Materiały źródłowe

• #1 Pathogenic mechanisms of pancreatitis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5292603/

  Pancreatitis is inflammation of pancreas and caused by a number of factors including pancreatic duct obstruction, alcoholism, and mutation in the cationic trypsinogen gene. […] These inflammatory cells are known to play a central role in initiating and promoting inflammation including pancreatic fibrosis, i.e., a major risk factor for pancreatic cancer. […] A number of inflammatory cytokines are known to involve in promoting pancreatic pathogenesis that lead pancreatic fibrosis. […] Pancreatic fibrosis is a dynamic phenomenon that requires an intricate network of several autocrine and paracrine signaling pathways. […] In this review, we have provided the details of various cytokines and molecular mechanistic pathways (i.e., Transforming growth factor-/SMAD, mitogen-activated protein kinases, Rho kinase, Janus kinase/signal transducers and activators, and phosphatidylinositol 3 kinase) that have a critical role in the activation of PSCs to promote chronic pancreatitis and trigger the phenomenon of pancreatic fibrogenesis.

• #1 Pathogenic mechanisms of pancreatitis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5292603/

  Our review also highlights the significance of several experimental animal models that have an important role in dissecting the mechanistic pathways operating in the development of chronic pancreatitis, including pancreatic fibrosis. […] During pancreatic injury, atrophic acinar cells activate several inflammatory key players like macrophages and granulocytes which release a number of pro-inflammatory cytokines [i.e., interleukin (IL)-1, IL-6, IL-8, IL-18, IL-33, and tumor necrosis factor (TNF)-]. These pro-inflammatory cytokines further activate pancreatic stellate cells (PSCs) to promote chronic pancreatitis. […] The detail of each cytokine involved in the pathogenesis of pancreatitis has been described independently. […] The main causes of pancreatitis are; obstruction in the main pancreatic duct, gallstones, alcohol misuse, smoking, hypercalcemia, hyperparathyroidism, drugs like valproate, thiazide toxicity, and genetic mutation.

• #1 Gallstone-related pathogenesis of acute pancreatitis | Pancreapedia

  https://pancreapedia.org/reviews/gallstone-related-pathogenesis-of-acute-pancreatitis

  Acute pancreatitis is now the most common reason for hospital admission among all gastrointestinal disorders. In most countries the presence of gallbladder stones represents the most frequent and significant risk factors for developing acute pancreatitis and underlying gallstone disease accounts for between 30 and 50% of cases with pancreatitis. […] Acute Pancreatitis is an inflammatory disorder of the exocrine pancreas caused, in most cases, by immoderate alcohol consumption or the passage of gallstones. […] Once a patient has developed pancreatitis due to gallstones the disease is likely to recur if the source of migrating bile duct stones is not removed or their impaction at the duodenal papilla is not prevented. […] Taken together these clinical and population-based observations indicate that a) carrying gallstones increases the risk of developing acute pancreatitis; b) only gallstones that are small enough to pass through the biliary tract, rather than the ones that remain asymptomatically in the gallbladder, confer a pancreatitis risk; c) strategies intended to remove the source of migrating gallstone or that prevent their impaction near the duodenal papilla reduce the risk of developing pancreatitis in the first place and the risk of a recurrence of pancreatitis; and d) preserving the flow from the pancreatic duct is an effective way of preventing ERCP-induced pancreatitis, a clinical entity considered to be caused by obstruction of the pancreatic duct.

• #1 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Acute-Pancreatitis-Pathogenesis.aspx

  Acute pancreatitis is generally considered to occur in three phases. […] In the first phase of pancreatitis there is premature activation of this enzyme called trypsin. […] There are several mechanisms by which this premature activation may take place. […] Once activated trypsin in turn activates several pancreatic digestive enzymes. These enzymes bring in the process of self digestion of the pancreatic cells. […] In this phase the activated trypsin causes inflammation within the pancreas. […] Both the second and third phase of inflammation is medicated by cytokines and other inflammatory mediators. […] The other inflammatory cells are activated and these bind to the cells lining the blood vessels. […] There is activation blood coagulation or clotting factors. […] In most patients acute pancreatitis is mild. In around 10 to 20% patients there may be severe inflammation. This may lead to systemic inflammatory response syndrome (SIRS).

• #1 Pancreatitis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK538337/

  Acute pancreatitis is an acute response to injury of the pancreas. Chronic pancreatitis can result in permanent damage to the structure and endocrine and exocrine functions of the pancreas. […] The pathogenesis of acute pancreatitis can occur by the following mechanisms: pancreatic duct and acinar injury. In acute pancreatitis, digestive enzymes within the pancreas are not secreted properly, and this leads to auto-digestion and inflammation of the pancreas. […] Alcohol can cause acute pancreatitis through direct toxicity and immunologic processes. Gallstones can lead to temporary obstruction of the pancreatic duct, and this is also believed to be the mechanism of ERCP-induced pancreatitis. […] Chronic pancreatitis can occur by repeated acute attacks which leads to inflammatory infiltrates and fibrosis within the pancreas. Over time, this leads to pancreatic insufficiency.

• #1 Acute pancreatitis – Wikipedia

  https://en.wikipedia.org/wiki/Acute_pancreatitis

  Acute pancreatitis occurs when there is abnormal activation of digestive enzymes within the pancreas. This occurs through inappropriate activation of inactive enzyme precursors called zymogens (or proenzymes) inside the pancreas, most notably trypsinogen. […] During an episode of acute pancreatitis, trypsinogen comes into contact with lysosomal enzymes (specifically cathepsin), which activate trypsinogen to trypsin. The active form trypsin then leads to further activation of other molecules of trypsinogen. The activation of these digestive enzymes lead to inflammation, edema, vascular injury, and even cellular death. The death of pancreatic cells occurs via two main mechanisms: apoptosis, which is physiologically controlled, and necrosis, which is less organized and more damaging. […] The balance between these two mechanisms of cellular death is mediated by caspases which regulate apoptosis and have important anti-necrosis functions during pancreatitis: preventing trypsinogen activation, preventing ATP depletion through inhibiting polyADP-ribose polymerase, and by inhibiting the inhibitors of apoptosis (IAPs). If, however, the caspases are depleted due to either chronic ethanol exposure or through a severe insult then necrosis can predominate.

• #1 Biochemical analyses of cystatin-C dimers and cathepsin-B reveals a trypsin-driven feedback mechanism in acute pancreatitis | Nature Communications

  https://www.nature.com/articles/s41467-025-56875-x

  Acute pancreatitis (AP) is characterised by self-digestion of the pancreas by its own proteases. This pathophysiological initiating event in AP occurs inside pancreatic acinar cells where intrapancreatic trypsinogen becomes prematurely activated by cathepsin B (CTSB), and induces the digestive protease cascade, while cathepsin L (CTSL) degrades trypsin and trypsinogen and therefore prevents the development of AP. […] Animal experiments, as well as clinical and genetic studies, suggest that the serine protease trypsin plays a key role in the pathogenesis of AP. […] Premature activation of trypsinogen within pancreatic acinar cells is a critical event for the onset of AP. […] In the absence of enterokinase, the lysosomal hydrolase cathepsin B (CTSB) is able to activate trypsinogen to active trypsin.

• #1

  https://journals.lww.com/jpancreatology/fulltext/2024/03000/acute_pancreatitis__pathogenesis_and_emerging.2.aspx

  There is a consensus that acinar cell calcium signaling changes usually initiate AP. […] In acinar cells, physiologic cytosolic calcium signals oscillate, are transient, and are essential for regulated digestive enzyme secretion. However, in the early phase of AP, acinar cell cytosolic calcium levels are elevated above physiologic responses (520-fold), prolonged, and physiologic calcium oscillations disappear. […] The changes in cytosolic calcium signaling can drive mitochondrial dysfunction with the opening of the mitochondrial transition pore and subsequent reductions in ATP levels, intracellular trypsinogen activation, disordered autophagy, endoplasmic reticulum (ER) stress, reduced apical and enhanced basolateral zymogen granule exocytosis, and tight-junction disruption. […] The precise mechanisms and signaling pathways governing the regenerative processes in the pancreas following AP remain incompletely understood.

• #1 Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP | Gut

  https://gut.bmj.com/content/65/8/1333

  Mitochondrial dysfunction has been implicated but the mechanism not established. […] MPTP opening was mediated by toxin-induced inositol trisphosphate and ryanodine receptor calcium channel release, and resulted in diminished ATP production, leading to impaired calcium clearance, defective autophagy, zymogen activation, cytokine production, phosphoglycerate mutase 5 activation and necrosis, which was prevented by intracellular ATP supplementation. […] This work demonstrates the mechanism and consequences of MPTP opening to be fundamental to multiple forms of acute pancreatitis and validates the MPTP as a drug target for this disease. […] Mitochondrial matrix calcium overload induces opening of the mitochondrial permeability transition pore (MPTP), a non-specific inner mitochondrial membrane channel that causes loss of mitochondrial membrane potential essential to ATP production.

• #1

  https://journals.lww.com/jpancreatology/fulltext/2024/03000/acute_pancreatitis__pathogenesis_and_emerging.2.aspx

  In pancreatic acinar cells, increased cytosolic Ca2+ activates calcineurin, a phosphatase that is central to the pathogenesis of AP. […] Past studies have demonstrated that these calcineurin inhibitors, or the genetic deletion of calcineurin, decrease the severity of experimental pancreatitis, including in a post-ERCP model. […] Mitochondrial dysfunction drives AP through multiple pathologic mechanisms, including the generation of reactive oxygen species (ROS) and reactive nitrogen species, reduced ATP generation, and release of cytochrome C. […] Oxidative damage and mitochondrial dysfunction contribute significantly to pancreatic acinar cell injury and death in AP. […] Dysfunction in one organelle impacts others through their metabolic interdependence and signaling crosstalk, ultimately leading to key features of pancreatitis like intrapancreatic trypsinogen activation, inflammation, and cell death. […] Targeted genetic disruption of organelle components like the lysosomal protein LAMP2 can cause spontaneous pancreatitis in mice, further demonstrating organelle dysfunctions key role in disease pathogenesis.

• #1 Molecular mechanism and potential role of mitophagy in acute pancreatitis | Molecular Medicine | Full Text

  https://molmed.biomedcentral.com/articles/10.1186/s10020-024-00903-x

  Mitophagy can contribute to either the mitigation or exacerbation of the inflammatory response observed in AP, contingent upon its efficiency and regulation. […] The onset of AP primarily involves pancreatic acinar cells, which are responsible for the synthesis, transportation, storage, and secretion of digestive enzymes. […] Mitochondrial function is of crucial significance for normal pancreatic protein synthesis and sorting, as well as for the maintenance of intracellular organelles and the secretion of enzymes. […] However, AP-induced mitochondrial dysfunction has been widely reported in numerous studies, resulting in pancreatic endoplasmic reticulum stress, impaired autophagy, and dysregulation of lipid metabolism. […] Impaired mitophagy may lead to mitochondrial dysfunction, excessive ROS production, and subsequent induction of pancreatic cell death.

• #1 Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP | Gut

  https://gut.bmj.com/content/65/8/1333

  Toxins that cause acute pancreatitis induce the MPTP in isolated murine and human pancreatic acinar cells via second messenger receptor calcium channel release and mitochondrial calcium but not reactive oxygen species overload, resulting in mitochondrial depolarisation, impaired ATP production and necrosis. […] Specific genetic or pharmacological inhibition of MPTP opening in a diverse range of clinically relevant mouse models dramatically improves all local pancreatic, systemic and distant pulmonary pathological responses. […] This study has shown the effectiveness in experimental acute pancreatitis of several drugs that target molecules that regulate the MPTP and that could be developed for the treatment of clinical acute pancreatitis. […] We report that MPTP opening is critical to all forms of pancreatitis investigated, causing diminished ATP production, defective autophagy, zymogen activation, cytokine release, phosphoglycerate mutase family member 5 (PGAM5) activation and necrosis.

• #1 The Pathogenesis of Pancreatitis and the Role of Autophagy

  https://www.mdpi.com/2036-7422/15/2/22

  The pathogenesis of acute and chronic pancreatitis has recently evolved as new findings demonstrate a complex mechanism operating through various pathways. […] As autophagy is now considered a fundamental mechanism in the pathophysiology of both acute and chronic pancreatitis, the fundamentals of the autophagy pathway were discussed to allow for a better understanding of the pathophysiological mechanisms of pancreatitis. […] The pathogenesis of both AP and CP is a complex process with many points that have not been fully investigated. Several mechanisms have been incriminated, such as acinar cell auto-digestion, mitochondrial abnormalities, and the involvement of immunity and inflammation. Recently, the role of autophagy has been recognized but not yet fully investigated. Therefore, in this review, we report an outline of the pathophysiology of pancreatitis, with a detailed presentation of the role of autophagy.

• #1 A narrative review of acute pancreatitis and its diagnosis, pathogenetic mechanism, and management

  https://atm.amegroups.org/article/view/59660/html

  Impaired autophagy is a prominent pathological event in AP that is associated with the abnormal activation of pancreatic enzymes. […] The occurrence and development of AP are closely related to ER stress. […] The pathogenesis of AP needs to be further explored to identify effective therapeutic targets and improve therapeutic effect and patients quality of life.

• #1 Molecular mechanism and potential role of mitophagy in acute pancreatitis | Molecular Medicine | Full Text

  https://molmed.biomedcentral.com/articles/10.1186/s10020-024-00903-x

  Acute pancreatitis (AP) is a multifaceted inflammatory disorder stemming from the aberrant activation of trypsin within the pancreas. […] Despite the contribution of various factors to the pathogenesis of AP, such as trypsin activation, dysregulated increases in cytosolic Ca2+ levels, inflammatory cascade activation, and mitochondrial dysfunction, the precise molecular mechanisms underlying the disease are still not fully understood. […] Mitophagy, a cellular process that preserves mitochondrial homeostasis under stress, has emerged as a pivotal player in the context of AP. […] Research suggests that augmenting mitophagy can mitigate pancreatic injury by clearing away malfunctioning mitochondria. […] Elucidating the role of mitophagy in AP may pave the way for novel therapeutic strategies.

• #1 Acute Pancreatitis – Gastrointestinal Disorders – MSD Manual Professional Edition

  https://www.msdmanuals.com/professional/gastrointestinal-disorders/pancreatitis/acute-pancreatitis

  Regardless of the etiology, an early event in the pathogenesis of acute pancreatitis is intra-acinar activation of pancreatic enzymes (including trypsin, phospholipase A2, and elastase), leading to the autodigestive injury of the gland itself. The enzymes can damage tissue and activate the complement system and the inflammatory cascade, producing cytokines and causing inflammation and edema. This process causes necrosis in a few cases. Acute pancreatitis increases the risk of infection by compromising the gut barrier, leading to bacterial translocation from the gut lumen to the circulation. […] Activated enzymes and cytokines that enter the peritoneal cavity cause a chemical burn and third spacing of fluid; those that enter the systemic circulation cause a systemic inflammatory response that can result in acute respiratory distress syndrome and acute kidney injury. The systemic effects are mainly the result of increased capillary permeability and decreased vascular tone, which result from the released cytokines and chemokines. Phospholipase A2 is thought to injure alveolar membranes of the lungs.

• #1 Acute Pancreatitis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/181364-overview

  Activated neutrophils then exacerbate the problem by releasing superoxide (the respiratory burst) or proteolytic enzymes (cathepsins B, D, and G; collagenase; and elastase). Finally, macrophages release cytokines that further mediate local (and, in severe cases, systemic) inflammatory responses. The early mediators defined to date are tumor necrosis factor-alpha (TNF-), interleukin (IL)-6, and IL-8. […] These mediators of inflammation cause an increased pancreatic vascular permeability, leading to hemorrhage, edema, and eventually pancreatic necrosis. As the mediators are excreted into the circulation, systemic complications can arise, such as bacteremia due to gut flora translocation, acute respiratory distress syndrome (ARDS), pleural effusions, gastrointestinal (GI) hemorrhage, and renal failure.

• #1 Mechanism of Severe Acute Pancreatitis: Focusing on Development and Progression

  https://www.kjpbt.org/journal/view.php?number=484

  Acute pancreatitis (AP) is an inflammatory disorder and the severity range from mild to severe form. […] Although pathogenesis of AP is still not fully understood, autodigestion theory is regarded as an initial common pathophysiologic mechanism of AP for about 2 centuries. However, it is obscure which mechanisms are involving the disease severity. Upregulation of adhesion molecules, leukocytes, proinflammatory cytokines and chemokines are also concerned local injury, systemic exacerbation of inflammation and ultimately organ failure. […] The patterns of acinar cell death are closely correlated with disease severity of AP. The degree of acinar cell apoptosis is reversed correlated whereas necrotic cell death is proportionate to severity. […] Inflammatory mediators is another very important pathophysiologic mechanism of AP.

• #1 Mechanism of Severe Acute Pancreatitis: Focusing on Development and Progression

  https://www.kjpbt.org/journal/view.php?number=484

  The early measurement of serum ICAM-1 levels within 24 hours can distinguish severe AP from mild AP. […] Cytokines are low molecular weight glycoproteins that are secreted by antigen presenting cells and act as mediators of immunity and inflammation. […] It was reported that acinar cell itself like leukocyte can produce cytokine such as tumor necrosis factor (TNF-) in AP and this cytokine influence the patterns of acinar cell death. […] The proposed mechanisms of TNF- induced pancreas injury are direct pancreas duct cell injury, formation of microthrombus, ischemia, hemorrhage, necrosis and edema. […] The NF-B could upregulate the expression of cytokine including TNF-, IL-1, and chemokines in AP. […] The patterns of acinar cell death in AP are closed related with the disease severity. Necrotic cell death is correlated with severe AP whereas apoptotic cell death is associated with mild AP in experimental models.

• #1 Pathogenesis of Chronic Pancreatitis | Pancreapedia

  https://pancreapedia.org/reviews/pathogenesis-of-chronic-pancreatitis

  Chronic pancreatitis is a progressive inflammatory disorder characterized by loss of functional pancreatic tissue, fibrous tissue conversion and ultimately loss of endocrine and exocrine function. However, although morphologic and clinical features have been well described, the pathogenesis of chronic pancreatitis is incompletely understood. […] Currently development of chronic pancreatitis is considered to be the result of a pathology involving pancreatic acinar, ductal and stellate cells. Our current understanding of the pathogenesis arises from experimental animal models as well as epidemiological and genetic studies in humans. Therefore this section will address both pathophysiological mechanisms, including results from established animal models, and known genetic and etiological factors that are associated with chronic pancreatitis.

• #1 Chronic Pancreatitis – Gastrointestinal Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/gastrointestinal-disorders/pancreatitis/chronic-pancreatitis

  The pathogenesis of chronic pancreatitis is not well understood. Several mechanisms have been proposed. […] The stone and duct obstruction theory proposes that disease is due to ductal obstruction caused by formation of protein-rich plugs as a result of protein-bicarbonate imbalance for unknown reasons. These plugs may calcify and eventually form stones within the pancreatic ducts. If obstruction is chronic, persistent inflammation leads to fibrosis, pancreatic ductal distortion, strictures, and atrophy. After several years, progressive fibrosis and atrophy lead to loss of exocrine and endocrine function. […] The necrosis-fibrosis hypothesis posits that repeated attacks of acute pancreatitis with necrosis are key to the pathogenesis of chronic pancreatitis. Over years, the healing process replaces the necrotic tissue with fibrotic tissue, leading to the development of chronic pancreatitis. This hypothesis has evolved into the sentinel acute pancreatitis event (SAPE) model. The SAPE model proposes that an initial episode of acute pancreatitis leads to a hypersensitive pancreas. A sensitized pancreas is more vulnerable to minor stressors (alcohol, tobacco) that can cause recurrent acute pancreatitis events, whereas similar stressors would not result in acute pancreatitis before the SAPE. […] In more advanced chronic pancreatitis, neuronal sheath hypertrophy and perineural inflammation occur and may contribute to chronic pain.

• #1 Pathogenic mechanisms of pancreatitis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5292603/

  Chronic pancreatitis develops fibrosis and it is the common pathological characteristic feature and major risk factor for pancreatic cancer. […] Chronic pancreatitis is characterized by marked stroma formation with an increased number of infiltrating macrophages and stellate cells, which are believed to play a central role in triggering inflammation and disease progression. […] The treatment of chronic pancreatitis and pancreatic cancer remains problematic as tissue becomes fibrotic due to injury that triggers several inflammatory, cellular as well as molecular signaling cascades that lead to formation and deposition of extra cellular matrix (ECM) at the site of injury. […] The available facts suggest that these activated PSCs are the main cells in the development of fibrosis during chronic pancreatitis via secretion of TGF-, FGF and COX-2 which leads to synthesis of ECM.

• #1 Pathogenic mechanisms of pancreatitis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5292603/

  A schematic mechanistic pathway involved in the progression of chronic pancreatitis is shown below in Figure 2. […] Furthermore, activated PSCs have the ability to synthesize and secrete several matrix proteins, matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases, thus indicating that PSCs have dual functions to regulate the physiology of the exocrine pancreas, i.e., they can synthesize as well as degrade the extracellular matrix. […] Fibrosis is a complex process and the mechanism of pancreatic fibrosis is still not well understood. […] Herein, we provide a summary of various molecular signaling pathways [i.e., TGF-/SMAD, mitogen-activated protein kinase (MAPK), Rho kinase, JAK/STAT, and phosphatidylinositol 3 kinase (PI3K)] that have been shown to play a critical role in the activation of PSCs during chronic pancreatitis and trigger the phenomenon of fibrogenesis in pancreas.

• #1 Pathogenic mechanisms of pancreatitis

  https://www.wjgnet.com/2150-5349/full/v8/i1/10.htm

  Fibrosis is a complex process and the mechanism of pancreatic fibrosis is still not well understood. […] Herein, we provide a summary of various molecular signaling pathways [i.e., TGF-/SMAD, mitogen-activated protein kinase (MAPK), Rho kinase, JAK/STAT, and phosphatidylinositol 3 kinase (PI3K)] that have been shown to play a critical role in the activation of PSCs during chronic pancreatitis and trigger the phenomenon of fibrogenesis in pancreas.

• #1 Gallstone-related pathogenesis of acute pancreatitis | Pancreapedia

  https://pancreapedia.org/reviews/gallstone-related-pathogenesis-of-acute-pancreatitis

  It is firmly established today that the initiation of pancreatitis requires the passage of a gallstone from the gallbladder through the biliary tract and gallstones, that remain in the gallbladder will not cause pancreatitis. […] Taken together these data suggest that the initial pathophysiological events during the course of gallstone-induced pancreatitis affect acinar cells and are triggered, in accordance with Opies initial hypothesis, by obstruction or impairment of flow form the pancreatic duct. A reflux of bile into the pancreatic duct either through a common channel created by an impacted gallstone or through an incompetent spincter caused by the passage of a gallstone is neither required nor likely to occur during the initial course of acute pancreatitis. […] These experiments suggest that pancreatic duct obstruction, the critical event involved in gallstone-induced pancreatitis, rapidly changes the physiological response of the exocrine pancreas to a pathological Ca2+-signaling pattern. This pathological Ca2+-signaling is associated with premature digestive enzyme activation and the onset of pancreatitis both of which can be prevented by administration of an intracellular calcium chelator.

• #1 Acute Pancreatitis: Mechanisms, Diagnosis, and Management – Clinical Advisor

  https://www.clinicaladvisor.com/features/acute-pancreatitis/

  The pancreas is a glandular organ found in the retroperitoneal cavity that is responsible for both endocrine and exocrine functions. […] The complex interaction between environmental factors such as high-fat diets, alcohol use disorder, and tobacco use may impair the physiologic functions of the pancreas, leading to inflammation of the pancreas and ultimately acute pancreatitis. […] The 2 most common etiologies of acute pancreatitis, accounting for nearly 30% to 50% of all cases, are cholelithiasis (gallstones) and excessive alcohol intake, particularly in individuals consuming 4 to 5 drinks daily for 5 years or more. […] Gallstones, the predominant cause of acute pancreatitis, can potentially obstruct the duodenal papilla, impeding the normal flow of pancreatic secretions from the pancreatic duct.

• #1 Acute Pancreatitis: Mechanisms, Diagnosis, and Management – Clinical Advisor

  https://www.clinicaladvisor.com/features/acute-pancreatitis/

  Chronic excessive alcohol use is thought to increase the viscosity of pancreatic secretions, which form protein plugs and later calculi within the pancreatic ducts. […] Alcohol also causes autodigestion of the pancreas by triggering premature activation of trypsinogen and other digestive enzymes before they are released into the duodenum. […] Hypertriglyceridemia, typically serum triglyceride concentrations greater than 1000 mg/dL, accounts for nearly 10% of acute pancreatitis cases and is frequently associated with recurrent attacks. […] High triglyceride and chylomicron levels increase blood viscosity, which promotes tissue ischemia within the pancreas. […] Tissue ischemia prompts the transition to anaerobic glycolysis, which raises lactate levels, leading to acidosis. […] Acidotic conditions promote the cytotoxic properties of free fatty acids, causing vascular damage and the premature activation of trypsinogen.

• #1 Coagulation in acute pancreatitis | JIR

  https://www.dovepress.com/pathogenesis-and-therapy-of-coagulation-disorders-in-severe-acute-panc-peer-reviewed-fulltext-article-JIR

  Ischemia superimposed upon pancreatic edema leads to acute necrotizing pancreatitis. […] Current experimental and clinical data provided compelling evidence that the disorders in the blood coagulation system play a critical role in the pathogenesis of severe acute pancreatitis (SAP). […] However, the mechanism of coagulopathy underlying SAP is not yet clear, although some anticoagulant drugs have entered clinical practice showing improvement in prognosis. […] The microcirculation perfusion of intra- and extrapancreatic organs, such as the liver, kidney, are impaired in SAP. […] One reason may be the intravascular thrombosis, since fibrin deposits have been detected in pancreatic capillaries by electron microscopy, […] and the process of coagulation in blood samples collected from SAP patients starts in 3 min and culminates within 5 min.

• #1 Coagulation in acute pancreatitis | JIR

  https://www.dovepress.com/pathogenesis-and-therapy-of-coagulation-disorders-in-severe-acute-panc-peer-reviewed-fulltext-article-JIR

  Thus, the local and systemic coagulopathy, which is in the range between scattered intravascular thrombosis in pancreatic microcirculation to disseminated intravascular coagulation (DIC), causes tissue damage or multiple organ failure (MOF). […] Previous studies have shown that inflammation shifts the hemostatic mechanisms in favor of thrombosis. […] This may encompass the key molecular and intercellular interactions related to triggers and pathways of the coagulation system that characterize the clotting disorders during SAP. […] During inflammation, the major source of TF is the circulatory system from monocytes. […] A high level of TF triggers the extrinsic pathway by binding factor VII/factor VIIa (FVII/FVIIa) to form TF-FVIIa complex, converting factor X (FX) to factor Xa (FXa).

• #1

  https://veterinarypartner.vin.com/doc/?id=4952412&pid=19239

  The pancreas has numerous safety mechanisms to prevent self-digestion. One of these mechanisms is the fact that the enzymes it creates are stored in an inactive form. They are harmless until they are mixed with activating enzymes made by the duodenum. If duodenal fluids backwash up the pancreatic duct and into the pancreas, enzymes are prematurely activated, and pancreatitis results. This is apparently the most common pancreatitis mechanism in humans, though it is not very common in veterinary patients. […] Pancreatitis is a highly inflammatory disease. Fever, elevated white blood cell (WBC) count, and other signs of inflammation occur frequently in patients with pancreatitis. Infection is rare in pancreatitis, but when it does happen, it can lead to serious complications. […] Pancreatitis is inflammation of the pancreas. The pancreas secretes digestive enzymes that break down nutrients. If digestive enzymes are activated too early, they can digest the body itself instead of food. It can be painful and life threatening as well as acute or chronic, mild or severe. Signs include appetite loss, vomiting, diarrhea, painful abdomen, and fever. Certain additional problems can occur, such as affecting the lung to the point of respiratory failure. In most cases the cause is unknown but these issues can contribute: Backwash (reflux), hormonal imbalances, certain drugs, trauma, pancreatic tumor, sudden high fat meal, or obesity. Diagnosis is generally made with lab tests. Ultrasound is more useful than radiographs. Sometimes surgery is the only way to diagnose it. Treatment is rehydrating with IV fluids to restore the circulation, which generally means being hospitalized for almost a week. Pain and anti-nausea medications are needed. After release, your dog will need an ultra low-fat diet that your veterinarian will provide. When 80% of the pancreas is damaged and insulin cannot be produced, diabetes results.

• #1 The Pathogenesis of Pancreatitis and the Role of Autophagy

  https://www.mdpi.com/2036-7422/15/2/22

  Macrophages are recognized as important mediators of inflammation and innate immunity. […] Autophagy has been associated with both protection and aggravation of experimental and human pancreatitis. […] Autophagy is the common denominator behind practically every mechanism involved in the pathogenesis of pancreatitis and a target for possible therapeutic interventions in this disease.

• #1 Mechanism of Severe Acute Pancreatitis: Focusing on Development and Progression

  https://www.kjpbt.org/journal/view.php?number=484

  The inflammatory response and mediators are playing an important role in the development and progression of AP. […] The progression of AP can be viewed as a three-phase continuum: local inflammation of the pancreas, a generalized inflammatory response, and the final stage of sepsis, with multiple organ damage. […] The disease process can extend to any of the three phases, and is often resolved after the local inflammatory process, resulting in mild AP. […] The excessive leukocyte stimulation involves in the pathogenesis of severe AP and leukocyte proposed as a prognostic marker in AP. […] The leukocytes play an important role in release of pro-inflammatory cytokines and oxygen derived free radicals influence to development of acinar necrosis. […] The degree of microcirculation derangement is related with concentration of adhesion molecules and the peripheral blood neutrophil ICAM-1 expression is significant increase at early stage in severe AP but not in mild AP.

• #1 The role of mast cells in the pathogenesis of pain in chronic pancreatitis | BMC Gastroenterology | Full Text

  https://bmcgastroenterol.biomedcentral.com/articles/10.1186/1471-230X-5-8

  The biological basis of pain in chronic pancreatitis is poorly understood. Mast cells have been implicated in the pathogenesis of pain in other conditions. We hypothesized that mast cells play a role in the pain of chronic pancreatitis. […] Mast cells are also increased in both acute and chronic pancreatitis but their role in the generation of pain in pancreatitis has not been investigated. […] We hypothesized that mast cells are involved in the pathogenesis of pain in chronic pancreatitis. […] One of the preferential locations of mast cells was around and within the perineurium of nerve fibers in tissue samples of patients with chronic pancreatitis, suggesting the potential for interactions between mast cells and the nervous system. […] Mast cells may therefore contribute to the pathogenesis of pain in pancreatitis through degranulation products that can sensitize pancreatic afferent neurons in an ongoing vicious circle of neuronally mediated mast cell degranulation.

• #1 Mechanism of Severe Acute Pancreatitis: Focusing on Development and Progression

  https://www.kjpbt.org/journal/view.php?number=484

  The inflammasomes are required for the development of inflammation in acute pancreatitis and use of their antagonist demonstrated a reduced pancreatitis response. […] The pathogenesis of organ failure in AP is complicated. Proteases, inflammatory cells and its mediators which secreted from pancreas into blood circulation and impairment of microcirculations are explaining as the main contributed factors for organ failure in AP. […] The proposed pathogenesis of gut barrier dysfunction were mucosal ischemia, disruption of mucosal epithelial integrity, reperfusion injury, disruption of intestinal bacterial ecology, hypovolemia, impaired mucosal immunity, endotoxemia and cytokines. […] The pathophysiology of severe AP is complicated and caused by combines of manifold factors. During the initiation and progression of AP, inflammatory cells, cytokines, chemokines, transcription factors, gut barrier dysfunction and patterns of acinar cell death interact and mediate the development of severe AP.

• #1 Immunopathogenesis of pancreatitis | Mucosal Immunology

  https://www.nature.com/articles/mi2016101

  The conventional view of the pathogenesis of acute and chronic pancreatitis is that it is due to a genetic- or environment-based abnormality of intracellular acinar trypsinogen activation and thus to the induction of acinar cell injury that, in turn, sets in motion an intra-pancreatic inflammatory process. […] More recent studies, reviewed here, present strong evidence that while such trypsinogen activation is likely a necessary first step in the inflammatory cascade underlying pancreatitis, sustained pancreatic inflammation is dependent on damage-associated molecular patterns-mediated cytokine activation causing the translocation of commensal (gut) organisms into the circulation and their induction of innate immune responses in acinar cells. […] These recent studies thus establish that pancreatitis is quite a unique form of inflammation and one susceptible to newer, more innovative therapy.

• #1 Severe acute pancreatitis-associated cardiac injury – review | JIR

  https://www.dovepress.com/comprehensive-mechanism-novel-markers-and-multidisciplinary-treatment–peer-reviewed-fulltext-article-JIR

  Acute pancreatitis (AP) is one of the common acute abdominal inflammatory diseases in clinic with acute onset and rapid progress. […] About 20% of the patients will eventually develop into severe acute pancreatitis (SAP) characterized by a large number of inflammatory cells infiltration, gland flocculus flaky necrosis and hemorrhage, finally inducing systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). […] Pancreatic enzyme activation, intestinal endotoxemia (IETM), cytokine activation, microcirculation disturbance, autonomic nerve dysfunction and autophagy dysregulation all play an essential role in the occurrence and progression of SAP. […] The pathogenesis of SACI is hugely complex, and it is a process of inflammatory injury induced by multi-factors, multi-links and multi-organs.

• #1 Severe acute pancreatitis-associated cardiac injury – review | JIR

  https://www.dovepress.com/comprehensive-mechanism-novel-markers-and-multidisciplinary-treatment–peer-reviewed-fulltext-article-JIR

  The pathophysiology of myocardial dysfunction caused by SAP is unclear, and scientific investigations on its mechanism are still very scarce. […] However, some inspiration and guidance can be obtained from the pathogenesis of myocardial injury caused by sepsis. […] Trypsin, inflammatory mediators, ROS, endotoxin, vascular disorders, and autonomic nerves play important roles in the pancreas-heart axis. […] Currently, timely, diverse and combined treatment methods have been adopted for the myocardial injury caused by SIRS. […] Therefore, it is extremely urgent to explore the pathogenesis of myocardial injury associated with acute pancreatitis and develop specific drugs targeting its molecular level.

• #1 Severe acute pancreatitis-associated cardiac injury – review | JIR

  https://www.dovepress.com/comprehensive-mechanism-novel-markers-and-multidisciplinary-treatment–peer-reviewed-fulltext-article-JIR

  These inflammation-related factors regulate and induce each other and jointly cause abnormal electrical activity of cardiomyocytes, mitochondrial damage, energy metabolism disorder, systolic myocardial dysfunction, myocardial hypertrophy, fibrosis and apoptosis by activating complex signal pathway networks. […] The specific pathways of myocardial injury and cardiac dysfunction caused by inflammation-related factors. […] The animal study by Toldo et al showed that IL-1 caused a remarkable increase in IL-18, and the myocardial contractile dysfunction induced by IL-1 was attenuated after applicating IL-18 receptor blockers, suggesting that the effect of IL-1 on myocardial contractile function may be realized by up-regulating the level of IL-18. […] The bulk of the evidence suggested that IL-6 is continuously up-regulated in various experimental models of cardiac injury and heart failure.

• #1 The role of mast cells in the pathogenesis of pain in chronic pancreatitis | BMC Gastroenterology | Full Text

  https://bmcgastroenterol.biomedcentral.com/articles/10.1186/1471-230X-5-8

  Mast cells may play an important role in the pathogenesis of pain in chronic pancreatitis. […] Significantly more mast cells were present in pancreatic tissue from patients with a history of painful chronic pancreatitis, indicating an association with this condition and a potential role for these cells in the pathogenesis of pain in painful chronic pancreatitis. […] Mast cells produce a variety of degranulation products in the setting of inflammation that may activate and/or sensitize primary nociceptive neurons. […] We speculate that mast cell products released in pancreatitis contribute to the development of pain by direct effects on nociceptors located on pancreatic afferent neurons. […] Our data should increase awareness of the importance of mast cells in the pathogenesis of painful inflammatory conditions such as chronic pancreatitis and encourage experimental studies for further testing of this hypothesis.

• #1 Pathophysiology of acute kidney injury in severe acute pancreatitis-an overview – MedCrave online

  https://medcraveonline.com/GHOA/pathophysiology-of-acute-kidney-injury-in-severe-acute-pancreatitis-an-overview.html

  Acute pancreatitis (AP) is a common disorder of the pancreas and its severity ranges from mild self-limited disease to severe acute pancreatitis (SAP). […] Acute kidney injury (AKI) is a frequent complication of severe acute pancreatitis and carries a very poor prognosis, particularly if renal replacement therapy (RRT) is required, with mortality rates between 25% and 75%. […] Different key pathophysiologic processes include release of pancreatic enzymes with resulting impairment of renal microcirculation, hypoxemia, hypovolemia, intra abdominal hypertension, endotoxin and cytokines mediated injury. […] The exact mechanism of AKI in patients with AP is complex and not very well understood. […] The key pathophysiologic process involves release of pancreatic enzymes from inflamed pancreas leading to autodigestion of pancreas and triggering cascade of events contributing to AKI.

• #1 Coagulation in acute pancreatitis | JIR

  https://www.dovepress.com/pathogenesis-and-therapy-of-coagulation-disorders-in-severe-acute-panc-peer-reviewed-fulltext-article-JIR

  The major source of increased plasma TFPI is the injured ECs, which is an adequate marker of endothelial injury in AP. […] The raised level of TFPI cannot counteract hypercoagulability caused by vascular injury. […] In conclusion, in the early stage of SAP, TF is highly upregulated. […] As a result, TFPI is insufficient in contrast to the hypercoagulable state, and exogenous administration of recombinant TFPI may protect against thrombosis, impeding the progression from MAP to SNP. […] The PC system is damaged in AP patients characterized by low levels of PC and APC, high APC/PC ratios, and significantly increased levels of plasma soluble TM (sTM) and EPCR. […] As a result, the antithrombotic effectiveness of the PC system is impaired, simplifying the development of DIC. […] Thus, clinical studies using ATIII combined with an appropriate dose of heparin are recommended. […] The marked increase in PAI-1 level causes fibrinolytic shutdown, subsequently failing to counteract the systemic deposition of fibrin clots during system inflammatory reaction syndrome, leading to thrombosis and DIC. […] Thus, a single-target therapy may be insufficient, requiring novel drugs.

• #1 Acute Pancreatitis: Disease Cause and Therapeutic Approaches < Yale School of Medicine

  https://medicine.yale.edu/news-article/acute-pancreatitis-disease-cause-therapeutic-approaches/

  Acute pancreatitis is a severe inflammatory disorder of the pancreas, spanning the spectrum of mild discomfort to life-threatening illness. […] Studies have shown that a common mechanism of injury involves the pancreatic acinar cell, including changes in calcium signaling, dysfunction mitochondria and lysosomes, and changes in the levels of inflammatory mediators. […] High levels of fats in the blood or released from damaged fat cells can be broken down into toxic fatty acids and also cause acute pancreatitis. […] With the spectrum of converging mechanisms impacting disease progression, therapies ranging from peptides, small molecules, and monoclonal antibodies are currently being evaluated in multiple randomized controlled trials to assess the impact of targeting this range of causes shown to impact disease progression.

• #1 Molecular mechanism and potential role of mitophagy in acute pancreatitis | Molecular Medicine | Full Text

  https://molmed.biomedcentral.com/articles/10.1186/s10020-024-00903-x

  In experimental models with specific mitophagy defects, there is an increased susceptibility to AP, indicating that mitophagy might be a crucial factor in the disease process. […] This is in line with the multifactorial nature of AP, where genetic predisposition, environmental factors, and lifestyle choices all play a role. […] Defective mitophagy could exacerbate the injury response in the presence of other triggers, resulting in a more severe or frequent occurrence of AP. […] Mitophagy is likely to be a component of a multifactorial process. […] While mitophagy defects may not be the sole cause of AP, they could significantly modulate the disease’s progression and severity. […] Understanding the molecular mechanisms underlying the restoration of mitochondrial function, including mitochondrial dynamics and mitophagy, is of crucial significance for developing new therapeutic strategies for AP.

• #2 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Acute-Pancreatitis-Pathogenesis.aspx

  Acute pancreatitis is generally considered to occur in three phases. […] In the first phase of pancreatitis there is premature activation of this enzyme called trypsin. […] There are several mechanisms by which this premature activation may take place. […] Once activated trypsin in turn activates several pancreatic digestive enzymes. These enzymes bring in the process of self digestion of the pancreatic cells. […] In this phase the activated trypsin causes inflammation within the pancreas. […] Both the second and third phase of inflammation is medicated by cytokines and other inflammatory mediators. […] The other inflammatory cells are activated and these bind to the cells lining the blood vessels. […] There is activation blood coagulation or clotting factors. […] In most patients acute pancreatitis is mild. In around 10 to 20% patients there may be severe inflammation. This may lead to systemic inflammatory response syndrome (SIRS).

• #2 The Pathogenesis of Pancreatitis and the Role of Autophagy

  https://www.mdpi.com/2036-7422/15/2/22

  The main etiologies of both acute (AP) and chronic pancreatitis (CP) are still gallstones and prolonged alcohol consumption. […] Chronic pancreatitis develops in about 10% of patients after the first episode of AP and in about 30% of patients with recurrent AP. […] The pathogenesis of both AP and CP is a complex process with many points that have not been fully investigated. […] The role of autophagy has been recognized but not yet fully investigated. […] The pathogenesis of both acute and chronic pancreatitis is a complicated process involving several pathways. The traditional theory of premature activation of trypsinogen into the acinar cells has been complemented by various signals in both acinar and ductal cells of the pancreas. […] Mitochondrial dysfunction and ER stress are prominent features of pancreatitis pathophysiology.

• #2 Acute Pancreatitis: Mechanisms, Diagnosis, and Management – Gastroenterology Advisor

  https://www.gastroenterologyadvisor.com/features/acute-pancreatitis/

  The 2 most common etiologies of acute pancreatitis, accounting for nearly 30% to 50% of all cases, are cholelithiasis (gallstones) and excessive alcohol intake, particularly in individuals consuming 4 to 5 drinks daily for 5 years or more. […] The complex interaction between environmental factors such as high-fat diets, alcohol use disorder, and tobacco use may impair the physiologic functions of the pancreas, leading to inflammation of the pancreas and ultimately acute pancreatitis. […] Chronic excessive alcohol use is thought to increase the viscosity of pancreatic secretions, which form protein plugs and later calculi within the pancreatic ducts. Over time, these protein plugs and calculi induce pancreatic inflammation and fibrosis, further damaging the glandular tissue. Alcohol also causes autodigestion of the pancreas by triggering premature activation of trypsinogen and other digestive enzymes before they are released into the duodenum.

• #2 Pancreatic Morphology, Immunology, and the Pathogenesis of Acute Pancreatitis

  https://www.mdpi.com/2227-9059/12/11/2627

  Acute pancreatitis is a complex inflammatory disorder with significant morbidity and mortality. This review aims to integrate the current knowledge of pancreatic morphology and immunology with the pathogenesis of acute pancreatitis, providing a comprehensive understanding of this critical condition. […] The pathophysiology of acute pancreatitis is multifaceted, centered around the premature activation of digestive enzymes within the pancreas, leading to autodigestion and a cascade of inflammatory responses. This process begins with the activation of trypsinogen to trypsin within the acinar cells, rather than in the duodenal lumen. Factors such as ductal obstruction, calcium homeostasis disruption, and pH changes can trigger this premature activation. […] The central pathophysiological event in acute pancreatitis is the premature activation of trypsinogen to trypsin within the pancreatic acinar cells, instead of within the duct lumen. This leads to the activation of additional digestive enzymes, such as elastase and phospholipases, which contribute to extensive tissue destruction. Factors, such as increased ductal pressure, disturbances in calcium homeostasis, and changes in pH, can precipitate this premature activation.

• #2 Acute pancreatitis: Etiology and common pathogenesis

  https://www.wjgnet.com/1007-9327/full/v15/i12/1427.htm

  Acute pancreatitis is an inflammatory disease of the pancreas. The etiology and pathogenesis of acute pancreatitis have been intensively investigated for centuries worldwide. Many causes of acute pancreatitis have been discovered, but the pathogenetic theories are controversial. The most common cause of acute pancreatitis is gallstone impacting the distal common bile-pancreatic duct. […] Acute pancreatitis occurs when intracellular protective mechanisms to prevent trypsinogen activation or reduce trypsin activity are overwhelmed. […] We hypothesize that acute biliary pancreatitis and other causes of acute pancreatitis possess a common pathogenesis. Pancreatic hyperstimulation and pancreatic duct obstruction increase pancreatic duct pressure, active trypsin reflux, and subsequent unregulated activation of trypsin within pancreatic acinar cells. Enzyme activation within the pancreas leads to auto-digestion of the gland and local inflammation.

• #2 Gallstone-related pathogenesis of acute pancreatitis | Pancreapedia

  https://pancreapedia.org/reviews/gallstone-related-pathogenesis-of-acute-pancreatitis

  It is firmly established today that the initiation of pancreatitis requires the passage of a gallstone from the gallbladder through the biliary tract and gallstones, that remain in the gallbladder will not cause pancreatitis. […] Taken together these data suggest that the initial pathophysiological events during the course of gallstone-induced pancreatitis affect acinar cells and are triggered, in accordance with Opies initial hypothesis, by obstruction or impairment of flow form the pancreatic duct. A reflux of bile into the pancreatic duct either through a common channel created by an impacted gallstone or through an incompetent spincter caused by the passage of a gallstone is neither required nor likely to occur during the initial course of acute pancreatitis. […] These experiments suggest that pancreatic duct obstruction, the critical event involved in gallstone-induced pancreatitis, rapidly changes the physiological response of the exocrine pancreas to a pathological Ca2+-signaling pattern. This pathological Ca2+-signaling is associated with premature digestive enzyme activation and the onset of pancreatitis both of which can be prevented by administration of an intracellular calcium chelator.

• #2 Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP | Gut

  https://gut.bmj.com/content/65/8/1333

  Toxins that cause acute pancreatitis induce the MPTP in isolated murine and human pancreatic acinar cells via second messenger receptor calcium channel release and mitochondrial calcium but not reactive oxygen species overload, resulting in mitochondrial depolarisation, impaired ATP production and necrosis. […] Specific genetic or pharmacological inhibition of MPTP opening in a diverse range of clinically relevant mouse models dramatically improves all local pancreatic, systemic and distant pulmonary pathological responses. […] This study has shown the effectiveness in experimental acute pancreatitis of several drugs that target molecules that regulate the MPTP and that could be developed for the treatment of clinical acute pancreatitis. […] We report that MPTP opening is critical to all forms of pancreatitis investigated, causing diminished ATP production, defective autophagy, zymogen activation, cytokine release, phosphoglycerate mutase family member 5 (PGAM5) activation and necrosis.

• #2 Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP | Gut

  https://gut.bmj.com/content/65/8/1333

  Mitochondrial dysfunction has been implicated but the mechanism not established. […] MPTP opening was mediated by toxin-induced inositol trisphosphate and ryanodine receptor calcium channel release, and resulted in diminished ATP production, leading to impaired calcium clearance, defective autophagy, zymogen activation, cytokine production, phosphoglycerate mutase 5 activation and necrosis, which was prevented by intracellular ATP supplementation. […] This work demonstrates the mechanism and consequences of MPTP opening to be fundamental to multiple forms of acute pancreatitis and validates the MPTP as a drug target for this disease. […] Mitochondrial matrix calcium overload induces opening of the mitochondrial permeability transition pore (MPTP), a non-specific inner mitochondrial membrane channel that causes loss of mitochondrial membrane potential essential to ATP production.

• #2 Molecular mechanism and potential role of mitophagy in acute pancreatitis | Molecular Medicine | Full Text

  https://molmed.biomedcentral.com/articles/10.1186/s10020-024-00903-x

  Acute pancreatitis (AP) is a multifaceted inflammatory disorder stemming from the aberrant activation of trypsin within the pancreas. […] Despite the contribution of various factors to the pathogenesis of AP, such as trypsin activation, dysregulated increases in cytosolic Ca2+ levels, inflammatory cascade activation, and mitochondrial dysfunction, the precise molecular mechanisms underlying the disease are still not fully understood. […] Mitophagy, a cellular process that preserves mitochondrial homeostasis under stress, has emerged as a pivotal player in the context of AP. […] Research suggests that augmenting mitophagy can mitigate pancreatic injury by clearing away malfunctioning mitochondria. […] Elucidating the role of mitophagy in AP may pave the way for novel therapeutic strategies.

• #2 Pathogenic mechanisms of pancreatitis

  https://www.wjgnet.com/2150-5349/full/v8/i1/10.htm

  The detail of each cytokine involved in the pathogenesis of pancreatitis has been described independently. […] Chronic pancreatitis develops fibrosis and it is the common pathological characteristic feature and major risk factor for pancreatic cancer. […] Chronic pancreatitis is characterized by marked stroma formation with an increased number of infiltrating macrophages and stellate cells, which are believed to play a central role in triggering inflammation and disease progression. […] The treatment of chronic pancreatitis and pancreatic cancer remains problematic as tissue becomes fibrotic due to injury that triggers several inflammatory, cellular as well as molecular signaling cascades that lead to formation and deposition of extra cellular matrix (ECM) at the site of injury. […] The available facts suggest that these activated PSCs are the main cells in the development of fibrosis during chronic pancreatitis via secretion of TGF-, FGF and COX-2 which leads to synthesis of ECM.

• #2 Pathogenic mechanisms of pancreatitis

  https://www.wjgnet.com/2150-5349/full/v8/i1/10.htm

  Fibrosis is a complex process and the mechanism of pancreatic fibrosis is still not well understood. […] Herein, we provide a summary of various molecular signaling pathways [i.e., TGF-/SMAD, mitogen-activated protein kinase (MAPK), Rho kinase, JAK/STAT, and phosphatidylinositol 3 kinase (PI3K)] that have been shown to play a critical role in the activation of PSCs during chronic pancreatitis and trigger the phenomenon of fibrogenesis in pancreas.

• #2 Acute Pancreatitis: Mechanisms, Diagnosis, and Management – Gastroenterology Advisor

  https://www.gastroenterologyadvisor.com/features/acute-pancreatitis/

  Hypertriglyceridemia, typically serum triglyceride concentrations greater than 1000 mg/dL, accounts for nearly 10% of acute pancreatitis cases and is frequently associated with recurrent attacks. High triglyceride and chylomicron levels increase blood viscosity, which promotes tissue ischemia within the pancreas. Tissue ischemia prompts the transition to anaerobic glycolysis, which raises lactate levels, leading to acidosis. Acidotic conditions promote the cytotoxic properties of free fatty acids, causing vascular damage and the premature activation of trypsinogen.

• #2 Pathogenic mechanisms of pancreatitis

  https://www.wjgnet.com/2150-5349/full/v8/i1/10.htm

  Our review also highlights the significance of several experimental animal models that have an important role in dissecting the mechanistic pathways operating in the development of chronic pancreatitis, including pancreatic fibrosis. […] The main causes of pancreatitis are; obstruction in the main pancreatic duct, gallstones, alcohol misuse, smoking, hypercalcemia, hyperparathyroidism, drugs like valproate, thiazide toxicity, and genetic mutation. During pancreatic injury, atrophic acinar cells activate several inflammatory key players like macrophages and granulocytes which release a number of pro-inflammatory cytokines [i.e., interleukin (IL)-1, IL-6, IL-8, IL-18, IL-33, and tumor necrosis factor (TNF)-]. These pro-inflammatory cytokines further activate pancreatic stellate cells (PSCs) to promote chronic pancreatitis.

• #2 The role of mast cells in the pathogenesis of pain in chronic pancreatitis | BMC Gastroenterology | Full Text

  https://bmcgastroenterol.biomedcentral.com/articles/10.1186/1471-230X-5-8

  Mast cells may play an important role in the pathogenesis of pain in chronic pancreatitis. […] Significantly more mast cells were present in pancreatic tissue from patients with a history of painful chronic pancreatitis, indicating an association with this condition and a potential role for these cells in the pathogenesis of pain in painful chronic pancreatitis. […] Mast cells produce a variety of degranulation products in the setting of inflammation that may activate and/or sensitize primary nociceptive neurons. […] We speculate that mast cell products released in pancreatitis contribute to the development of pain by direct effects on nociceptors located on pancreatic afferent neurons. […] Our data should increase awareness of the importance of mast cells in the pathogenesis of painful inflammatory conditions such as chronic pancreatitis and encourage experimental studies for further testing of this hypothesis.

• #3 Pathogenesis of acute pancreatitis – UpToDate

  https://www.uptodate.com/contents/pathogenesis-of-acute-pancreatitis

  Pathogenesis of acute pancreatitis […] However, the pathogenesis of this disorder is not fully understood. […] This topic review will focus on the pathogenesis of acute pancreatitis. […] Thus, despite the limitations of animal models, the data suggest that a similar cascade of events occurs once pancreatitis begins that is independent of the inciting event or initial mechanism. […] It is not clear from these studies why some individuals experience only interstitial or edematous pancreatitis, while others go on to develop the necrotizing form of the disease.

• #3 Acute Pancreatitis – Gastrointestinal Disorders – MSD Manual Professional Edition

  https://www.msdmanuals.com/professional/gastrointestinal-disorders/pancreatitis/acute-pancreatitis

  Regardless of the etiology, an early event in the pathogenesis of acute pancreatitis is intra-acinar activation of pancreatic enzymes (including trypsin, phospholipase A2, and elastase), leading to the autodigestive injury of the gland itself. The enzymes can damage tissue and activate the complement system and the inflammatory cascade, producing cytokines and causing inflammation and edema. This process causes necrosis in a few cases. Acute pancreatitis increases the risk of infection by compromising the gut barrier, leading to bacterial translocation from the gut lumen to the circulation. […] Activated enzymes and cytokines that enter the peritoneal cavity cause a chemical burn and third spacing of fluid; those that enter the systemic circulation cause a systemic inflammatory response that can result in acute respiratory distress syndrome and acute kidney injury. The systemic effects are mainly the result of increased capillary permeability and decreased vascular tone, which result from the released cytokines and chemokines. Phospholipase A2 is thought to injure alveolar membranes of the lungs.

• #3 Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP | Gut

  https://gut.bmj.com/content/65/8/1333

  Toxins that cause acute pancreatitis induce the MPTP in isolated murine and human pancreatic acinar cells via second messenger receptor calcium channel release and mitochondrial calcium but not reactive oxygen species overload, resulting in mitochondrial depolarisation, impaired ATP production and necrosis. […] Specific genetic or pharmacological inhibition of MPTP opening in a diverse range of clinically relevant mouse models dramatically improves all local pancreatic, systemic and distant pulmonary pathological responses. […] This study has shown the effectiveness in experimental acute pancreatitis of several drugs that target molecules that regulate the MPTP and that could be developed for the treatment of clinical acute pancreatitis. […] We report that MPTP opening is critical to all forms of pancreatitis investigated, causing diminished ATP production, defective autophagy, zymogen activation, cytokine release, phosphoglycerate mutase family member 5 (PGAM5) activation and necrosis.

• #4 Acute Pancreatitis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/181364-overview

  Acute pancreatitis may occur when factors involved in maintaining cellular homeostasis are out of balance. The initiating event may be anything that injures the acinar cell and impairs the secretion of zymogen granules; examples include alcohol use, gallstones, and certain drugs. […] At present, it is unclear exactly what pathophysiologic event triggers the onset of acute pancreatitis. It is believed, however, that both extracellular factors (eg, neural and vascular response) and intracellular factors (eg, intracellular digestive enzyme activation, increased calcium signaling, and heat shock protein activation) play a role. In addition, acute pancreatitis can develop when ductal cell injury leads to delayed or absent enzymatic secretion, as seen in patients with the CFTR gene mutation. […] Once a cellular injury pattern has been initiated, cellular membrane trafficking becomes chaotic, with the following deleterious effects: Lysosomal and zymogen granule compartments fuse, enabling activation of trypsinogen to trypsin. Intracellular trypsin triggers the entire zymogen activation cascade. Secretory vesicles are extruded across the basolateral membrane into the interstitium, where molecular fragments act as chemoattractants for inflammatory cells.

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