The Acinar Cell and Early Pancreatitis Responses

doi:10.1016/j.cgh.2009.07.036

Clinical Gastroenterology and Hepatology

Volume 7, Issue 11, Supplement, November 2009, Pages S10-S14

https://doi.org/10.1016/j.cgh.2009.07.036 Get rights and content

Pathologic responses arising from the pancreatic acinar cell appear to have a central role in initiating acute pancreatitis. Environmental factors that sensitize the acinar cell to harmful stimuli likely have a critical role in many forms of pancreatitis, including that induced by alcohol abuse. Activation of zymogens within the acinar cell and an inhibition of secretion are critical, but poorly understood, early pancreatitis events. While there is firm evidence relating trypsinogen activation to pancreatitis, the importance of other zymogens has been less studied. Preliminary studies suggest that trypsin may be activated by mechanisms that are distinct from other zymogens. Further, unlike the small intestine, it may not catalyze the activation of other zymogens. These features could affect strategies aimed at inhibiting proteases to treat pancreatitis. Specific intracellular signals are required to activate pancreatitis pathways in the acinar cell. The most important is calcium. Recent studies have suggested that calcium release through specific calcium channels in the endoplasmic reticulum is the means by which pathological elevations in cytosolic calcium occur. Although the targets of abnormal calcium signaling are unknown, calcineurin, a calcium-dependent phosphatase, may serve such a role. Finally, recent work suggests that an acute acid load might sensitize the acinar cell to pancreatitis responses. Therapies aimed at preventing or reversing the effects of an acid load on the pancreas may be important for treatment.

Section snippets

Sensitization

One feature of acute pancreatitis is that the pathologic acinar cell responses that have been linked to disease often represent modifications of physiologic stimuli and cellular responses. As shown in Table 1, both neural and humoral pathways stimulate the acinar cell's physiologic response to a meal. Much like the nervous system's “excitatory neurotoxicity” response to supraphysiologic concentrations of endogenous ligands, supraphysiologic concentrations of cholecystokinin (CCK) cause

Zymogen Activation

A series of molecular and cellular mechanisms have developed to protect the pancreas from enzymes that are activated in the cell, especially proteases. First, many of the digestive enzymes, and all of the proteases, are synthesized and stored as inactive proproteins known as zymogens. Second, the storage of zymogens in zymogen granules limits their access to other acinar cell compartments should they become active. Under physiologic conditions, zymogens are converted to active enzymes only

Cell Signaling

Two pathologic intracellular signals in the acinar cell have been linked to the initiation of acute pancreatitis. First, acute changes in cytosolic Ca²⁺ signaling have been firmly associated with several forms of acute pancreatitis. Features of this abnormal signal include a loss of Ca²⁺ oscillations and the appearance of sustained elevated peak levels of cytosolic Ca²⁺. Although there are likely several mechanisms for developing this pathologic signal, it appears that a Ca²⁺ release channel in

Inhibition of Secretion

A recognized feature of acute pancreatitis is decreased secretion into the small intestine. A number of factors probably contribute to this response.¹⁸ These include reduced apical secretion from the acinar cell, enhanced basolateral secretion, and disruption of the paracellular barrier (Figure 2). These responses occur soon after the onset of disease.¹⁹ For example, reduced secretion from the acinar cell and disruption of the paracellular barrier can be observed within 15 minutes of disease

Low pH Effects

One of the features of zymogen activation in the pancreatic acinar cell is that it appears to require a low pH compartment. Early studies used purified enzyme preparations to demonstrate that the processing of trypsinogen to trypsin, through autoactivation or by cathepsin B, required an acidic pH.²³ Subsequent studies used chloroquine and monensin, drugs that nonselectively raise intracellular pH, to demonstrate that a low-pH compartment is required for activation of procarboxypeptidases,

Summary

Pathologic responses arising from the pancreatic acinar cell have a central role in initiating acute pancreatitis. Trypsinogen activation is a critical component of the disease. Although genetic studies unequivocally link trypsinogen mutations directly to pancreatitis and as a risk factor for developing disease, the impact of trypsin versus other proteases in disease pathogenesis remains unclear. There is growing evidence that the mechanisms for activating trypsinogen may differ from those that

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Cholecystokinin (CCK): a neuromodulator with therapeutic potential in Alzheimer's and Parkinson's disease
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Cholecystokinin (CCK) is a neuropeptide modulating digestion, glucose levels, neurotransmitters and memory. Recent studies suggest that CCK exhibits neuroprotective effects in Alzheimer’s disease (AD) and Parkinson’s disease (PD). Thus, we review the physiological function and therapeutic potential of CCK. The neuropeptide facilitates hippocampal glutamate release and gates GABAergic basket cell activity, which improves declarative memory acquisition, but inhibits consolidation. Cortical CCK alters recognition memory and enhances audio-visual processing. By stimulating CCK-1 receptors (CCK-1Rs), sulphated CCK-8 elicits dopamine release in the substantia nigra and striatum. In the mesolimbic pathway, CCK release is triggered by dopamine and terminates reward responses via CCK-2Rs. Importantly, activation of hippocampal and nigral CCK-2Rs is neuroprotective by evoking AMPK activation, expression of mitochondrial fusion modulators and autophagy. Other benefits include vagus nerve/CCK-1R-mediated expression of brain-derived neurotrophic factor, intestinal protection and suppression of inflammation. We also discuss caveats and the therapeutic combination of CCK with other peptide hormones.
Mitochondrial dysfunction in the pathogenesis of acute pancreatitis
2024, Hepatobiliary and Pancreatic Diseases International
The mechanism of cell damage during acute pancreatitis (AP) has not been fully elucidated, and there is still a lack of specific or effective treatments. Increasing evidence has implicated mitochondrial dysfunction as a key event in the pathophysiology of AP. Mitochondrial dysfunction is closely related to calcium (Ca²⁺) overload, intracellular adenosine triphosphate depletion, mitochondrial permeability transition pore openings, loss of mitochondrial membrane potential, mitophagy damage and inflammatory responses. Mitochondrial dysfunction is an early triggering event in the initiation and development of AP, and this organelle damage may precede the release of inflammatory cytokines, intracellular trypsin activation and vacuole formation of pancreatic acinar cells. This review provides further insight into the role of mitochondria in both physiological and pathophysiological aspects of AP, aiming to improve our understanding of the underlying mechanism which may lead to the development of therapeutic and preventive strategies for AP.
Decreased neutrophil counts prolong inflammation in acute pancreatitis and cause inflammation spillover to distant organs
2023, Pancreatology
Acute pancreatitis is an aseptic inflammation caused by pathologically activated pancreatic enzymes and inflammatory mediators produced secondarily by neutrophils and other inflammatory cells and is one of the most difficult diseases to treat. This study aimed to investigate the role of neutrophils in pancreatitis by examining tissue dynamics.
We created a model of caerulein-induced pancreatitis in 12-week-old male granulocyte colony-stimulating factor knockout mice (G–CSF–KO) and wild-type littermate control mice (six intraperitoneal injections of caerulein [80 μg/kg body weight] at hourly intervals for 2 days). Mice were sacrificed 0, 3, 6, 12, 24, 36, 48, 72, and 168 h after caerulein administration and examined histologically.
The survival rate after one week of caerulein administration was 100 % in the control mice, whereas it was significantly lower (10 %) in the G–CSF–KO mice. Histological examination revealed significant hemorrhage and inflammatory cell migration in the G–CSF–KO mice, indicating prolonged inflammation.
Prolonged inflammation was observed in the G–CSF–KO mice. Tissue cleanup by neutrophils during the acute phase of inflammation may influence healing through the chronic phase.
Estimation of exocrine pancreatic insufficiency in children with acute pancreatitis using the <sup>13</sup>C mixed triglyceride breath test
2023, Pancreatology
/Objective: The extent of exocrine pancreatic insufficiency (EPI) in the paediatric population with acute pancreatitis (AP) is unknown. The primary objective was to use a 6 h stable-isotope breath test to determine the prevalence of EPI in children with AP. The secondary objective was to determine the diagnostic ability of a 4 h abbreviated breath test in the detection of EPI.
¹³C-mixed triglyceride (MTG) breath test was used to measure fat digestibility in 12 children with AP and 12 normal children. EPI was diagnosed based on a cumulative dose percentage recovery (cPDR) cut-off value < 26.8% present in literature. To reduce the test burden, the diagnostic accuracy of an abbreviated 4 h test was evaluated, using a cPDR cut-off that was the 2.5^th percentile of its distribution in control children.
The cPDR of cases was significantly lower than that of controls (27.71 ± 7.88% vs 36.37 ± 4.70%, p = 0.005). The cPDR during acute illness was not significantly different to that at 1 month follow up (24.69 ± 6.83% vs 26.98 ± 11.10%, p = 0.52). The 4 h and 6 h breath test results correlated strongly (r = 0.93, p < 0.001) with each other. The new 4 h test had 87.5% sensitivity and 93.8% specificity for detecting EPI.
Two-thirds (66.7%) of this sample of children with AP had EPI during admission, which persisted at 1 month follow up. The 4 h abbreviated ¹³C-MTG breath test has good diagnostic ability to detect EPI in children and may improve its clinical utility in this age group.
High Clinical and Genetic Similarity Between Chronic Pancreatitis Associated With Light-to-Moderate Alcohol Consumption and Classical Alcoholic Chronic Pancreatitis
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Genetic Variants Associated With Increased Plasma Levels of Triglycerides, via Effects on the Lipoprotein Lipase Pathway, Increase Risk of Acute Pancreatitis
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Almost one third of adults in the West have increased plasma levels of triglycerides. Even mild to moderate hypertriglyceridemia (2–10 mmol/L or 177–886 mg/dL) is associated with an increased risk of acute pancreatitis. However, it is not clear whether hypertriglyceridemia is a cause or result of acute pancreatitis. Lipoprotein lipase degrades plasma triglycerides. Variants in LPL, APOA5, APOC3, ANGPTL3, and ANGPTL4, which regulate the lipoprotein lipase pathway, result in increased or reduced plasma triglyceride levels. We investigated associations between these variants and acute pancreatitis in a study of the general population.
In a prospective cohort study, men and women randomly selected from the area of Copenhagen were invited to complete a questionnaire, undergo a physical examination, and provide blood samples for biochemical and genetic analyses, from 2003 through 2015. We obtained triglyceride measurements from 117,427 participants. We examined for 15 genetic variants that are associated with lipoprotein lipase function in DNA samples from 102,888 participants and analyzed data from 117,427 participants in observational analyses. Diagnoses of acute pancreatitis (970 diagnoses among participants in the genetic analysis and 527 among participants in the observational study) were obtained from Danish registries. We performed a 1-sample Mendelian randomization analysis in which specific variants were used as markers of the plasma level of triglycerides to determine the association between the plasma level of triglyceride and acute pancreatitis. We calculated unweighted, internally weighted, and externally weighted allele scores for each participant by adding numbers of triglyceride-increasing alleles.
The highest genetic allele score correlated with a higher plasma level of triglycerides of 0.54 mmol/L (48 mg/dL). Among participants with the highest vs the lowest genetic allele score, the odds ratio for acute pancreatitis was 1.55 (95% CI, 1.08–2.23). Using instrumental variable analysis, integrating the effect of genotype on both triglycerides levels and risk of acute pancreatitis, we associated higher unweighted allele scores with an increased risk of acute pancreatitis (odds ratio [OR], 1.76; 95% CI, 1.16–2.65), as well as internally weighted higher allele scores (OR, 1.41; 95% CI, 1.01–1.97) and externally weighted higher allele scores (OR, 1.44; 95% CI, 1.01–2.04). Every 1 mmol/L (89 mg/dL) increase in triglycerides was observationally associated with an increase in OR of 1.09 (95% CI, 1.05–1.14) after multivariable adjustment.
Based on an analysis of individuals with genetic variants associated with an increased level of triglycerides, via their effects on the lipoprotein lipase pathway, we associated an increased plasma levels of triglycerides with an increased risk of acute pancreatitis. Strategies to reduce plasma levels of triglycerides, by increasing lipoprotein lipase function, might be developed for prevention of acute pancreatitis.

View all citing articles on Scopus

: Conflict of interest The authors disclose no conflicts.

: Funding Funding from the NIH DK54021 and a Veterans Administration Merit Award.

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The Acinar Cell and Early Pancreatitis Responses

Section snippets

Sensitization

Zymogen Activation

Cell Signaling

Inhibition of Secretion

Low pH Effects

Summary

Gastroenterology

Gastroenterology

Gastroenterology

Endocrinol Metab Clin North Am

Gastroenterology

J Biol Chem

Gastroenterology

Gastroenterology

J Biol Chem

Am J Gastroenterol

J Biol Chem

Effect of ethanol on cholecystokinin-stimulated zymogen conversion in pancreatic acinar cells

Am J Physiol

Hereditary pancreatitis is caused by a mutation on the cationic trypsinogen gene

Nat Genet

Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis

Nat Genet

Zymogen activation in a reconstituted pancreatic acinar cell system

Am J Physiol Gastrointest Liver Physiol

Involvement of autophagy in trypsinogen activation within the pancreatic acinar cells

J Cell Biol

Impaired autolysosome formation correlates with Lamp-2 depletion: role of apoptosis, autophagy, and necrosis in pancreatitis

Gastroenterology

The ryanodine receptor mediates early zymogen activation in pancreatitis

Proc Natl Acad Sci U S A