Materiały źródłowe

• #1 Chronic Pancreatitis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482325/

  Chronic pancreatitis is a progressive fibroinflammatory disease characterized by irreversible damage to the pancreatic tissue, resulting in exocrine and endocrine dysfunction. […] Chronic pancreatitis is a progressive inflammatory disease affecting both pancreatic functions. Exocrine dysfunction leads to pancreatic insufficiency, steatorrhea, and weight loss, occurring when over 90% of the organ is damaged. […] In 2016, international pancreas societies adopted a mechanistic definition of chronic pancreatitis. This definition characterizes end-stage chronic pancreatitis as pancreatic atrophy, fibrosis, pain syndromes, duct distortion and strictures, calcifications, pancreatic exocrine dysfunction, pancreatic endocrine dysfunction, and dysplasia, but also addresses the disease mechanism as a pathological fibroinflammatory syndrome of the pancreas in individuals with genetic, environmental, or other risk factors who develop persistent pathologic responses to parenchymal injury or stress.

• #1 Pathophysiology of chronic pancreatitis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3831204/

  Chronic pancreatitis (CP) is an inflammatory disease of the pancreas characterized by progressive fibrotic destruction of the pancreatic secretory parenchyma. […] Despite the heterogeneity in pathogenesis and involved risk factors, processes such as necrosis/apoptosis, inflammation or duct obstruction are involved. […] The etiological risk-factors associated with CP are multiple and involve both genetic and environmental factors. […] The secretory parenchyma is destroyed by processes such as necrosis/apoptosis, inflammation or duct obstruction. […] Increasing evidence indicates that pancreatic stellate cells (PSC) are the major mediators of fibrosis, resulting in the formation of extracellular matrix (ECM) in the interstitial spaces and in the areas where acinar cells disappear or duct cells are injured.

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

  https://emedicine.medscape.com/article/181554-overview

  Although alcohol greatly influences the understanding of its pathophysiology because it is the most common etiology (60-70%), approximately 20-30% of cases are idiopathic and 10% of cases are due to rare diseases. […] A mutation in the gene encoding the serine protease inhibitor, Kazal type 1, has been identified in patients with chronic pancreatitis. The N34S mutation was detected in 5.8% of 274 patients with alcoholic chronic pancreatitis, compared with 1.0% of people with alcoholism without pancreatitis. Although all patients were heterozygous for the mutation, it provides evidence for abnormalities in the pancreatic protease/protease inhibitor system playing a role in the pathogenesis of alcoholic chronic pancreatitis.

• #1 Chronic pancreatitis – Wikipedia

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

  Chronic pancreatitis is a long-standing inflammation of the pancreas that alters the organ’s normal structure and functions. […] It is a disease process characterized by irreversible damage to the pancreas as distinct from reversible changes in acute pancreatitis. […] Tobacco smoke and alcohol misuse are two of the most frequently implicated causes, and the two risk factors are thought to have a synergistic effect with regards to the development of chronic pancreatitis. […] The mechanism of chronic pancreatitis viewed from a genetic standpoint indicates early onset of severe epigastric pain beginning in childhood. […] It is an autosomal dominant disease; chronic pancreatitis disease is identified in the cationic trypsinogen gene PRSS1, and mutation, R122H. […] R122H is the most common mutation for hereditary chronic pancreatitis with replacement of arginine with histidine at amino acid position 122 of the trypsinogen protein. […] There are, of course, other mechanisms alcohol, malnutrition, smoking each exhibiting its own effect on the pancreas.

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

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

  Chronic inflammation of the pancreas is caused by acinar and ductular cell injury driven by alcohol, smoking, hypercalcemia, genetic factors, or any combination of the above. […] 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. […] Interestingly, a genetic mutation in claudin 2 may synergize with alcohol consumption in the development of pancreatitis, indicating the interplay between external and genetic factors in the pathogenesis of pancreatitis. […] The relationship of ethanol and smoking to CP has been unequivocally proved. […] The amount and duration of ethanol consumption have been estimated to be either a median of 5.1 drinks/d or a consumption of up to 110–277 g ethanol/d over 5–25 years, similarly to AP.

• #1 Pathophysiology of chronic pancreatitis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3831204/

  To describe the heterogeneity of the underlying pathophysiology we have throughout the review used the M-ANNHEIM classification, comprising detailed description of multiple risk factors such as: alcohol-consumption, nicotine-consumption, nutritional factors, hereditary factors, efferent duct factors, immunological factors and miscellaneous including rare metabolic factors.

• #1 Etiology and pathogenesis of chronic pancreatitis in adults – UpToDate

  https://www.uptodate.com/contents/etiology-and-pathogenesis-of-chronic-pancreatitis-in-adults/print

  Chronic pancreatitis is a syndrome involving inflammation, fibrosis, and loss of acinar and islet cells, which can manifest with pancreatic-type abdominal pain, steatorrhea, derangements in pancreatic function (exocrine and endocrine insufficiency), and visible pancreatic damage on imaging studies. Chronic pancreatitis has a variety of etiologies with genetic and environmental risk factors for both initiation and disease progression, variable clinical and imaging features, and complications. […] This topic will review the etiology and pathogenesis of chronic pancreatitis. […] Alcohol is associated with approximately one-half of all cases of chronic pancreatitis in the United States. Idiopathic chronic pancreatitis accounts for approximately 10 to 30 percent of all cases. The number of patients labeled as idiopathic depends in large part on how detailed and comprehensive the search is for an etiology.

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

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

  Chronic pancreatitis is persistent inflammation of the pancreas that results in permanent structural damage with fibrosis and ductal strictures, followed by a decline in exocrine and endocrine function (pancreatic insufficiency). […] 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. […] The necrosis-fibrosis hypothesis posits that repeated attacks of acute pancreatitis with necrosis are key to the pathogenesis of chronic pancreatitis. […] In more advanced chronic pancreatitis, neuronal sheath hypertrophy and perineural inflammation occur and may contribute to chronic pain. […] Recurrent attacks of acute pancreatitis may cause chronic persistent inflammation, ductal damage, and ultimately fibrosis, leading to chronic pancreatitis.

• #1 Chronic pancreatitis | PPT

  https://www.slideshare.net/slideshow/chronic-pancreatitis-70607886/70607886

  Chronic pancreatitis is a progressive inflammatory condition of the pancreas characterized by irreversible morphological changes and loss of function. It is most commonly caused by long term heavy alcohol use. […] Chronic Pancreatitis Definition: it is a benign inflammatory process and fibrosing disorder characterized by irreversible morphologic changes, Progressive and permanent loss of exocrine and endocrine function. […] Pathogenesis Protein Plug hypothesis: Alcohol Protein conc in pancreatic secretion Glycoprotein2 secretions in acinar cells formation of protein precipitates protein plug calcification of ppt. ductal stone formation duct obstruction Ulceration of epithelium, fibrosis. […] Pathogenesis Toxic metabolite hypothesis: fatty acid ethyl esters and reactive O2 species Increase fragility in intraacinar organelles such as zymogen granules and lysosomes, Damage acinar cells scarring of the pancreatic parenchyma Impair microcirculation Acetaldehyde causes direct acinar injury.

• #1 Pathogenesis of Chronic Pancreatitis-induced Pain – Marina Vardanyan – Discovery Medicine

  https://www.discoverymedicine.com/Marina-Vardanyan/2010/04/10/pathogenesis-of-chronic-pancreatitis-induced-pain-2/

  Chronic pancreatitis is generally considered to result from a combination of factors, including increased intraductal and intraparenchymal pressure, alterations in pancreatic nerves, pancreatic ischemia, and scarring of pancreatic nerves. Complications, including pseudocysts, common bile duct obstruction, and progression to pancreatic cancer, may be associated with pancreatic pain. […] Increased intraductal pressure has traditionally been deemed the major contributor to pancreatic pain. Pancreatic duct hypertension, ranging from 20 to 80 mm Hg (as compared with the normal range of 7 to 15 mm Hg), has been documented in patients with chronic pancreatitis. Yet other studies have found no association between the severity of pancreatitis and the manometric findings. […] Increased intraparenchymal pressure, up to 30 mm Hg (as compared with the normal measurement of 7 mm Hg), has been observed in patients with chronic pancreatitis.

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

  https://emedicine.medscape.com/article/181554-overview

  Evidence indicates the involvement of distinct chemokines in the initiation and perpetuation of chronic pancreatitis. […] The proposed pathologic mechanisms of chronic pancreatitis are as follows: Intraductal plugging and obstruction – Eg, ethanol (ETOH) abuse, stones, tumors; Direct toxins and toxic metabolites – These act on the pancreatic acinar cells to stimulate the release of cytokines, which stimulate the stellate cells to produce collagen and to lay down fibrous tissue; cytokines also act to stimulate inflammation by neutrophils, macrophages, and lymphocytes (eg, ETOH, tropical sprue); Oxidative stress – Eg, idiopathic pancreatitis; Necrosis-fibrosis – Recurrent acute pancreatitis that heals with fibrosis; Ischemia – From obstruction and fibrosis; important in exacerbating or perpetuating disease rather than in initiating disease; Autoimmune disorders – Chronic pancreatitis has been found in association with other autoimmune diseases, such as Sjgren syndrome, primary biliary cirrhosis, and renal tubular acidosis.

• #1 Current Approaches in Chronic Pancreatitis | IntechOpen

  https://www.intechopen.com/chapters/76868

  Normally, the enzymes are produced as inactive precursors, packed into zymogen granules, and segregated from mainly lysosomal enzymes in order to avoid premature activation. […] Alcohol leads to destabilization of lysosomes and zymogen granules via by oxidant stress produced by cholesteryl esters (CEs), which accumulate in the pancreas during ethanol consumption; and fatty acid ethyl esters (FAEEs), which are nonoxidative metabolites of alcohol. […] The enzyme synthesis is increased, but the secretion is also impaired. […] Therefore, it predisposes the gland to autodigestive injury. […] The cytokines released during prolonged injury and the ethanol itself via its metabolite acetaldehyde causes activation of the PSC (specific, highly plastic type of myofibroblast) leading to excess deposition of extra cellular matrix and active tissue remodeling and resulting in fibrosis and replacement of functional tissue.

• #1 Alcohol-Induced Pancreatitis

  https://www.uspharmacist.com/article/alcohol-induced-pancreatitis

  The metabolic byproducts created during both of these processes have been linked to significant increases in both digestive and lysosomal enzymes, as well as to an increase in the contact between these enzymes. This is thought to lead to premature intracellular activation of digestive enzymes and results in autodigestion (predisposing the pancreas to the breakdown of its own enzymes) and necroinflammation. […] Repeated episodes of necroinflammation may trigger the activation of pancreatic stellate cells (PSCs), which in a normal pancreas are usually inactive and are a major source of extracellular matrix proteins that make up fibrous tissue, and thus have been found predominantly in areas of fibrosis. […] Continuous activation of PSCs will ultimately lead to chronic pancreatitis.

• #1 Chronic Pancreatitis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482325/

  The pathogenesis of chronic pancreatitis appears to be influenced by genetic and environmental factors. Studies have identified pancreatitis susceptibility genes associated with loss of function. Two main theories explain the development of chronic pancreatic disease. […] The first theory suggests that impaired bicarbonate secretion fails to counterbalance increased pancreatic protein secretion. As a result, excess proteins form plugs within the lobules and ducts, leading to calcification and stone formation. The second theory involves the intraparenchymal activation of digestive enzymes within the pancreas, potentially triggered by genetic predisposition or external influences such as alcohol consumption. […] Recent research suggests that alcohol diminishes the cell’s ability to respond to calcium signaling. This reduced response disrupts the feedback mechanism and initiates a cycle of cellular damage, leading to cell death.

• #1 Pancreatitis – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/pancreatitis/symptoms-causes/syc-20360227

  Gallstones are a common cause of pancreatitis. Gallstones, produced in the gallbladder, can slip out of the gallbladder and block the bile duct, stopping pancreatic enzymes from traveling to the small intestine and forcing them back into the pancreas. The enzymes then begin to irritate the cells of the pancreas, causing the inflammation associated with pancreatitis. […] Chronic pancreatitis is a long-term condition. The damage to the pancreas can get worse over time. […] If the enzymes are turned on too soon, they can start acting like digestive juices inside the pancreas. The action can irritate, damage or destroy cells. This problem, in turn, leads to immune system responses that cause swelling and other events that affect how the pancreas works. […] Conditions that can lead to chronic pancreatitis include: Damage from repeated acute pancreatitis. Heavy alcohol use. Inherited genes linked to pancreatitis. High triglyceride levels in the blood. High calcium levels in the blood. […] A number of genes have been linked to chronic pancreatitis. A family history of the disease is linked to an increased risk, especially when combined with other risk factors. […] Long-standing inflammation in the pancreas is a risk factor for cancer of the pancreas.

• #1 Chronic Pancreatitis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482325/

  Recurrent episodes of acute pancreatitis increase the risk of developing chronic pancreatitis. Although the first and second episodes rarely lead to chronic disease, the likelihood rises from 16% to 50% after the third or fourth episode. […] A proposed explanation is that alcoholic pancreatitis is more likely to recur than biliary pancreatitis, which typically occurs only once. Continued alcohol consumption contributes to progressive pancreatic damage. In addition, each recurrent episode causes further injury to an already compromised pancreas. By the third episode and beyond, acute pancreatitis tends to be more severe than the initial occurrences. Individuals with 3 or more episodes of acute pancreatitis often exhibit clinical, biochemical, and imaging findings consistent with chronic pancreatitis.

• #1

  https://link.springer.com/article/10.1007/s12262-019-02059-z

  Chronic pancreatitis is an inflammatory condition characterized by structural change within the pancreas, that leads to progressive and irreversible loss of functioning pancreatic parenchyma, exocrine/endocrine dysfunction and an increased risk of pancreatic ductal adenocarcinoma. […] The most widely accepted mechanistic model behind the development of CP is the Sentinel Acute Pancreatitis Event hypothesis, whereby a single index or sentinel event of acute pancreatitis sensitizes the pancreas to further, more minor, inflammatory insults (e.g. alcohol or oxidative stress). […] Alcohol and its metabolites (including acetaldehyde) promote auto-digestion of the pancreatic acinar cells (through a combination of activating pro-enzymes, together with degradation of lysosome stability) and ongoing fibrosis by stimulation of the pancreatic stellate cells.

• #1 Chronic pancreatitis, pseudotumors and other tumor-like lesions | Modern Pathology

  https://www.nature.com/articles/3800690

  In recent years, the plug hypothesis has been challenged by the necrosis-fibrosis sequence concept. […] A third hypothesis, called the toxic-metabolic hypothesis was put forth by Bordalo et al. This hypothesis postulates that chronic alcohol consumption induces progressive acinar lipid deposition with acinar atrophy and intrapancreatic fibrosis by exerting direct toxic and metabolic effects on the acinar cells. […] The fourth hypothesis, the oxidative stress hypothesis, postulates that oxidative stress in pancreatic acinar cells induced by excess free radicals causes a blockade of the intracellular pathway, fusion of lysosomal and zymogenic compartments, and membrane lipid oxidation. […] It has recently been shown that the genetic alterations in hereditary chronic pancreatitis involve the cationic trypsinogen gene (PRSS1) or the serine protease inhibitor Kazal type 1 (SPINK1) gene. […] The inflammatory duct changes seen in autoimmune pancreatitis point to potential antigens within the duct epithelium that have become targets of an immune process.

• #1 Chronic pancreatitis pathophysiology – wikidoc

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

  Chronic pancreatitis is a progressive inflammatory process leading to irreversible structural damage to the pancreas resulting in exocrine and endocrine dysfunction. The pathogenesis is still unclear and multifactorial. Decreased bicarbonate secretion and intrapancreatic activation of digestive enzymes is thought to play an important role in the pathogenesis of chronic pancreatitis. Other factors that are thought to play an important role in the pathogenesis of chronic pancreatitis may include intraductal plugging and obstruction, direct injury to pancreatic cells induced by toxins and toxic metabolites, antioxidants, ischemia, autoimmune disorders, the sentinal acute pancreatitis event (SAPE), necrosis and fibrosis. Genes involved in the pathogenesis of chronic pancreatitis include CFTR-cystic fibrosis gene mutation, SPINK-1 mutation, which encodes for trypsin inhibitor, PRSS-1 gene mutation linked to hereditary pancreatitis, claudin-2 (CLDN2), and carboxypeptidase A1 (CPA1) gene mutations.

• #1 Current Approaches in Chronic Pancreatitis | IntechOpen

  https://www.intechopen.com/chapters/76868

  Premature intrapancreatic activation or inappropriate inhibition of the trypsinogen can lead to pathologic event resulting in CP. […] Hereditary pancreatitis (HP) is a specific subtype of CP. […] The mutations in the human cationic trypsinogen (PRSS1) can cause the premature activation of the trypsinogen in various ways. […] The p.N29I variant causes an increase in N-terminal processing, decreased CTRC -dependent degradation, and an increased propensity for autoactivation of the trypsin. […] The p.R122C and p.R122H mutations mainly prevent CTRC-mediated trypsinogen degradation. […] Mutations in the CTRC gene have been shown to increase the risk of CP and they are 30% prevalent among patients with CP. […] The three main pathways explaining the increased risk of CP involve (i) impaired trypsinogen and/or trypsin degradation; (ii) impaired activation of A-type carboxypeptidases, and (iii) induction of ER stress due to defective secretion.

• #1 Pathogenesis of Chronic Pancreatitis

  http://www.scielo.org.co/scielo.php?pid=S0120-99572008000300014&script=sci_abstract

  Chronic Pancreatitis is characterized by progressive and irreversible damage of the pancreas, many etiologies are known but chronic alcohol ingestion is the primary cause. […] Recently there have been important advances in knowledge of the pathogenesis of alcohol damage. Important advances have also been made in regard to the mechanisms of pancreatic fibrinogenesis and the role of the stellate cells in the fibrosis of this disease. […] Genetic mutations involved in the process of activation/inactivation of trypsinogen in the pancreas, and other mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) that affect bicarbonate secretion, have been described as related to the development of chronic Pancreatitis of different etiologies such as idiopathic, alcoholic and tropical Pancreatitis.

• #1 Pathogenesis of Chronic Pancreatitis | Pancreapedia

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

  Each cell type that is found in the pancreas either acinar or ductal or stellate cells – is suspected to contribute to chronic pancreatitis. In addition the extra-pancreatic environment including inflammatory cells contributes to the progress of both acute and chronic inflammatory pancreatic diseases. […] There is much evidence that pancreatic proteases and their premature intracellular activation are responsible for the pathogenesis of acute pancreatitis. Therefore these enzymes also might be of interest for chronic pancreatitis, not least because findings of genetic studies in humans underline their critical role. […] Taken together these observations support the critical role of the protease/antiprotease system, in particular trypsin, in the pathogenesis of pancreatitis. However, it should be mentioned that less than 60% of patients with hereditary chronic pancreatitis and less than 20% of patients with idiopathic chronic pancreatitis harbour mutations in the PRSS1 gene so that an inappropriate trypsinogen cannot be the only causative factor for chronic pancreatitis.

• #1 Current Approaches in Chronic Pancreatitis | IntechOpen

  https://www.intechopen.com/chapters/76868

  The pancreas consists of three critical cell lineages: acinar, ductal and endocrine. […] Adjacent to the acinar cells around small pancreatic ducts and blood vessels are pancreatic stellate cells, that compromise around 47% of all parenchymal cells. […] The hypotheses mentioned above lead to cellular injury, which turns into chronic inflammation and then eventually fibrosis. […] Increasing evidence indicates that pancreatic stellate cells (PSC) are the major mediators of fibrosis, resulting in the formation of extracellular matrix (ECM) in the organ. […] Fibrosis causes acinar cells and duct cells to injure and disappeared. […] This process ultimately leads to progressive loss of the lobular morphology and structure of the pancreas resulting in functional impairment of both exocrine and endocrine functions, eventually leading to clinical symptoms such as pain, malnutrition, or diabetes.

• #1 Molecular Mechanism of Pancreatic Stellate Cells Activation in Chronic Pancreatitis and Pancreatic Cancer

  https://www.jcancer.org/v11p1505.htm

  Activated pancreatic stellate cells (PSCs) are the main effector cells in the process of fibrosis, a major pathological feature in pancreatic diseases that including chronic pancreatitis and pancreatic cancer. […] Many cellular signals are revealed contributing to the activation of PSCs, such as transforming growth factor-, platelet derived growth factor, mitogen-activated protein kinase (MAPK), Smads, nuclear factor-B (NF-B) pathways and so on. Therefore, investigating the role of these factors and signaling pathways in PSCs activation will promote the development of PSCs-specific therapeutic strategies that may provide novel options for pancreatic cancer therapy. […] During tumorigenesis, stroma cells and pancreatic cancer cells will secret a variety of stimulating factors (e.g. transforming growth factor-, TGF-) to activate PSCs.

• #1 Pathophysiology of chronic pancreatitis

  https://www.wjgnet.com/1007-9327/full/v19/i42/7231.htm

  The fibrotic destruction of the pancreatic gland is irreversible and the morphological and structural changes lead to functional impairment of both exocrine and endocrine functions, eventually leading to malnutrition and/or diabetes. […] The onset of pancreatic fibrogenesis is caused by injury which may involve interstitial mesenchymal cells, the duct cells and/or the acinar cells. […] However, destruction to any one of these pancreatic tissue compartments is associated with transformation of resident fibroblasts/pancreatic stellate cells into myofibroblast-like phenotypes; a process called activation. […] The exact pathophysiological mechanisms initiating and maintaining the development of fibrosis in the pancreas are poorly understood, but may be viewed as a progression similar to, e.g., liver fibrosis.

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

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

  As in AP, a synergy among genetic, immune, and environmental factors may be important. […] The pathogenesis of CP is characterized by the activation of pancreatic stellate cells (PSCs) and the subsequent development of fibrosis. […] Macrophages are the main inflammatory cells implicated in CP fibrosis. […] Fibrogenesis in CP is induced when macrophages and other inflammatory cells are attracted by tissue damage and infiltrate the pancreas. […] Activated PSCs can also secrete CTGF, IL-1/16, and endothelin-1 (ET-1) and further promote the activation of PSCs through autocrine and paracrine signaling, which forms a vicious cycle. […] The influence of external risk factors is very strong. […] In patients with CP, the pooled prevalence of alcohol as a risk factor is 65% compared to the risk factor of 61% of tobacco. […] Macrophages and pancreatic stellate cells are in the center of extensive investigation to clarify their role in the pathogenesis of CP.

• #1 Pathophysiology of chronic pancreatitis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3831204/

  The exact pathophysiological mechanisms initiating and maintaining the development of fibrosis in the pancreas are poorly understood, but may be viewed as a progression similar to, e.g., liver fibrosis. […] The initial injury to one or all of the various tissue compartments or cell types of the pancreas leads to cell necrosis and/or apoptosis and consequently release of cytokines/growth factors. […] In the final stage, myofibroblasts produce and extracellular matrix deposits replace the inflammatory infiltrate and affect the architecture and function of the remaining pancreatic tissues. […] Pancreatic stellate cells express both mediators of matrix remodeling and the regulatory cytokine TGF-1 that, by autocrine inhibition of MMP-3 and MMP-9, may enhance fibrogenesis by reducing collagen degradation.

• #1 Immunological Responses Involved In Promoting Acute and Chronic Pancreatitis

  https://www.scivisionpub.com/articles/immunological-responses-involved-in-promoting-acute-and-chronic-pancreatitis-14.html

  Pancreatitis is the inflammatory disease of pancreas induced by unusual food habit, alcohol abuse, and genetic defect in cationic trypsinogen gene. […] During the complex process of pancreatitis several pro-inflammatory cells, cytokines and chemokines play very critical role in initiation and progression of the disease. […] The factors involved in promoting chronic pancreatitis from acute pancreatitis are completely unidentified that progresses into the pancreatic fibrosis and further leads to the pancreatic malignancy. […] Therefore, an urgent need to understand the immune mechanism involved in promoting pancreatitis. […] The current review provides a comprehensive understanding and crucial role of complex interwoven network of various immune related cell types such as neutrophils, eosinophils, mast cells, T cells, dendritic cells, pro-inflammatory cytokines (TNF , IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-13, IL-18, IL-33) and chemokines (MCP-1, MIF, CXCL-8, CXCL-1, Eotaxin-1, Eotaxin-2) in the development of pathogenesis of acute and chronic pancreatitis; that might be useful for scientists and physician to focus on the role of particular cell types and their associated mediators in pancreatitis pathogenesis.

• #1 Pain and chronic pancreatitis: A complex interplay of multiple mechanisms

  https://www.wjgnet.com/1007-9327/full/v19/i42/7282.htm

  Abdominal pain is the most significant symptom and a major clinical challenge in chronic pancreatitis (CP). It is present in up to 90% of the patients and the primary cause of hospitalization. The etiology of pain in CP is increasingly better understood and likely involves multiple mechanisms. Traditional theories focused on the role of local pathology within or in close proximity to the pancreas, as the main generator of pain, but since the late 1990s there has been a shift towards a neurobiological understanding of pain in CP. Accordingly, there is solid histological and neurophysiological evidence for an abnormal pain processing in many of these patients. Various mechanisms responsible for this altered pain processing have been proposed, among them sensitization of the peripheral and central nerves, reorganization of the cerebral cortex and alterations in pain control systems. The aim of this review is to highlight current theories regarding the pain mechanisms in CP. This is important in order to understand the complexity of this debilitating disease and why pain management is often insufficient. Also, optimal treatment will only be achieved on the basis of a better understanding of the mechanisms underlying pain in CP. The mainstay of pain treatment in CP has for many years focused on the pancreatic gland based on the assumption, that pain is generated by increased pressure in the pancreatic duct or in the pancreatic parenchyma. This mechanistic understanding of pain, termed the plumbing theory, has been the most widely accepted theory regarding the cause of pain and it is the theoretical background of most interventions including surgical and endoscopic drainage procedures. The source of pain in chronic pancreatitis is complex and almost certainly multifactorial, and the relative contribution of different factors can be difficult to determine in the individual patient. Intense abdominal pain is a dominant feature of CP and it is associated with poor mental and physical quality of life. Basic studies of pancreatic nerves and experimental human pain research have provided evidence that pain processing is abnormal in these patients and in many cases resembles that seen in neuropathic and chronic pain disorders. This neurobiological view of pain is somewhat in opposition to the traditional view of pain etiology in CP, where pain was assumed to arise from pathology in or in close proximity to the pancreatic gland. However, these theories are not mutually exclusive, and aspects of both may contribute in the generation and perpetuation of pain. Therefore, it is important to consider the different mechanisms, when evaluating the origin of pain in CP patients, and it is plausible that the collective abdominal pain is a result of a complex interplay of several mechanisms.

• #1 Pathogenesis and Treatment of Pain in Chronic Pancreatitis | Pancreapedia

  https://pancreapedia.org/reviews/pathogenesis-and-treatment-of-pain-in-chronic-pancreatitis

  An inflammatory process of the pancreas, which is replaced by fibrosis and progressive destruction, characterizes chronic pancreatitis (CP). […] Even though the pain can be caused by a variety of factors, obstruction of the flow from acinar cells and destruction of the nerves has been thought to be of major importance. […] This mechanistic understanding of pain has been the most widely accepted theory and it is the theoretical background for most interventions including surgical and endoscopic drainage procedures. […] Recent studies based on endoscopic manometry have, however, not documented ductal hypertension in CP, and no difference in pressure levels in patients with the presence or absence of pain. […] However, pancreatic atrophy and ductal pathology were associated with diabetes, and low levels of phosphate and haemoglobin.

• #1 Pain in chronic pancreatitis: the role of neuropathic pain mechanisms | Gut

  https://gut.bmj.com/content/57/11/1616

  Pain mechanisms in patients with chronic pancreatitis are incompletely understood and probably multifactorial. […] Recently, evidence from experimental human pain research has indicated that in many of these patients pain processing in the central nervous system is abnormal and mimics that seen in neuropathic pain disorders. […] The current review focuses on several lines of evidence supporting this hypothesis. […] Hence, the spontaneous and postprandial pain in chronic pancreatitis may reflect the characteristic pain features seen in patients with neuropathic pain. […] Biochemical and histopathological findings in tissues from patients with chronic pancreatitis are similar to those observed in patients with other nerve fibre lesions. […] Experimental studies have shown that patients with chronic pancreatitis show signs of spinal hyper-excitability counter-balanced by segmental and descending inhibition.

• #1 Severe pain in chronic pancreatitis patients | JPR

  https://www.dovepress.com/severe-pain-in-chronic-pancreatitis-patients-considering-mental-health-peer-reviewed-fulltext-article-JPR

  Patients with severe, painful CP that is not controlled within 2-3 years often develop a syndrome called central sensitization or central pain. […] Chronic pain also drives changes in psychological processes including perception, attention, mood, motivation, learning and memory. […] Understanding CP requires the transition from a traditional monolithic view of disease to a more holistic view where each case is an independent combination of multiple risk factors that act in a pathogenic way to cause disease. […] New investigations of the overlap of pain, depression and anxiety demonstrate that multiple genetic risk loci for depression and anxiety are associated with constant severe pain experience and that the effects are manifest in the brain. […] Severe pain in patients with CP can be identified and quantified, but tools to understand the underlying and variable mechanisms contributing to the severe pain experience in these patients are lacking.

• #1 Pathogenesis of Chronic Pancreatitis-induced Pain – Marina Vardanyan – Discovery Medicine

  https://www.discoverymedicine.com/Marina-Vardanyan/2010/04/10/pathogenesis-of-chronic-pancreatitis-induced-pain-2/

  Recent evidence suggests that BDNF may play a key role as a pain modulator. […] Another mechanism implicated in pain generation in patients with chronic pancreatitis is elevation of cholecystokinin (CCK) levels in the blood. […] Those studies of the brain, together with the failure of a total pancreatectomy to provide pain relief in 33% of patients with chronic pancreatitis, clearly suggest that reorganization of the central nervous system plays an important role in maintaining chronic pancreatitis-induced pain. […] Despite the significant progress in elucidating its mechanisms, its pathogenesis is still not entirely understood. The complex pathology of pancreatitis makes pain management difficult and often inadequate. Many factors have been implicated in pain generation and data from different studies are often contradictory.

• #1 Chronic Pancreatitis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482325/

  Key pathological changes include: Immune dysregulation leading to fibrosis or sclerosis, Acinar cell dysfunction leading to exocrine pancreatic insufficiency, Islet cell dysfunction leading to pancreatogenic diabetes mellitus (T3c), Characteristic pain leading to chronic pain syndrome, Metaplasia leading to pancreatic ductal adenocarcinoma (PDAC).

• #1 Pathophysiology of chronic pancreatitis

  https://www.wjgnet.com/1007-9327/full/v19/i42/7231.htm

  Chronic pancreatitis (CP) is an inflammatory disease of the pancreas characterized by progressive fibrotic destruction of the pancreatic secretory parenchyma. Despite the heterogeneity in pathogenesis and involved risk factors, processes such as necrosis/apoptosis, inflammation or duct obstruction are involved. […] The etiological risk-factors associated with CP are multiple and involve both genetic and environmental factors. […] The secretory parenchyma is destroyed by processes such as necrosis/apoptosis, inflammation or duct obstruction. […] Increasing evidence indicates that pancreatic stellate cells (PSC) are the major mediators of fibrosis, resulting in the formation of extracellular matrix (ECM) in the interstitial spaces and in the areas where acinar cells disappear or duct cells are injured.

• #1 Chronic Pancreatitis | Universitair Pijn Centrum Maastricht

  https://www.pijn.com/en/chronic-pancreatitis-0

  In the pathogenesis of the pain, nociceptive, neuropathic and neural inflammatory mechanisms play a role. […] In chronic pancreatitis, exocrine function of the pancreas is frequently affected earlier and more seriously than endocrine function. […] The mechanism regarding how alcohol causes pancreatitis is not yet clear.

• #1

  https://link.springer.com/article/10.1007/s12262-019-02059-z

  Evidence of pathologically enhanced peripheral nociception secondary to CP has been demonstrated in both experimental animal models (e.g. enhanced sensory nerve excitability and upregulation of substance P) and in resected human pancreatic tissue (including neuritis and nerve hypertrophy). […] The risk of pancreatic ductal adenocarcinoma is increased in patients with chronic pancreatitis, but particularly so in cases of hereditary pancreatitis or predisposing genetic mutations. […] The absence of conclusive randomised clinical trial data does not warrant dismissal of the accumulating evidence that is currently available to suggest that early surgical intervention may offer the benefits of more effective pain relief, reduced need for re-intervention and improved preservation of pancreatic function.

• #1 Pancreatic Cancer in Chronic Pancreatitis: Pathogenesis and Diagnostic Approach

  https://www.mdpi.com/2072-6694/15/3/761

  Chronic pancreatitis is one of the main risk factors for pancreatic cancer, but it is a rare event. […] Inflammation and oncogenes work hand in hand as key promoters of this disease. […] During alcoholic chronic pancreatitis, the cumulative risk of cancer is estimated at 4% after 15 to 20 years. […] The diagnosis is difficult due to: (i) clinical symptoms of cancer shared with those of chronic pancreatitis; (ii) the parenchymal and ductal remodeling of chronic pancreatitis rendering imaging analysis difficult; and (iii) differential diagnoses, such as pseudo-tumorous chronic pancreatitis and paraduodenal pancreatitis. […] CP is a risk factor for pancreatic ductal adenocarcinoma (PDAC). […] Clinical approach is peculiarly delicate and both positive and differential diagnosis of PDAC developed on CP is a real challenge due to the rather low specificity of symptoms, imaging signs, and biological markers.

• #1 Pancreatic Cancer in Chronic Pancreatitis: Pathogenesis and Diagnostic Approach

  https://www.mdpi.com/2072-6694/15/3/761

  Chronic pancreatitis and PDAC were historically considered as unrelated diseases as they were thought to arise from two different cells in the pancreas, namely acinar and ductal cells. […] However, this progression model of PanINs-PDAC has been questioned regarding the molecular status of the transgenic model of PDAC in mice. […] All these important and converging observations led to the conclusion that pancreatic cancer can originate from acinar cells via acinar metaplasia leading to ductal metaplasia. […] Several closely related mechanisms can contribute to the transformation of acinar cell metaplasia into cancer: oxidative stress, activation of inflammatory pathways (such as Cyclooxygenase-2 (Cox2)), and activation of NF-κB and STAT3 pathways. […] The immune cells and macrophages are also activated (and in turn produce cytokines and interleukins) as well as other stromal components, such as endothelial cells and pancreatic stellate cells, that in turn produce inflammatory cytokines and chemokines (such as Interleukin 6).

• #1 Pathogenesis of Chronic Pancreatitis | Pancreapedia

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

  Recent knowledge on the pathogenesis of chronic pancreatitis has been gained by both genetic linkage analyses and experimental in-vitro and animal studies. There are multiple genetic susceptibility factors, which mostly involve the protease/antiprotease system of the exocrine pancreas. Recent genome wide association studies have identified genetic variants affecting proteins seemingly unrelated to the trypsin-centered pathway whose underlying cellular mechanisms are still unclear. From animal models we can learn that at least two principal mechanisms seem to predispose to the development of chronic pancreatitis which are recurrent pathologic stimuli on the pancreas or one single severe event such as an obstruction of the bile or pancreatic duct. Furthermore new theories postulate that a sequence of two events is essential for the pathogenesis of chronic pancreatitis. […] It can be assumed that not a single but rather a combination of different pathologic stimuli, including immune mediated processes, will eventually be necessary to develop chronic pancreatitis. The pathogenesis of this disease is too complex to get reduced to one single event.

• #1 Mechanisms of Disease: advances in understanding the mechanisms leading to chronic pancreatitis | Nature Reviews Gastroenterology & Hepatology

  https://www.nature.com/articles/ncpgasthep0025

  Chronic pancreatitis remains a challenging and frustrating clinical problem. […] In the past few years, however, advances in genetic and immunologic research have spawned new insights and approaches to chronic pancreatitis. Genetic and environmental risk assessment may help identify individuals who are likely to develop severe chronic pancreatitis early in the disease course, and allow targeted attention to reduce confounding risks and slow or prevent this problem in the future.

• #2 A New Insight into Chronic Pancreatitis

  https://www.jstage.jst.go.jp/article/tjem/248/4/248_225/_html/-char/en

  Although the pathological mechanisms and pathophysiology have long been largely unknown, this disease has become understood from a new point of view recently thanks to several breakthroughs in the past two decades. […] The mechanistic definition can be understood as a definition that considers the pathological mechanism of CP. […] The new definition is composed of two parts. The first part describes CP as a pathologic fibro-inflammatory syndrome of the pancreas in individuals with genetic, environmental and/or other risk factors who develop persistent pathologic responses to parenchymal injury or stress. […] The second part states that the common features of established and advanced CP include pancreatic atrophy, fibrosis, pain syndromes, duct distortion and strictures, calcifications, pancreatic exocrine dysfunction, pancreatic endocrine dysfunction and dysplasia.

• #2 Pathophysiology of chronic pancreatitis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3831204/

  To describe the heterogeneity of the underlying pathophysiology we have throughout the review used the M-ANNHEIM classification, comprising detailed description of multiple risk factors such as: alcohol-consumption, nicotine-consumption, nutritional factors, hereditary factors, efferent duct factors, immunological factors and miscellaneous including rare metabolic factors.

• #2 Etiology and pathogenesis of chronic pancreatitis in adults – UpToDate

  https://www.uptodate.com/contents/etiology-and-pathogenesis-of-chronic-pancreatitis-in-adults/print

  Chronic pancreatitis is a syndrome involving inflammation, fibrosis, and loss of acinar and islet cells, which can manifest with pancreatic-type abdominal pain, steatorrhea, derangements in pancreatic function (exocrine and endocrine insufficiency), and visible pancreatic damage on imaging studies. Chronic pancreatitis has a variety of etiologies with genetic and environmental risk factors for both initiation and disease progression, variable clinical and imaging features, and complications. […] This topic will review the etiology and pathogenesis of chronic pancreatitis. […] Alcohol is associated with approximately one-half of all cases of chronic pancreatitis in the United States. Idiopathic chronic pancreatitis accounts for approximately 10 to 30 percent of all cases. The number of patients labeled as idiopathic depends in large part on how detailed and comprehensive the search is for an etiology.

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

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

  Chronic inflammation of the pancreas is caused by acinar and ductular cell injury driven by alcohol, smoking, hypercalcemia, genetic factors, or any combination of the above. […] 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. […] Interestingly, a genetic mutation in claudin 2 may synergize with alcohol consumption in the development of pancreatitis, indicating the interplay between external and genetic factors in the pathogenesis of pancreatitis. […] The relationship of ethanol and smoking to CP has been unequivocally proved. […] The amount and duration of ethanol consumption have been estimated to be either a median of 5.1 drinks/d or a consumption of up to 110–277 g ethanol/d over 5–25 years, similarly to AP.

• #2 Etiology of Pancreatitis and Risk Factors | IntechOpen

  https://www.intechopen.com/chapters/47453

  Chronic pancreatitis (CP) is a progressive fibro-inflammatory disorder which eventually culminates in permanent impairment of the exocrine and/or endocrine pancreatic function. […] The risk of acute alcohol-induced pancreatitis increases in a dose-dependent manner, with a threshold for CP of approximately 4-5 drinks/day. Chronic alcoholic patients eventually develop CP after 10 to 20 years of continuous alcohol abuse. […] Alcohol may act directly on the acinar cells as a toxic by promoting the synthesis of enzymes, activation of pancreatic proteases, changes in cellular lipid metabolism, induction of oxidative stress, activation of stellate cells and/or by increasing the sensitivity of the gland to other genetic and environmental factors. […] The proposed pathogenic mechanism is the relative obstruction to pancreatic juice flow through the minor papilla, leading to increased intraductal pressure.

• #2 Chronic pancreatitis pathophysiology – wikidoc

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

  Chronic pancreatitis is a progressive inflammatory process leading to irreversible structural damage to the pancreas resulting in exocrine and endocrine dysfunction. The pathogenesis is still unclear and multifactorial. Decreased bicarbonate secretion and intrapancreatic activation of digestive enzymes is thought to play an important role in the pathogenesis of chronic pancreatitis. Other factors that are thought to play an important role in the pathogenesis of chronic pancreatitis may include intraductal plugging and obstruction, direct injury to pancreatic cells induced by toxins and toxic metabolites, antioxidants, ischemia, autoimmune disorders, the sentinal acute pancreatitis event (SAPE), necrosis and fibrosis. Genes involved in the pathogenesis of chronic pancreatitis include CFTR-cystic fibrosis gene mutation, SPINK-1 mutation, which encodes for trypsin inhibitor, PRSS-1 gene mutation linked to hereditary pancreatitis, claudin-2 (CLDN2), and carboxypeptidase A1 (CPA1) gene mutations.

• #2 Chronic pancreatitis | PPT

  https://www.slideshare.net/slideshow/chronic-pancreatitis-70607886/70607886

  Chronic pancreatitis is a progressive inflammatory condition of the pancreas characterized by irreversible morphological changes and loss of function. It is most commonly caused by long term heavy alcohol use. […] Chronic Pancreatitis Definition: it is a benign inflammatory process and fibrosing disorder characterized by irreversible morphologic changes, Progressive and permanent loss of exocrine and endocrine function. […] Pathogenesis Protein Plug hypothesis: Alcohol Protein conc in pancreatic secretion Glycoprotein2 secretions in acinar cells formation of protein precipitates protein plug calcification of ppt. ductal stone formation duct obstruction Ulceration of epithelium, fibrosis. […] Pathogenesis Toxic metabolite hypothesis: fatty acid ethyl esters and reactive O2 species Increase fragility in intraacinar organelles such as zymogen granules and lysosomes, Damage acinar cells scarring of the pancreatic parenchyma Impair microcirculation Acetaldehyde causes direct acinar injury.

• #2 Current Approaches in Chronic Pancreatitis | IntechOpen

  https://www.intechopen.com/chapters/76868

  Normally, the enzymes are produced as inactive precursors, packed into zymogen granules, and segregated from mainly lysosomal enzymes in order to avoid premature activation. […] Alcohol leads to destabilization of lysosomes and zymogen granules via by oxidant stress produced by cholesteryl esters (CEs), which accumulate in the pancreas during ethanol consumption; and fatty acid ethyl esters (FAEEs), which are nonoxidative metabolites of alcohol. […] The enzyme synthesis is increased, but the secretion is also impaired. […] Therefore, it predisposes the gland to autodigestive injury. […] The cytokines released during prolonged injury and the ethanol itself via its metabolite acetaldehyde causes activation of the PSC (specific, highly plastic type of myofibroblast) leading to excess deposition of extra cellular matrix and active tissue remodeling and resulting in fibrosis and replacement of functional tissue.

• #2 Chronic pancreatitis, pseudotumors and other tumor-like lesions | Modern Pathology

  https://www.nature.com/articles/3800690

  Chronic pancreatitis is a fibroinflammatory disease of the pancreas. Etiologically, most cases are related to alcohol abuse and smoking. Recently, gene mutations have been identified as the cause of hereditary pancreatitis. […] The pathology of chronic pancreatitis was formerly considered to be uniform, but currently it is more and more seen as varying according to the etiology of the disease. […] For the pathogenesis it is important to note that alcoholic chronic pancreatitis, hereditary pancreatitis and duodenal wall pancreatitis evolve from recurrent acute pancreatitis. […] In all westernized countries, alcohol is the most common cause of chronic pancreatitis. In addition, smoking seems to be an independent etiological factor. […] Several theories have been put forth to explain the pathogenesis of alcoholic chronic pancreatitis.

• #2 Chronic pancreatitis pathophysiology – wikidoc

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

  The pathogenesis is still unclear and multifactorial; but two mechanisms that play an important role in the pathogenesis of chronic pancreatitis, which are as follows: […] A decrease in bicarbonate secretion may be due to any of the following causes: […] Protein hypersecretion resulting in proteinaceous ductal plugs leading to ductal blockage and obstruction. […] Usually results from genetic causes leading to: […] Impaired enzyme activation and regulation. […] Other factors that are thought to play an important role in the pathogenesis of chronic pancreatitis include: […] Ischemia is an important precipitating factor in the pathogenesis of chronic pancreatitis. […] Chronic pancreatitis has been found to be associated with autoimmune conditions such as: […] Recurrent attacks of acute pancreatitis may lead to chronic pancreatitis due to: […] SAPE hypothesis explains the role of pancreatic stellate cells in chronic pancreatitis. […] It explains the pathogenesis of chronic pancreatitis as a continuum of 3 sequential changes.

• #2 Chronic Pancreatitis | Choose the Right Test

  https://arupconsult.com/content/pancreatitis-chronic

  Chronic pancreatitis includes a number of progressive inflammatory diseases, such as calcifying, chronic obstructive, and steroid-responsive or autoimmune chronic pancreatitis, which lead to pancreatic damage. […] The pathogenesis of chronic pancreatitis is not fully understood, but episodes of acute pancreatitis are associated with the development of chronic pancreatitis. […] Alcohol use, smoking, and genetic factors also influence risk. […] Other risk factors for chronic pancreatitis include recurrent episodes of acute pancreatitis, severe necrotizing acute pancreatitis, obesity, diabetes, and long-term ductal obstruction. […] A number of genetic variants are associated with chronic pancreatitis, including variants in CFTR, CTRC, PRSS1, SPINK1, CASR, PRSS2, and CLDN2. […] Genetic testing is indicated when the goal is to identify the etiology of chronic pancreatitis and to determine familial risk of the disease.

• #2 Current Approaches in Chronic Pancreatitis | IntechOpen

  https://www.intechopen.com/chapters/76868

  Premature intrapancreatic activation or inappropriate inhibition of the trypsinogen can lead to pathologic event resulting in CP. […] Hereditary pancreatitis (HP) is a specific subtype of CP. […] The mutations in the human cationic trypsinogen (PRSS1) can cause the premature activation of the trypsinogen in various ways. […] The p.N29I variant causes an increase in N-terminal processing, decreased CTRC -dependent degradation, and an increased propensity for autoactivation of the trypsin. […] The p.R122C and p.R122H mutations mainly prevent CTRC-mediated trypsinogen degradation. […] Mutations in the CTRC gene have been shown to increase the risk of CP and they are 30% prevalent among patients with CP. […] The three main pathways explaining the increased risk of CP involve (i) impaired trypsinogen and/or trypsin degradation; (ii) impaired activation of A-type carboxypeptidases, and (iii) induction of ER stress due to defective secretion.

• #2 Pathophysiology of chronic pancreatitis

  https://www.wjgnet.com/1007-9327/full/v19/i42/7231.htm

  Chronic pancreatitis (CP) is an inflammatory disease of the pancreas characterized by progressive fibrotic destruction of the pancreatic secretory parenchyma. Despite the heterogeneity in pathogenesis and involved risk factors, processes such as necrosis/apoptosis, inflammation or duct obstruction are involved. […] The etiological risk-factors associated with CP are multiple and involve both genetic and environmental factors. […] The secretory parenchyma is destroyed by processes such as necrosis/apoptosis, inflammation or duct obstruction. […] Increasing evidence indicates that pancreatic stellate cells (PSC) are the major mediators of fibrosis, resulting in the formation of extracellular matrix (ECM) in the interstitial spaces and in the areas where acinar cells disappear or duct cells are injured.

• #2 Chronic pancreatitis | PPT

  https://www.slideshare.net/slideshow/chronic-pancreatitis-70607886/70607886

  Pathogenesis Pancreatic stellate cells (PSCs): PSCs quiescent fibroblasts (base of acinar cells.) PDGF, TNF, IL-1, IL-6 Alcohol its metabolites activated myofibroblasts Synthesize proteins (collagen I and III, fibronectin, laminin, MMP) FIBROSIS. […] pathogenesis Primary duct hypothesis: immune reactions cause periductal inflammation scarring of the ducts outflow obstruction – destruction and fibrosis.

• #2 Current Approaches in Chronic Pancreatitis | IntechOpen

  https://www.intechopen.com/chapters/76868

  The pancreas consists of three critical cell lineages: acinar, ductal and endocrine. […] Adjacent to the acinar cells around small pancreatic ducts and blood vessels are pancreatic stellate cells, that compromise around 47% of all parenchymal cells. […] The hypotheses mentioned above lead to cellular injury, which turns into chronic inflammation and then eventually fibrosis. […] Increasing evidence indicates that pancreatic stellate cells (PSC) are the major mediators of fibrosis, resulting in the formation of extracellular matrix (ECM) in the organ. […] Fibrosis causes acinar cells and duct cells to injure and disappeared. […] This process ultimately leads to progressive loss of the lobular morphology and structure of the pancreas resulting in functional impairment of both exocrine and endocrine functions, eventually leading to clinical symptoms such as pain, malnutrition, or diabetes.

• #2 Pathophysiology of chronic pancreatitis

  https://www.wjgnet.com/1007-9327/full/v19/i42/7231.htm

  In the final stage, myofibroblasts produce and extracellular matrix deposits replace the inflammatory infiltrate and affect the architecture and function of the remaining pancreatic tissues. […] Pancreatic stellate cells express both mediators of matrix remodeling and the regulatory cytokine TGF-1 that, by autocrine inhibition of MMP-3 and MMP-9, may enhance fibrogenesis by reducing collagen degradation.

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

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

  As in AP, a synergy among genetic, immune, and environmental factors may be important. […] The pathogenesis of CP is characterized by the activation of pancreatic stellate cells (PSCs) and the subsequent development of fibrosis. […] Macrophages are the main inflammatory cells implicated in CP fibrosis. […] Fibrogenesis in CP is induced when macrophages and other inflammatory cells are attracted by tissue damage and infiltrate the pancreas. […] Activated PSCs can also secrete CTGF, IL-1/16, and endothelin-1 (ET-1) and further promote the activation of PSCs through autocrine and paracrine signaling, which forms a vicious cycle. […] The influence of external risk factors is very strong. […] In patients with CP, the pooled prevalence of alcohol as a risk factor is 65% compared to the risk factor of 61% of tobacco. […] Macrophages and pancreatic stellate cells are in the center of extensive investigation to clarify their role in the pathogenesis of CP.

• #2 Immunological Responses Involved In Promoting Acute and Chronic Pancreatitis

  https://www.scivisionpub.com/articles/immunological-responses-involved-in-promoting-acute-and-chronic-pancreatitis-14.html

  The disease-specific regulatory T-cell responses were observed in chronic pancreatitis. […] These findings indicate the existence of different T lymphocytes subsets during the progression of pancreatitis pathogenesis suggesting the role of T cells in the disease pathogenesis. […] The current review provides a comprehensive understanding and crucial role of complex interwoven network of various immune related cell types such as neutrophils, eosinophils, mast cells, T cells, dendritic cells, pro-inflammatory cytokines (TNF , IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-13, IL-18, IL-33) and chemokines (MCP-1, MIF, CXCL-8, CXCL-1, Eotaxin-1, Eotaxin-2) in the development of pathogenesis of acute and chronic pancreatitis.

• #2 Pain in chronic pancreatitis: the role of neuropathic pain mechanisms | Gut

  https://gut.bmj.com/content/57/11/1616

  Changes in the brain with cortical reorganisation to gut stimulation and increased activity in specific electroencephalographic features characteristic for neuropathic pain are also seen in patients with chronic pancreatitis. […] Finally, principles involved in the treatment of pancreatic pain have many similarities with those recommended in neuropathic pain disorders. […] In conclusion, a mechanism-based understanding of pain in chronic pancreatitis may have important implications for the treatment. […] Pain mechanisms are incompletely understood and probably multifactorial. […] In these cases the following pathophysiological mechanisms have been suggested: (1) increased intrapancreatic pressure either within the pancreatic duct or in the parenchyma causing tissue ischaemia; (2) inflammation in the pancreas; and (3) alterations in pancreatic nerves, including an increase in nerve fibre diameter and evidence for neurogenic inflammation.

• #2 Pain in chronic pancreatitis: the role of neuropathic pain mechanisms | Gut

  https://gut.bmj.com/content/57/11/1616

  Recently, evidence from experimental human pain research has indicated that pain processing in the central nervous system (CNS) is abnormal and in many cases may mimic that seen in neuropathic pain disorders. […] Although other pain mechanisms may also be of importance, the following lines of evidence point towards neuropathic pain mechanisms in patients with CP: Clinical features of the pain, Biochemical and histological findings, Spinal changes, with neuronal hyper-excitability and amplification of the incoming afferent activity, Changes in the braingut axis, Clinical and experimental profile of the drugs used to treat the pain. […] Although the characteristics listed above are not specific for neuropathic pain mechanisms, taken together they do support this theory. […] The spontaneous and postprandial pain in chronic pancreatitis may reflect the characteristic stimulus independent and stimulus dependent pain features seen in patients with neuropathic pain.

• #2 Pain in chronic pancreatitis: the role of neuropathic pain mechanisms | Gut

  https://gut.bmj.com/content/57/11/1616

  Pain mechanisms in patients with chronic pancreatitis are incompletely understood and probably multifactorial. […] Recently, evidence from experimental human pain research has indicated that in many of these patients pain processing in the central nervous system is abnormal and mimics that seen in neuropathic pain disorders. […] The current review focuses on several lines of evidence supporting this hypothesis. […] Hence, the spontaneous and postprandial pain in chronic pancreatitis may reflect the characteristic pain features seen in patients with neuropathic pain. […] Biochemical and histopathological findings in tissues from patients with chronic pancreatitis are similar to those observed in patients with other nerve fibre lesions. […] Experimental studies have shown that patients with chronic pancreatitis show signs of spinal hyper-excitability counter-balanced by segmental and descending inhibition.

• #2 Pancreatic Cancer in Chronic Pancreatitis: Pathogenesis and Diagnostic Approach

  https://www.mdpi.com/2072-6694/15/3/761

  Chronic pancreatitis is one of the main risk factors for pancreatic cancer, but it is a rare event. […] Inflammation and oncogenes work hand in hand as key promoters of this disease. […] During alcoholic chronic pancreatitis, the cumulative risk of cancer is estimated at 4% after 15 to 20 years. […] The diagnosis is difficult due to: (i) clinical symptoms of cancer shared with those of chronic pancreatitis; (ii) the parenchymal and ductal remodeling of chronic pancreatitis rendering imaging analysis difficult; and (iii) differential diagnoses, such as pseudo-tumorous chronic pancreatitis and paraduodenal pancreatitis. […] CP is a risk factor for pancreatic ductal adenocarcinoma (PDAC). […] Clinical approach is peculiarly delicate and both positive and differential diagnosis of PDAC developed on CP is a real challenge due to the rather low specificity of symptoms, imaging signs, and biological markers.

• #2 Pancreatic Cancer in Chronic Pancreatitis: Pathogenesis and Diagnostic Approach

  https://www.mdpi.com/2072-6694/15/3/761

  Thus, activation of NF-κB and STAT3 has been shown to be essential for pancreatic cancer initiation and progression. […] Experimental evidence shows that adult mice that endogenously express oncogenic mutated KRAS in the acinar cell develop PanIN and PDAC lesions with higher penetrance when subjected to acute or chronic inflammation induced by cerulein. […] Pancreatic inflammation induced by cerulein injections increases the burden of PanINs and PDAC in transgenic mice bearing KRAS and p16INK4a or Trp53 mutations.

• #3 Pathogenesis and Treatment of Pain in Chronic Pancreatitis | Pancreapedia

  https://pancreapedia.org/reviews/pathogenesis-and-treatment-of-pain-in-chronic-pancreatitis

  This new neurobiological view of pain following CP is somewhat in opposition to the traditional view of pain aetiology, where pain was assumed to arise from pathology in or in close proximity to the pancreatic gland. […] Therefore, it is important to consider the different mechanisms, when evaluating the origin of pain in pancreatitis patients and it is plausible that the collective abdominal pain is a result of a complex interplay of several mechanisms. […] The novel and improved understanding of pain pathophysiology in CP advocates a paradigm shift in pain management. […] Pain sensation in CP includes a complex interaction between the peripheral and central nervous system. […] Both arms of the nervous system are known to undergo neuroplastic alterations during the chronic inflammation of the pancreas, and this neuroplasticity seems to contribute considerably to the chronic and intensive character of the neuropathic pain syndrome in CP.

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