Materiały źródłowe

• #1 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. The majority of investigators accept that the main factors for acute billiary pancreatitis are pancreatic hyperstimulation and bile-pancreatic duct obstruction which increase pancreatic duct pressure and active trypsin reflux. 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. Once the hypothesis is confirmed, traditional therapeutic strategies against acute pancreatitis may be improved. Decompression of pancreatic duct pressure should be advocated in the treatment of acute pancreatitits which may greatly improve its outcome.

• #1 Acute Pancreatitis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482468/

  The localized destruction characterizes the pathophysiology of pancreatitis in the pancreas and systemic inflammatory response. The major inciting event is the premature activation of the enzyme trypsinogen to trypsin within the acinar cell instead of the duct lumen. The leading cause is an elevation in ductal pressures (such as duct obstruction) and problems with calcium homeostasis and pH. Many toxins responsible for causing pancreatitis cause ATP depletion, increasing the intra-acinar calcium concentrations that may stimulate the early activation of trypsinogen to trypsin, activating enzymes such as elastase and phospholipases. […] This premature activation of these zymogens causes extensive tissue damage and Damage Associated Molecular Patterns (DAMPs) release. This release of DAMPs is associated with recruiting neutrophils and initiating the inflammatory cascade. This inflammatory cascade then leads to the systemic manifestations of acute pancreatitis. It ultimately produces capillary permeability and endothelium damage with microvascular thrombosis that gives rise to multi-organ dysfunction syndrome (MODS) as the main cause of morbidity and mortality in the setting of acute pancreatitis.

• #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. […] This phase involves a premature activation of the powerful enzyme called trypsin. […] 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.

• #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. These pathological, sustained elevations in cytosolic calcium are an early event in models of AP and are seen in rodent and human acinar cells. […] 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.

• #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. […] A characteristic early AP response is the activation of protease zymogens, particularly trypsinogen, in the pancreatic acinar cell. […] This activation enhances their inflammatory state. […] Pathologic calcium signaling, mitochondrial dysfunction, organelle stress, zymogen activation, lipotoxicity, and uncontrolled inflammation are key mechanisms that drive acinar cell injury and systemic AP complications.

• #1 Azthena logo with the word Azthena

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

  There is activation blood coagulation or clotting factors. […] In addition to inflammatory cells, free radicals are also released along with other chemical mediators of inflammation like cytokines. […] 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 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 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. […] 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.

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

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

  Nuclear factor-kappaB (NF-B) that modulates the expression of most cytokines plays an important role in the initiation and progression of AP. In normal condition, NF-B is inactive state by inhibitors of B (IB). When cells are stimulated, IB was degraded and then NF-B is translocation into the nucleus and bind to its cognate DNA and increase the transcription of several proinflammatory genes. NF-B is activated in pancreas early phase of AP and subsequently distant tissues. Intra acinar activation of NF-B led to AP with local inflammation and systemic inflammatory response and the activation of NF-B in vital organs is related with development of MOF in AP. The activation of NF-B in AP is independently of trypsinogen activation, interestingly. Dawra et al. reported that trypsinogen is involved in pathologic activation and this leads to acinar cell death during early pancreatitis. However, progression of inflammation in AP is independent of trypsinogen activation. NF-B activation is a key early event independent of trypsinogen activation and may be responsible for progression of local and systemic inflammation. This result arouses a doubt to traditional believed trypsin-centered pathophysiologic mechanism of AP. In addition, activation of inflammatory signaling mechanisms in acinar cell is crucial to pathogenesis of AP. The NF-B could upregulate the expression of cytokine including TNF-, IL-1, and chemokines in AP. It is known that blocking the NF-B activation can reduce the pancreas and lung injury in experimental AP. In addition, inhibition of NF-B has been shown to results attenuated pancreatitis response with severity inversely proportional to the degree of NF-B inhibition.

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

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

  The systemic inflammatory response syndrome (SIRS) can also develop, leading to the development of systemic shock. Eventually, the mediators of inflammation can become so overwhelming that hemodynamic instability and death ensue. […] In acute pancreatitis, parenchymal edema and peripancreatic fat necrosis occur first; this is known as acute edematous pancreatitis. When necrosis involves the parenchyma, accompanied by hemorrhage and dysfunction of the gland, the inflammation evolves into hemorrhagic or necrotizing pancreatitis. Pseudocysts and pancreatic abscesses can result from necrotizing pancreatitis because enzymes can be walled off by granulation tissue (pseudocyst formation) or via bacterial seeding of the pancreatic or peripancreatic tissue (pancreatic abscess formation).

• #1

  https://link.springer.com/article/10.1007/BF01657981

  Acute pancreatitis involves autodigestion of the pancreas by its own secretions. The anatomical signal is tryptic necrosis. The severity of acute pancreatitis is determined by the state of preservation of the pancreatic capsule. Three stages may exist: (a) the gland is enlarged with solitary areas of necrosis and the capsule is preserved; (b) confluent necrosis with necrosis of the lipid tissue occurs, but the capsule is preserved; and (c) necrosis extends into surrounding areas, especially into the omental bursa and the retroperitoneum, and the capsule is destroyed. […] Shock is the most dangerous complication and is the most frequent cause of death.

• #1 Etiology of acute pancreatitis – UpToDate

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

  Acute pancreatitis is an inflammatory condition of the pancreas characterized by abdominal pain and elevated levels of pancreatic enzymes in the blood. Acute pancreatitis is the third leading gastrointestinal cause of hospitalization in the United States. Several conditions are associated with acute pancreatitis. Of these, gallstones and chronic alcohol use disorder account for approximately two-thirds of cases. […] The pathogenesis, clinical manifestations, diagnosis, and management of acute pancreatitis are discussed separately. […] Gallstones (including microlithiasis) are the most common cause of acute pancreatitis accounting for 40 to 70 percent of cases. However, only 3 to 7 percent of patients with gallstones develop pancreatitis. The mechanism by which the passage of gallstones induces pancreatitis is unknown. Two factors have been suggested as the possible initiating event in gallstone pancreatitis: reflux of bile into the pancreatic duct due to transient obstruction of the ampulla during passage of gallstones; or obstruction at the ampulla secondary to stone(s) or edema resulting from the passage of a stone.

• #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. […] In order to overcome the inconsistencies of the common channel hypothesis it was proposed that the passage of a gallstone could damage the duodenal sphincter in a manner that sphincter insufficiency results. […] 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. […] To investigate the cellular events involved in gallstone-induced pancreatitis an animal model based on pancreatic duct obstruction in rodents has been employed.

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

  https://pancreapedia.org/reviews/gallstone-related-pathogenesis-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. […] Essential events that have been identified are colocalization and transactivation of lysosomal cathepsins with zymogens and the above-mentioned pathological Ca2+-release from intracellular stores. […] The disease-aggravating effect of common bile duct obstruction in pancreatitis would therefore not require bile reflux into the pancreatic duct but be elicited readily by bile acids in the serum or interstitial space of jaundiced patients.

• #1 Acute pancreatitis pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Acute_pancreatitis_pathophysiology

  The aforementioned inflammatory process which primarily manifests as oversecretion of zymogens and activation of trypsinogen in the pancreas is often a result of transient obstruction of the pancreatic ducts. This obstruction is the triggering insult which is the underlying mechanism for the most common cause of acute pancreatitis – migrating gallstones or sludge. […] Alcohol is proposed to have a direct, toxic effect on the pancreas. It is metabolized by the pancreas and may result in oxidative stress and induce the release of pancreatic enzymes. This excessive release may result in auto-digestion of the gland. Additionally, alcohol may result in activation of pancreatic stellate cells which are primarily responsible for fibrosis of the gland and weakening of the intracellular membranes, which results in anatomical changes in the pancreas, further predisposing to pathological auto-digestion.

• #1 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. […] Gallstones, the predominant cause of acute pancreatitis, can potentially obstruct the duodenal papilla, impeding the normal flow of pancreatic secretions from the pancreatic duct. This results in increased pressure, inflammation, and cellular injury within the pancreas. […] 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.

• #1 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. […] Less commonly, tobacco use, endoscopic retrograde cholangiopancreatography (ERCP), hypercalcemia, trauma, hereditary and/or autoimmune causes, and certain medications like angiotensin-converting enzyme inhibitors, statins, oral contraceptives, antiviral therapies, and glucagon-like peptide 1 agonists, may also cause acute pancreatitis.

• #1 Acute pancreatitis pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Acute_pancreatitis_pathophysiology

  Triglyceride rich lipoproteins are primarily comprised of chylomicrons and VLDLs. These molecules are large and in abundance in conditions of hypertriglyceridemia. These molecules have been postulated to occlude pancreatic capillaries and result in subsequent acinar pancreatic structural changes. Additionally, this triggers the release of pancreatic lipases to catabolize the lipid rich molecules. It results in increased local oxidative stress which further contributes to the inflammatory response in the pancreas, resulting in the symptomatology of acute pancreatitis. […] The mechanism by which post-ERCP pancreatitis (PEP) occurs is not fully understood. However, it is proposed that mechanical, chemical, allergic, and thermally induced trauma to the pancreatic orifice and duct are the underlying causes. Instrumental manipulation of the pancreatic orifices, as well as chemical and allergic damage due to contrast injection contribute to the pathogenesis. Additionally, cauterization of the superficial and intraluminal pancreatic structures may result in thermal damage. These iatrogenic traumatic and toxic influences may, again, stimulate the fibrogenic pancreatic stellate cells to initiate a cascade of events responsible for activation of zymogens and autodigestion of the pancreas.

• #2 Immunopathogenesis of pancreatitis | Mucosal Immunology

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

  Over the past two decades, a great deal has been learned concerning its pathogenesis, particularly the role of inappropriate trypsinogen activation in the initiation of the inflammatory process. […] The most widely held understanding of the pathogenesis of pancreatitis is that it is an inflammation initiated and/or sustained by a disturbance in pancreatic acinar cell control of pancreatic digestive enzymes. […] Several mechanisms of such premature and inappropriate activation of normally inactive zymogens have been put forward and include trypsinogen autoactivation, activation of trypsinogen by lysosomal hydrolase cathepsin B (CatB) caused by shifting of trypsinogen into cellular compartments rich in proteases (lysosomes) and imbalances between degrading and activating acinar cell cathepsins.

• #2

  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. These pathological, sustained elevations in cytosolic calcium are an early event in models of AP and are seen in rodent and human acinar cells. […] 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.

• #2

  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. […] A characteristic early AP response is the activation of protease zymogens, particularly trypsinogen, in the pancreatic acinar cell. […] This activation enhances their inflammatory state. […] Pathologic calcium signaling, mitochondrial dysfunction, organelle stress, zymogen activation, lipotoxicity, and uncontrolled inflammation are key mechanisms that drive acinar cell injury and systemic AP complications.

• #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. […] This phase involves a premature activation of the powerful enzyme called trypsin. […] 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.

• #2 Azthena logo with the word Azthena

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

  There is activation blood coagulation or clotting factors. […] In addition to inflammatory cells, free radicals are also released along with other chemical mediators of inflammation like cytokines. […] 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 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.

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

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

  Nuclear factor-kappaB (NF-B) that modulates the expression of most cytokines plays an important role in the initiation and progression of AP. In normal condition, NF-B is inactive state by inhibitors of B (IB). When cells are stimulated, IB was degraded and then NF-B is translocation into the nucleus and bind to its cognate DNA and increase the transcription of several proinflammatory genes. NF-B is activated in pancreas early phase of AP and subsequently distant tissues. Intra acinar activation of NF-B led to AP with local inflammation and systemic inflammatory response and the activation of NF-B in vital organs is related with development of MOF in AP. The activation of NF-B in AP is independently of trypsinogen activation, interestingly. Dawra et al. reported that trypsinogen is involved in pathologic activation and this leads to acinar cell death during early pancreatitis. However, progression of inflammation in AP is independent of trypsinogen activation. NF-B activation is a key early event independent of trypsinogen activation and may be responsible for progression of local and systemic inflammation. This result arouses a doubt to traditional believed trypsin-centered pathophysiologic mechanism of AP. In addition, activation of inflammatory signaling mechanisms in acinar cell is crucial to pathogenesis of AP. The NF-B could upregulate the expression of cytokine including TNF-, IL-1, and chemokines in AP. It is known that blocking the NF-B activation can reduce the pancreas and lung injury in experimental AP. In addition, inhibition of NF-B has been shown to results attenuated pancreatitis response with severity inversely proportional to the degree of NF-B inhibition.

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

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

  The systemic inflammatory response syndrome (SIRS) can also develop, leading to the development of systemic shock. Eventually, the mediators of inflammation can become so overwhelming that hemodynamic instability and death ensue. […] In acute pancreatitis, parenchymal edema and peripancreatic fat necrosis occur first; this is known as acute edematous pancreatitis. When necrosis involves the parenchyma, accompanied by hemorrhage and dysfunction of the gland, the inflammation evolves into hemorrhagic or necrotizing pancreatitis. Pseudocysts and pancreatic abscesses can result from necrotizing pancreatitis because enzymes can be walled off by granulation tissue (pseudocyst formation) or via bacterial seeding of the pancreatic or peripancreatic tissue (pancreatic abscess formation).

• #2 Acute Pancreatitis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482468/

  The localized destruction characterizes the pathophysiology of pancreatitis in the pancreas and systemic inflammatory response. The major inciting event is the premature activation of the enzyme trypsinogen to trypsin within the acinar cell instead of the duct lumen. The leading cause is an elevation in ductal pressures (such as duct obstruction) and problems with calcium homeostasis and pH. Many toxins responsible for causing pancreatitis cause ATP depletion, increasing the intra-acinar calcium concentrations that may stimulate the early activation of trypsinogen to trypsin, activating enzymes such as elastase and phospholipases. […] This premature activation of these zymogens causes extensive tissue damage and Damage Associated Molecular Patterns (DAMPs) release. This release of DAMPs is associated with recruiting neutrophils and initiating the inflammatory cascade. This inflammatory cascade then leads to the systemic manifestations of acute pancreatitis. It ultimately produces capillary permeability and endothelium damage with microvascular thrombosis that gives rise to multi-organ dysfunction syndrome (MODS) as the main cause of morbidity and mortality in the setting of acute pancreatitis.

• #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

  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. […] 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.

• #3

  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. […] A characteristic early AP response is the activation of protease zymogens, particularly trypsinogen, in the pancreatic acinar cell. […] This activation enhances their inflammatory state. […] Pathologic calcium signaling, mitochondrial dysfunction, organelle stress, zymogen activation, lipotoxicity, and uncontrolled inflammation are key mechanisms that drive acinar cell injury and systemic AP complications.

• #3 Azthena logo with the word Azthena

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

  There is activation blood coagulation or clotting factors. […] In addition to inflammatory cells, free radicals are also released along with other chemical mediators of inflammation like cytokines. […] 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).

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

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

  The systemic inflammatory response syndrome (SIRS) can also develop, leading to the development of systemic shock. Eventually, the mediators of inflammation can become so overwhelming that hemodynamic instability and death ensue. […] In acute pancreatitis, parenchymal edema and peripancreatic fat necrosis occur first; this is known as acute edematous pancreatitis. When necrosis involves the parenchyma, accompanied by hemorrhage and dysfunction of the gland, the inflammation evolves into hemorrhagic or necrotizing pancreatitis. Pseudocysts and pancreatic abscesses can result from necrotizing pancreatitis because enzymes can be walled off by granulation tissue (pseudocyst formation) or via bacterial seeding of the pancreatic or peripancreatic tissue (pancreatic abscess formation).

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

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

  Nuclear factor-kappaB (NF-B) that modulates the expression of most cytokines plays an important role in the initiation and progression of AP. In normal condition, NF-B is inactive state by inhibitors of B (IB). When cells are stimulated, IB was degraded and then NF-B is translocation into the nucleus and bind to its cognate DNA and increase the transcription of several proinflammatory genes. NF-B is activated in pancreas early phase of AP and subsequently distant tissues. Intra acinar activation of NF-B led to AP with local inflammation and systemic inflammatory response and the activation of NF-B in vital organs is related with development of MOF in AP. The activation of NF-B in AP is independently of trypsinogen activation, interestingly. Dawra et al. reported that trypsinogen is involved in pathologic activation and this leads to acinar cell death during early pancreatitis. However, progression of inflammation in AP is independent of trypsinogen activation. NF-B activation is a key early event independent of trypsinogen activation and may be responsible for progression of local and systemic inflammation. This result arouses a doubt to traditional believed trypsin-centered pathophysiologic mechanism of AP. In addition, activation of inflammatory signaling mechanisms in acinar cell is crucial to pathogenesis of AP. The NF-B could upregulate the expression of cytokine including TNF-, IL-1, and chemokines in AP. It is known that blocking the NF-B activation can reduce the pancreas and lung injury in experimental AP. In addition, inhibition of NF-B has been shown to results attenuated pancreatitis response with severity inversely proportional to the degree of NF-B inhibition.

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