Role of proteases and antiprotease in the etiology of chronic pancreatitis

Kavutharapu, Srimanjari; Balakrishna, Nagalla; Abbagani, Vidyasagar; Porika, Shravan Kumar; Jyothy, A.; Nallari, Pratibha; Ananthapur, Venkateshwari

doi:10.4103/1319-3767.103427

Cited by 9 publications

(5 citation statements)

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“…[ 22 ] Ca 2+ -activated phosphatase and proteases are the targets of acinar cell Ca 2+ signaling generated during pancreatitis. [ 2 ] Calcineurin inhibitors can result in decreased zymogen activation. The first step of AP is characterized by Ca 2+ -mediated enzymatic activation, followed by a systemic inflammatory response as a second step.…”

Section: Premature Trypsinogen Activation In the Onset Of Pancreatitimentioning

confidence: 99%

“…[ 34 ] Inflammatory responses inhibit apoptosis during acute pancreatitis. [ 2 ] A study has shown that neutrophils play a role in the pathologic activation of digestive enzymes in AP through NADPH-oxidase dependent way. [ 35 ] Intrapancreatic activation of trypsinogen may also induce NFκB signaling.…”

Section: Premature Trypsinogen Activation In the Onset Of Pancreatitimentioning

confidence: 99%

“…The decreased activity of antitrypsin may lead to trypsinogen activation, which in turn drives inflammatory responses, and further activates the pancreatic stellate cells resulting in fibrosis. [ 2 ] This could further alter the balance between the synthesis and degradation of trypsin–antitrypsin system that subsequently leads to CP. We used to regard trypsin only as a protein-degrading enzyme; however, evidence now suggests that AAT is also a signaling molecule that plays an important role in modulating immunity, inflammation, coagulation, and apoptosis.…”

Section: Trypsin–antitrypsin Imbalance In Injury and Inflammationmentioning

confidence: 99%

“…Owing to its physiological functions, acinar cells are subjected to a high risk of autodigestion. [ 1 2 3 ] Under normal conditions, defensive coping mechanisms are sufficient to fully protect acinar cells from inappropriate activation of digestive zymogens. When stimuli overwhelm compensatory mechanisms or compensation reactions become excessive, pancreatic destruction and disease ensue.…”

mentioning

confidence: 99%

“…The etiological risk factors of pancreatitis are various, and include genetic background, environmental factors (eg., alcohol consumption, high-fat diets, hypercalcemia, drugs),[ 1 ] biliary obstruction and autoimmune factors. [ 2 3 4 ] It is presumed that exposure to these risk factors may result in premature enzyme activation that cause acute injury of acinar cells, duct cells, or interstitial mesenchymal cells, which if continued, leads to inflammatory responses with the activation of pancreatic stellate cells, resulting in extracellular matrix deposition and mediating fibrosis. [ 5 ] Chronic pancreatitis (CP) is believed to be the result from repeated attacks of acute pancreatitis (AP), and is characterized by persistent inflammation, acinar cell destruction as well as irreversible fibrotic replacement, leading to impaired endocrine and exocrine functions.…”

mentioning

confidence: 99%

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Framework for interpretation of trypsin-antitrypsin imbalance and genetic heterogeneity in pancreatitis

Lin

Gao

Chen

et al. 2015

Saudi J Gastroenterol

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Early intracellular premature trypsinogen activation was interpreted as the key initiator of pancreatitis. When the balance in the homeostasis of trypsin and antitrypsin system is disequilibrated, elevated aggressive enzymes directly attack the pancreatic tissue, which leads to pancreatic destruction and inflammation. However, trypsin alone is not enough to cause complications in pancreatitis, which may play a crucial role in modulating signaling events in the initial phase of the disease. NFκB activation is the major inflammatory pathway involved in the occurrence and development of pancreatitis and it can be induced by intrapancreatic activation of trypsinogen. Synthesis of trypsinogen occurs in endoplasmic reticulum (ER), and ER stress is an important early acinar cell event. Components of ER stress response are known to be able to trigger cell death as well as NFκB signaling cascade. The strongest evidence supporting the trypsin-centered theory is that gene mutations, which lead to the generation of more trypsin, or reduce the activity of trypsin inhibitors or trypsin degradation, are associated with pancreatitis. Thus, trypsin–antitrypsin imbalance may be the first step leading to pancreatic autodigestion and inducing other pathways. Continued experimental studies are necessary to determine the specific relationships between trypsin–antitrypsin imbalance and genetic heterogeneity in pancreatitis. In this article, we review the latest advances that contributed to the understanding of the basic mechanisms behind the occurrence and development of pancreatitis with a focus on the interpretation of trypsin–antitrypsin imbalance and their relationships with other inflammation pathways. We additionally highlight genetic predispositions to pancreatitis and possible mechanisms associated with them.

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Section: Premature Trypsinogen Activation In the Onset Of Pancreatitimentioning

confidence: 99%