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Current Opinion in Gastroenterology Sep 2012In this article, recent advances in the pathogenesis of acute pancreatitis have been reviewed. (Review)
Review
PURPOSE OF REVIEW
In this article, recent advances in the pathogenesis of acute pancreatitis have been reviewed.
RECENT FINDINGS
Pathologic intra-acinar trypsinogen activation had been hypothesized to be the central mechanism of pancreatitis for over a century. This hypothesis could be explored for the first time with the development of a novel mouse model lacking pathologic intra-acinar trypsinogen activation. It became clear that intra-acinar trypsinogen activation contributes to early acinar injury, but local and systemic inflammation progress independently during pancreatitis. Early intra-acinar nuclear factor kappa B (NFκB) activation, which occurs parallel to but independent of trypsinogen activation, may be crucial in pancreatitis. Although the mechanism of NFκB and trypsinogen activation is not entirely clear, further insights have been made into key pathogenic cellular events such as calcium signaling, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, autophagy and impaired trafficking, and lysosomal and secretory responses. Cellular intrinsic damage-sensing mechanisms that lead to activation of the inflammatory response aimed at repair, but lead to disease when overwhelmed, are beginning to be understood.
SUMMARY
New findings necessitate a paradigm shift in our understanding of acute pancreatitis. Intra-acinar trypsinogen activation leads to early pancreatic injury, but the inflammatory response of acute pancreatitis develops independently, driven by early activation of inflammatory pathways.
Topics: Acinar Cells; Animals; Autophagy; Calcium; Humans; Inflammasomes; Mitochondria; NF-kappa B; Pancreatitis; Trypsinogen
PubMed: 22885948
DOI: 10.1097/MOG.0b013e3283567f52 -
Postgraduate Medical Journal Dec 2006Trypsin activity is properly suppressed by pancreatic secretory trypsin inhibitor (PSTI), which is also known as serine protease inhibitor Kazal type 1 (SPINK1), thereby... (Review)
Review
Trypsin activity is properly suppressed by pancreatic secretory trypsin inhibitor (PSTI), which is also known as serine protease inhibitor Kazal type 1 (SPINK1), thereby preventing damage to pancreatic acinar cells as a first line of defence. However, if trypsin activation exceeds the capacity of PSTI/SPINK1, a subsequent cascade of events leads to the activation of various proteases that damage cells. Five mutations (R122H, N29I, A16V, D22G and K23R) in cationic trypsinogen and two mutations (N34S and M1T) in the PSTI/SPINK1 gene have been found to correlate significantly with the onset of pancreatitis. From analyses of hereditary pancreatitis and the phenotype of PSTI/SPINK1 (Spink3) knockout mice, we showed that the imbalance of trypsin activation and its inhibition by PSTI/SPINK1 would lead to the development of pancreatitis.
Topics: Animals; Carrier Proteins; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mice; Mutation; Pancreatitis; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen
PubMed: 17148697
DOI: 10.1136/pgmj.2006.050591 -
Romanian Journal of Gastroenterology Mar 2005The understanding of pathogenesis of acute and chronic pancreatitis has benefited from the progress made in genetic investigations. The discoveries of the gain of... (Review)
Review
The understanding of pathogenesis of acute and chronic pancreatitis has benefited from the progress made in genetic investigations. The discoveries of the gain of function mutations of cationic trypsinogen gene (PRSS1) and the loss of function mutations of pancreatic secretory trypsin inhibitor (SPINK 1) or other potential defects in genes that regulate pancreatic secretory function or modulate inflammatory response to pancreatic injury has changed our current concepts on the pathogenesis of pancreatitis. Genetic factors play an important role in the susceptibility to pancreatic injury, severity and evolution of inflammatory process, leading in some cases to chronic inflammation and/or fibrosis. Acute pancreatitis is viewed as an event and chronic pancreatitis as a process, sequentially linked, reflecting a complex interaction between genetic and environmental factors.
Topics: Carrier Proteins; Cystic Fibrosis Transmembrane Conductance Regulator; DNA Mutational Analysis; Fibrosis; Genetic Predisposition to Disease; Genetic Testing; Humans; Inflammation; Pancreas; Pancreatitis; Trypsin; Trypsin Inhibitor, Kazal Pancreatic; Trypsinogen
PubMed: 15800694
DOI: No ID Found -
World Journal of Gastroenterology Jan 2019Rapid urinary trypsinogen-2 dipstick test and levels of urinary trypsinogen-2 and trypsinogen activation peptide (TAP) concentration have been reported as prognostic...
BACKGROUND
Rapid urinary trypsinogen-2 dipstick test and levels of urinary trypsinogen-2 and trypsinogen activation peptide (TAP) concentration have been reported as prognostic markers for the diagnosis of acute pancreatitis.
AIM
To reconfirm the validity of all these markers in the diagnosis of acute pancreatitis by undertaking a multi-center study in Japan.
METHODS
Patients with acute abdominal pain were recruited from 17 medical institutions in Japan from April 2009 to December 2012. Urinary and serum samples were collected twice, at enrollment and on the following day for measuring target markers. The diagnosis and severity assessment of acute pancreatitis were assessed based on prognostic factors and computed tomography (CT) Grade of the Japanese Ministry of Health, Labour, and Welfare criteria.
RESULTS
A total of 94 patients were enrolled during the study period. The trypsinogen-2 dipstick test was positive in 57 of 78 patients with acute pancreatitis (sensitivity, 73.1%) and in 6 of 16 patients with abdominal pain but without any evidence of acute pancreatitis (specificity, 62.5%). The area under the curve (AUC) score of urinary trypsinogen-2 according to prognostic factors was 0.704, which was highest in all parameter. The AUC scores of urinary trypsinogen-2 and TAP according to CT Grade were 0.701 and 0.692, respectively, which shows higher than other pancreatic enzymes. The levels of urinary trypsinogen-2 and TAP were significantly higher in patients with extended extra-pancreatic inflammation as evaluated by CT Grade.
CONCLUSION
We reconfirmed urinary trypsinogen-2 dipstick test is useful as a marker for the diagnosis of acute pancreatitis. Urinary trypsinogen-2 and TAP may be considered as useful markers to determine extra-pancreatic inflammation in acute pancreatitis.
Topics: Adult; Aged; Aged, 80 and over; Area Under Curve; Biomarkers; Female; Humans; Japan; Male; Middle Aged; Oligopeptides; Pancreatitis; Prognosis; Prospective Studies; Retrospective Studies; Severity of Illness Index; Trypsin; Trypsinogen
PubMed: 30643362
DOI: 10.3748/wjg.v25.i1.107 -
Current Opinion in Lipidology Apr 2023Not all patients with severe hypertriglyceridemia develop acute pancreatitis. We surveyed recent literature on inter-individual genetic variation in susceptibility to... (Review)
Review
PURPOSE OF REVIEW
Not all patients with severe hypertriglyceridemia develop acute pancreatitis. We surveyed recent literature on inter-individual genetic variation in susceptibility to pancreatitis.
RECENT FINDINGS
Genetic determinants of pancreatitis include: rare Mendelian disorders caused by highly penetrant pathogenic variants in genes involved in trypsinogen activation; uncommon susceptibility variants in genes involved in trypsinogen activation, protein misfolding as well as calcium metabolism and cystic fibrosis, that have variable penetrance and show a range of odds ratios for pancreatitis; and common polymorphisms in many of the same genes that have only a small effect on risk. The role of these genetic variants in modulating pancreatitis risk in hypertriglyceridemia is unclear. However, among genetic determinants of plasma triglycerides, those predisposing to more severe hypertriglyceridemia associated with chylomicronemia appear to have higher pancreatitis risk.
SUMMARY
Currently, among patients with severe hypertriglyceridemia, the most consistent predictor of pancreatitis risk is the triglyceride level. Furthermore, pancreatitis risk appears to be modulated by a higher genetic burden of factors associated with greater magnitude of triglyceride elevation. The role of common and rare genetic determinants of pancreatitis itself in this metabolic context is unclear.
Topics: Humans; Pancreatitis; Acute Disease; Trypsinogen; Hypertriglyceridemia; Triglycerides
PubMed: 36752614
DOI: 10.1097/MOL.0000000000000866 -
Nature Communications Nov 2022Enteropeptidase (EP) initiates intestinal digestion by proteolytically processing trypsinogen, generating catalytically active trypsin. EP dysfunction causes a series of...
Enteropeptidase (EP) initiates intestinal digestion by proteolytically processing trypsinogen, generating catalytically active trypsin. EP dysfunction causes a series of pancreatic diseases including acute necrotizing pancreatitis. However, the molecular mechanisms of EP activation and substrate recognition remain elusive, due to the lack of structural information on the EP heavy chain. Here, we report cryo-EM structures of human EP in inactive, active, and substrate-bound states at resolutions from 2.7 to 4.9 Å. The EP heavy chain was observed to clamp the light chain with CUB2 domain for substrate recognition. The EP light chain N-terminus induced a rearrangement of surface-loops from inactive to active conformations, resulting in activated EP. The heavy chain then served as a hinge for light-chain conformational changes to recruit and subsequently cleave substrate. Our study provides structural insights into rearrangements of EP surface-loops and heavy chain dynamics in the EP catalytic cycle, advancing our understanding of EP-associated pancreatitis.
Topics: Humans; Enteropeptidase; Cryoelectron Microscopy; Trypsinogen; Trypsin
PubMed: 36376282
DOI: 10.1038/s41467-022-34364-9 -
Scientific Reports Oct 2018The domestic ferret (Mustela putorius furo) recently emerged as a novel model for human pancreatic diseases. To investigate whether the ferret would be appropriate to...
The domestic ferret (Mustela putorius furo) recently emerged as a novel model for human pancreatic diseases. To investigate whether the ferret would be appropriate to study hereditary pancreatitis associated with increased trypsinogen autoactivation, we purified and cloned the trypsinogen isoforms from the ferret pancreas and studied their functional properties. We found two highly expressed isoforms, anionic and cationic trypsinogen. When compared to human cationic trypsinogen (PRSS1), ferret anionic trypsinogen autoactivated only in the presence of high calcium concentrations but not in millimolar calcium, which prevails in the secretory pathway. Ferret cationic trypsinogen was completely defective in autoactivation under all conditions tested. However, both isoforms were readily activated by enteropeptidase and cathepsin B. We conclude that ferret trypsinogens do not autoactivate as their human paralogs and cannot be used to model the effects of trypsinogen mutations associated with human hereditary pancreatitis. Intra-pancreatic trypsinogen activation by cathepsin B can occur in ferrets, which might trigger pancreatitis even in the absence of trypsinogen autoactivation.
Topics: Animals; Chromatography, Ion Exchange; Cloning, Molecular; Enzyme Activation; Female; Ferrets; Genome; Isoenzymes; Pancreas; Proteolysis; Recombinant Proteins; Sequence Analysis, DNA; Substrate Specificity; Trypsinogen
PubMed: 30305676
DOI: 10.1038/s41598-018-33423-w -
The FEBS Journal Oct 2021An enigmatic and never described hyper-reactivity of most of the cysteines resident in the reduced, molten globule-like intermediate of a few proteins has been recently...
An enigmatic and never described hyper-reactivity of most of the cysteines resident in the reduced, molten globule-like intermediate of a few proteins has been recently discovered. In particular, all ten cysteines of chymotrypsinogen showed hundred times increased reactivity against hydrophobic reagents. A single cysteine (Cys1) was also found thousand times more reactive toward GSSG, making speculate that a single glutathionylation could represent the primordial event of its oxidative folding. In the present study, we compare these kinetic properties with those present in trypsinogen taken in its reduced, molten globule-like intermediate and identify the origin of these unusual properties. Despite the divergent evolution of these two proteins, the different amount of disulfides and the very different 3D localization of three disulfides, their hyper-reactivity toward hydrophobic thiol reagents and disulfides is very similar. Mass spectrometry identifies two cysteines in trypsinogen, Cys148 and Cys197, 800 times more reactive toward GSSG than an unperturbed protein cysteine. These results point toward a stringent and accurate preservation of these peculiar kinetic properties during a divergent evolution suggesting some important role, which at the present can only be hypothesized. Similar extraordinary hyper-reactivity has been found also in albumin, ribonuclease, and lysozyme confirming that it cannot be considered a kinetic singularity of a single protein. Interestingly, the very flexible and fluctuating structures like those typical of the molten globule status prove capable of enabling sophisticated actions typical of enzymes such as binding to GSSG with relevant specificity and high affinity (K = 0.4 mm) and accelerating the reaction of its cysteines by thousands of times.
Topics: Chymotrypsinogen; Cysteine; Disulfides; Evolution, Molecular; Glutathione; Humans; Oxidation-Reduction; Protein Folding; Trypsinogen
PubMed: 33876866
DOI: 10.1111/febs.15886 -
Nature Communications Dec 2022The progression of cancer from localized to metastatic disease is the primary cause of morbidity and mortality. The interplay between the tumor and its microenvironment...
The progression of cancer from localized to metastatic disease is the primary cause of morbidity and mortality. The interplay between the tumor and its microenvironment is the key driver in this process of tumor progression. In order for tumors to progress and metastasize they must reprogram the cells that make up the microenvironment to promote tumor growth and suppress endogenous defense systems, such as the immune and inflammatory response. We have previously demonstrated that stimulation of Tsp-1 in the tumor microenvironment (TME) potently inhibits tumor growth and progression. Here, we identify a novel tumor-mediated mechanism that represses the expression of Tsp-1 in the TME via secretion of the serine protease PRSS2. We demonstrate that PRSS2 represses Tsp-1, not via its enzymatic activity, but by binding to low-density lipoprotein receptor-related protein 1 (LRP1). These findings describe a hitherto undescribed activity for PRSS2 through binding to LRP1 and represent a potential therapeutic strategy to treat cancer by blocking the PRSS2-mediated repression of Tsp-1. Based on the ability of PRSS2 to reprogram the tumor microenvironment, this discovery could lead to the development of therapeutic agents that are indication agnostic.
Topics: Humans; Thrombospondin 1; Tumor Microenvironment; Neoplasms; Trypsin; Trypsinogen
PubMed: 36575174
DOI: 10.1038/s41467-022-35649-9 -
Current Opinion in Gastroenterology Sep 2013In this article, we review important advances in our understanding of the mechanisms of pancreatitis. (Review)
Review
PURPOSE OF REVIEW
In this article, we review important advances in our understanding of the mechanisms of pancreatitis.
RECENT FINDINGS
The relative contributions of intrapancreatic trypsinogen activation and nuclear factor kappa B (NFκB) activation, the two major early independent cellular events in pancreatitis, have been investigated using novel genetic models. Trypsinogen activation has traditionally held the spotlight for many decades as the central pathogenic event of pancreatitis. However, recent experimental evidence points to the role of trypsin activation in early acinar cell damage but not in the inflammatory response of acute pancreatitis, which was shown to be induced by NFκB activation. Further, chronic pancreatitis developed independently of trypsinogen activation in the caerulein model. Sustained NFκB activation, but not persistent intra-acinar expression of active trypsin, was shown to result in chronic pancreatitis. Calcineurin-NFAT (nuclear factor of activated T-cells) signaling was shown to mediate downstream effects of pathologic rise in intracellular calcium. Interleukin-6 was identified as a key cytokine mediating pancreatitis-associated lung injury.
SUMMARY
Recent advances challenge the long-believed trypsin-centered understanding of pancreatitis. It is becoming increasingly clear that activation of intense inflammatory signaling mechanisms in acinar cells is crucial to the pathogenesis of pancreatitis, which may explain the strong systemic inflammatory response in pancreatitis.
Topics: Acute Disease; Genetic Predisposition to Disease; Humans; Mutation; NF-kappa B; Pancreatitis; Pancreatitis, Chronic; Signal Transduction; Systemic Inflammatory Response Syndrome; Trypsin; Trypsinogen
PubMed: 23892538
DOI: 10.1097/MOG.0b013e328363e399