatitis

Acute pancreatitis (AP) is a common inflammatory response that occurs in the pancreas with mortality rates as high as 30 %. However, there is still no consistent and effective treatment for AP now. MicroRNA-148 was reported to be involved in AP through IL-6 signaling pathway. Therefore, we aimed to further explore the detailed mechanisms of AP, to develop more therapeutic approach for AP. Exosomes were isolated from peripheral blood mononuclear cells of 20 AP patients and 20 healthy volunteers to evaluate the abnormally expressed miRNA. Then pancreatic acinar cells (PACs) were transfected with retrovirus to overexpress miR-148a/miR-551b-5p to evaluate their function. Both miR-148a and miR-551b-5p were highly expressed in AP patients than these in healthy cases. Then overexpressing miR-551b-5p in PACs could regulate autophagy through directly binding to Baculoviral IAP Repeat Containing 6, leading to the increased secretions of interleukin-1β (IL-1β) and interleukin-18 (IL-18) through interleukin-1 (IL-1) signaling pathway. Moreover, overexpressing miR-148a in PACs could decrease the secretions of IL-1β and IL-18 to modulate autophagy. The exosomal miRNA-148a and miRNA-551b-5p derived from peripheral blood mononuclear cells of AP patients may two-way mediate autophagy damage through IL-6/STAT3 signaling pathway, which participated in the AP pathogenesis. Our findings may provide new targets for the diagnosis and treatment of AP.

Role of obesity in pathogenesis of acute pancreatitis

Role of obesity in pathogenesis of acute pancreatitis

Risk factors for drug-related acute pancreatitis: an analysis of the FDA adverse event reporting system (FAERS).

Objective: While several drugs have been linked to acute pancreatitis (AP), the AP-related risk of most drugs remains unclear. This study investigated the risk factors for drug-induced AP by analyzing a large dataset from the FDA Adverse Event Reporting System (FAERS). Methods: The reporting odds ratios (ROR) were used to assess the reports of drug-induced AP from the first quarter of 2004 to the second quarter of 2022. Single-factor, LASSO, and multi-factor regression analysis were performed to explore drug-related AP-related risk factors. Bonferroni correction was applied for the multiple comparisons performed. Results: A total of 264 drugs associated with AP, including antineoplastic drugs (35/264), antidiabetic drugs (28/264), antibacterial drugs (24/264), immunomodulatory drugs (11/264), antipsychotic drugs (6/264), and other drugs (160/264) were retrieved. Multi-factor analysis showed that males, age 41-54years old, and 36 drugs, including Tigecycline, were risk factors for drug-related AP. The median time to drug-related AP onset was 31days (interquartile range [IQR] 7-102days) and about 75% of adverse events occurred within 100days. Conclusion: These findings may help clinicians to identify drug-related AP at the early stage and can be used to inform future studies of drug-related AP pathogenesis.

Role of unknown significance (VUS) and non-disease-causing (NDC) CFTR gene mutations in the pathogenesis of acute pancreatitis

Role of unknown significance (VUS) and non-disease-causing (NDC) CFTR gene mutations in the pathogenesis of acute pancreatitis

The role of iron and ferroptosis in the pathogenesis of acute pancreatitis

ABSTRACT Acute pancreatitis (AP) is an inflammatory disease of the pancreas. Iron is an essential element for life and is involved in many metabolic processes. Ferroptosis is a type of regulated cell death that is triggered by iron and oxidative stress. A well-established mouse AP model was adopted to study the role of iron and ferroptosis in the pathogenesis of pancreatitis. Mice were injected with cerulein to induce AP, and pancreatic tissue samples were analyzed to determine the pathology, cell death, iron deposition, expression of iron transporters, and lipid peroxidation. The role of iron was studied by giving mice extra iron or iron chelator. In vitro studies with acinar cells with ferroptosis activator and inhibitor were also performed to assess the inflammatory response. Iron was found accumulated in the pancreatic tissue of mice who suffered cerulein-induced pancreatitis. Cell death and lipid peroxidation increased in these tissues and could be further modulated by iron dextran or iron chelator. Mice given Hemin through gavage had reduced levels of GSH in pancreatic tissue and increased inflammatory response. Studies with acinar cells showed increased levels of lipid peroxidation and ferroptosis-specific mitochondrial damage when treated with ferroptosis inducer and inflammatory cytokines.

Role of lncRNAs in acute pancreatitis: pathogenesis, diagnosis, and therapy.

Acute pancreatitis (AP) is one of the most common acute abdominal diseases characterized by an injury and inflammatory disorder of the pancreas with complicated pathological mechanisms. Long non-coding RNAs (lncRNAs) have been shown to play an important role in various physiological and pathological processes in humans, and they have emerged as potential biomarkers of diagnosis and therapeutic targets in various diseases. Recently, accumulating evidence has shown significant alterations in the expression of lncRNAs, which are involved in the pathogenesis of AP, such as premature trypsinogen activation, impaired autophagy, inflammatory response, and acinar cell death. Moreover, lncRNAs can be the direct target of AP treatment and show potential as biomarkers for the diagnosis. Thus, in this review, we focus on the role of lncRNAs in the pathogenesis, diagnosis, and therapy of AP and emphasize the future directions to study lncRNAs in AP, providing new insight into understanding the cellular and molecular mechanisms of AP and seeking novel biomarkers for the diagnosis and therapeutic targets to improve clinical management in the future.

The role of predictive and prognostic values of inflammatory markers in acute pancreatitis: a narrative review

Pancreatitis is an inflammatory condition affecting the pancreas and is classified into 2 types, acute and chronic, which can manifest in various forms. This review article summarizes the role of predictive and prognostic values of inflammatory markers in the pathogenesis of acute pancreatitis, mainly focused on preclinical and clinical studies. It includes serum amyloid A (SAA), monocyte chemotactic protein-1 (MCP-1), erythrocyte sedimentation rate (ESR), interleukin-6 (IL-6), C-reactive protein (CRP), IL-10, myeloperoxidase, pentraxin 3, and plasminogen activator inhibitor 1. SAA3 plays a crucial role in developing acute pancreatitis by triggering a receptor-interacting protein 3–dependent necroptosis pathway in acinar cells. Targeting SAA3 could be a potential strategy for treating acute pancreatitis. The recruitment of monocytes/macrophages and the activation of the systemic MCP-1 signaling pathway play a role in the progression of pancreatitis, and blocking MCP-1 may have a suppressive effect on the development of pancreatic fibrosis. The ESR can predict severe acute pancreatitis with slightly lower accuracy than CRP. When ESR and CRP levels are combined at 24 hours, they predict severe acute pancreatitis accurately. IL-6 plays a crucial role in activating the Janus kinase/signal transducers and activators of the transcription pathway, exacerbating pancreatitis and contributing to the initiation and progression of pancreatic cancer. Endogenous IL-10 plays a crucial role in controlling the regenerative phase and limiting the severity of fibrosis and glandular atrophy induced by repeated episodes of acute pancreatitis in mice. The predictive and diagnostic roles of these inflammatory factors in pancreatitis were introduced in detail in this review.

Immune-Mediated Hemolytic Anemia and Clinically Suspected Acute Pancreatitis in Dogs, a Pilot Study

Acute pancreatitis can be a complication of massive hemolysis, above all when intravascular in nature. Therefore, the aim of this study was to investigate the association between canine immune mediated hemolytic anemia (IMHA) and clinically suspected acute pancreatitis (CSAP) and the role of calculated free plasma hemoglobin (Hbfp) in CSAP occurrence/development. In this cohort study the records of 95 dogs with IMHA and 95 sick dogs with pathologies other than IMHA were compared for CSAP occurrence/development. At presentation, 12/95 dogs with IMHA met criteria for CSAP, while only 3/95 sick control dogs met these criteria (χ2 =1.58, P = .008). Within 7 days of hospitalization 9 additional dogs with IMHA had developed CSAP. The Hbfp was calculated and compared for dogs with IMHA that had/developed CSAP and for those without CSAP. In dogs with IMHA, a calculated Hbfp concentration ≥ 0.08 g/dL resulted in an increased relative risk (RR) of having/developing CSAP (RR = 2.54, 95% CI, 1.51-4.29; P = .003). No significant effect on short-term prognosis in dogs with IMHA was found between those having/developing CSAP and those without CSAP. This study showed that dogs with IMHA have an increased risk of having CSAP and Hbfp concentration may be involved in the pathogenesis of acute pancreatitis.

Decreased syntaxin17 expression contributes to the pathogenesis of acute pancreatitis in murine models by impairing autophagic degradation.

Acute pancreatitis (AP) is an inflammatory disease of the exocrine pancreas. Disruptions in organelle homeostasis, including macroautophagy/autophagy dysfunction and endoplasmic reticulum (ER) stress, have been implicated in human and rodent pancreatitis. Syntaxin 17 (STX17) belongs to the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) subfamily. The Qa-SNARE STX17 is an autophagosomal SNARE protein that interacts with SNAP29 (Qbc-SNARE) and the lysosomal SNARE VAMP8 (R-SNARE) to drive autophagosome-lysosome fusion. In this study, we investigated the role of STX17 in the pathogenesis of AP in male mice or rats induced by repeated intraperitoneal injections of cerulein. We showed that cerulein hyperstimulation induced AP in mouse and rat models, which was characterized by increased serum amylase and lipase activities, pancreatic edema, necrotic cell death and the infiltration of inflammatory cells, as well as markedly decreased pancreatic STX17 expression. A similar reduction in STX17 levels was observed in primary and AR42J pancreatic acinar cells treated with CCK (100 nM) in vitro. By analyzing autophagic flux, we found that the decrease in STX17 blocked autophagosome-lysosome fusion and autophagic degradation, as well as the activation of ER stress. Pancreas-specific STX17 knockdown using adenovirus-shSTX17 further exacerbated pancreatic edema, inflammatory cell infiltration and necrotic cell death after cerulein injection. These data demonstrate a critical role of STX17 in maintaining pancreatic homeostasis and provide new evidence that autophagy serves as a protective mechanism against AP.

MODERN IDEAS ON THE ROLE OF HEMODYNAMIC DISORDERS IN THE PATHOGENESIS OF ACUTE PANCREATITIS

Acute pancreatitis remains one of the most common abdominal diseases, causing a large number of both local and systemic complications. Acute pancreatitis has a high death rate. The pathogenesis of acute pancreatitis is complex and needs careful examination. Many authors suppose, that hemodynamic disorders lead to the development of complications, often fatal. Thus, such disorders need be studied separately. &#x0D; The review is based on the analysis of articles included in such databases as elibrary.ru, cyberleninka.ru, and e-versions of specialized open access journals. All the articles outline modern views on the role of hemodynamic disorders in the pathogenesis of acute pancreatitis.&#x0D; The causes and mechanisms of development of hemodynamic disorders are considered in terms of central and regional hemodynamics, and microcirculation. The authors describe their mutual influence and role in the development of both local and systemic complications of acute pancreatitis.&#x0D; Contractility disorders can be observed in the pathogenesis of central hemodynamics. They can be caused by a highly active myocardial depressant factor. These disorders are supported and aggravated by other organs and systems with the development of multiple organ failure.&#x0D; Violations of regional hemodynamics are associated mainly with an increase in intra-abdominal pressure. A direct dependence of intestinal wall perfusion on intra-abdominal pressure is established. Intestinal barrier dysfunction contributes to the infection of necrosis foci.&#x0D; Microcirculation disorders are the most important element in the pathogenesis of acute pancreatitis, often defining its outcome. Microcirculation disorders include angiospasm, venous stasis, microthrombi formation, and interstitial edema. A decrease in local perfusion due to impaired gland microcirculation can cause tissue ischemia and pancreonecrosis.

Targeting extracellular CIRP with an X-aptamer shows therapeutic potential in acute pancreatitis

Severe acute pancreatitis (AP) is associated with a high mortality rate. Cold-inducible RNA binding protein (CIRP) can be released from cells in inflammatory conditions and extracellular CIRP acts as a damage-associated molecular pattern. This study aims to explore the role of CIRP in the pathogenesis of AP and evaluate the therapeutic potential of targeting extracellular CIRP with X-aptamers. Our results showed that serum CIRP concentrations were significantly increased in AP mice. Recombinant CIRP triggered mitochondrial injury and ER stress in pancreatic acinar cells. CIRP-/- mice suffered less severepancreatic injury and inflammatory responses. Using a bead-based X-aptamer library, we identified an X-aptamer that specifically binds to CIRP (XA-CIRP).Structurally, XA-CIRP blocked the interaction between CIRP and TLR4. Functionally, it reduced CIRP-induced pancreatic acinar cell injury invitro andL-arginine-induced pancreatic injury and inflammation invivo. Thus, targeting extracellular CIRP with X-aptamers may be a promising strategy to treat AP.

The Emerging Roles of the Adaptive Immune Response in Acute Pancreatitis.

Acute pancreatitis (AP) is an abrupt, variable inflammatory condition of the pancreas, potentially escalating to severe systemic inflammation, rampant pancreatic necrosis, and multi-organ failure. Its complex pathogenesis involves an intricate immune response, with different T cell subsets (Th1, Th2, Th9, Th17, Th22, TFH, Treg, and CD8+ T cells) and B cells playing pivotal roles. Early T cell activation initiates the AP development, triggering cytokines associated with the Th1 response, which stimulate macrophages and neutrophils. Other T cell phenotypes contribute to AP's pathogenesis, and the balance between pro-inflammatory and anti-inflammatory cytokines influences its progression. Regulatory T and B cells are crucial for moderating the inflammatory response and promoting immune tolerance. B cells further contribute through antibody production, antigen presentation, and cytokine secretion. Understanding these immune cells' roles in AP could aid in developing new immunotherapies to enhance patient outcomes. However, further research is required to define these cells' precise roles in AP and their potential as therapeutic targets.

Changes in the biochemical parameters of blood and the morphological structure of the pancreas in rats with acute pancreatitis and their correction using corvitin

Acute pancreatitis (AP) is an inflammation of the pancreas characterized by a severe course and a high mortality rate. The pathogenesis of AP is still not fully understood, so there is currently a lack of treatment. Corvitin is a water-soluble form of quercetin that retains all the properties of quercetin and has powerful antioxidant, anti-inflammatory and anti-apoptotic properties. The aim of our study was to evaluate the effect of corvitin on biochemical blood parameters and morphological features of the pancreas in rats with AP caused by intraperitoneal administration of L-arginine (200 mg/100 g). This model of AP is non-invasive, highly reproducible and causes selective, dose-dependent necrosis of acinar cells and is ideal both for studying the pathomechanisms of AP and for observing and influencing changes in the course of the disease. The legality of using this model is confirmed by the morphostructural changes in the pancreas that are characteristic of AP. In rats with AP, an increase in the blood concentration of α-amylase (twice), alanine aminotransferase (ALT) (three times), aspartate aminotransferase (AST) (one and a half times) compared to control values was observed already on the first day of the pathology development. On the second day of AP, the level of glucose and urea in the blood of rats increased by 34 and 22%, respectively, while the creatinine content did not change. Under the influence of corvitin (50 mg/kg), the levels of α-amylase, ALT and glucose decreased already after a day, while the content of AST and urea increased and remained so until the 8th day of observation. The most positive dynamics of morphological changes in the pancreas of rats was observed when corvitin was used on the first day of AP induction.