Recent Insights Into the Pathogenic Mechanism of Pancreatitis

Gukovskaya, Anna S.; Gorelick, Fred S.; Groblewski, Guy E.; Mareninova, Olga A.; Lugea, Aurelia; Antonucci, Laura; Waldron, Richard T.; Habtezion, Aida; Karin, Michael; Pandol, Stephen J.; Gukovsky, Ilya

doi:10.1097/mpa.0000000000001298

Cited by 49 publications

(64 citation statements)

References 137 publications

(260 reference statements)

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“…A prospective analysis of 145 886 participants found that, among smokers, pancreatitis was highest among those who consumed more than four drinks a day (hazard ratio 2.06, 95% confidence interval 1.28 to 3.30) 11. Understanding of the mechanisms of pancreatitis and the roles of alcohol and smoking has increased and is covered in recent reviews 320…”

Section: Trends In Causes Of Pancreatitismentioning

confidence: 99%

Management of severe acute pancreatitis

Hines

Pandol

2019

BMJ

120

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The risks, measurements of severity, and management of severe acute pancreatitis and its complications have evolved rapidly over the past decade. Evidence suggests that initial goal directed therapy, nutritional support, and vigilance for pancreatic complications are best practice. Patients can develop pancreatic fluid collections including acute pancreatic fluid collections, pancreatic pseudocysts, acute necrotic collections, and walled-off necrosis. Several randomized controlled trials and cohort studies have recently highlighted the advantage of managing these conditions with a progressive approach, with initial draining for infection followed by less invasive techniques. Surgery is no longer an early intervention and may not be needed. Instead, interventional radiologic and endoscopic methods seem to be safer with at least as good survival outcomes. Newly developed evidence based quality indicators are available to assess and improve performance. Development and clinical testing of drugs to target the mechanisms of disease are necessary for further advancements.

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Section: Trends In Causes Of Pancreatitismentioning

confidence: 99%

Management of severe acute pancreatitis

Hines

Pandol

2019

BMJ

120

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“…The precise mechanisms of initiation and progression of CP are unclear. CP is considered to result from unresolved, recurrent fibroinflammation and is characterized by extensive loss of the normal exocrine parenchyma, widespread fibrosis and inflammation, and impairment of both exocrine and endocrine pancreatic functions (Majumder and Chari, 2016; Yang and Forsmark, 2017; Gukovskaya et al, 2019). Accumulating evidence supports the concept that pancreatitis is initiated in the pancreatic acinar cell, the main cell type in the exocrine parenchyma, with stresses causing cellular dysfunction that triggers activation of pro-inflammatory signaling, activation of neighboring quiescent pancreatic stellate cells (PaSC), and immune cell infiltration into the pancreas (Gukovskaya et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Yes-Associated Protein 1 Plays Major Roles in Pancreatic Stellate Cell Activation and Fibroinflammatory Responses

Yang

et al. 2019

Front. Physiol.

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Background: Yes-associated protein 1 (YAP), a transcriptional co-activator and major effector of the Hippo pathway, regulates cell differentiation and morphology in many cell types and supports aberrant tumor growth. Recent studies showed that YAP is expressed in pancreas tissues in pancreatic ductal adenocarcinoma (PDAC) patients and experimental models of PDAC, with YAP largely found in cancer cells and pancreatic stellate cells (PaSC) in the stroma.Methods and Results: We studied here the role of YAP in the activated phenotype of PaSC. We found that YAP is expressed at low levels in normal mouse pancreas, but protein levels significantly increased after pancreas inflammatory damage induced by repeated cerulein administration in wild-type mice or upon initiation of neoplastic transformation of the pancreas parenchyma in Ptf1-Cre;LSL-KrasG12D/+ (KC) mice. In these animal models, YAP upregulation occurred in parallel with activation and proliferation of PaSC. Consistent with these findings, we found robust YAP expression in culture-activated mouse and human PaSC but not in quiescent, freshly isolated cells. Fully activated PaSC isolated from KC mice or PDAC patient tissues exhibited robust nuclear YAP suggesting YAP transcriptional activity. Agents that induce quiescence such as the Bromodomain and Extra-Terminal (BET) inhibitor iBET151 and the p38 MAPK inhibitor SB203580 reduced YAP levels in PaSC. Stimulation of PaSC with the potent mitogen PDGF elicited marked YAP Ser127 phosphorylation. However, unexpectedly, this effect did not diminish YAP nuclear localization, suggesting that YAP phosphorylation at this site does not govern YAP cellular localization in PaSC. siRNA-mediated knockdown of YAP reduced PDGF-induced PaSC expansion in culture and blunted the persistent activation of Akt and ERK elicited by PDGF stimulation, supporting a role for YAP in PDGF-induced cell growth. YAP knockdown also blunted fibroinflammatory gene expression responses both in unstimulated and transforming growth factor beta 1 (TGFβ1)-stimulated PaSC.Conclusion: Our data suggest a central role for YAP in sustaining the activated phenotype and fibroinflammatory responses in PaSC. Moreover, our findings indicate that a complex crosstalk between YAP, TGFβ1, and PDGF pathways regulates PaSC activity and growth.

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“…In this study, we demonstrated that SPINK1 could inhibit intra-acinar trypsin activation via amelioration of impaired autophagy in cellular model of in vitro acute pancreatitis, a well-accepted AR42J-related AP setting nowadays. Since the past decade, researchers have noticed that impaired autophagy was existed during the development of acute pancreatitis [14,15 ], though the mechanisms was unraveled. On the other hand, SPINK1, as an active trypsin inhibitor, has been found to be a negative regulator of autophagy in normal pancreatic acinar cell, and the slightly enhanced trypsin activity can be detected in the isolated pancreatic acinar cells of SPINK1 knockout mouse pups [2,16].…”

Section: Discussionmentioning

confidence: 99%

SPINK1-induced amelioration of impaired autophagy contributes to suppression of trypsinogen activation in a model of acute pancreatitis

Zhao

Jia

Shopit

et al. 2020

Preprint

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SPINK1 has been regarded as a reversible trypsinogen inhibitor for the inappropriate activation of trypsin, a key step in the initiation of acute pancreatitis (AP). However, the mechanisms of its action remains largely unclear and controversial. Here, we reported an unexpected effects of SPINK1 on inhibiting trypsinogen activation through the regulation of impaired autophagy in cerulein-stimulated AR42J cells, a well-established in vitro model of acute pancreatitis. Firstly, we found that the impaired autophagic flux was induced and trypsinogen activity enhanced in the above setting. Then, we showed that SPINK1 overexpression could inhibit the level of increased autophagic activity, improving the hindered autophagy flux, and significantly decreased the trypsinogen activity, whereas shRNA-caused downregulation of SPINK1 exacerbated the impairment of autophagic flux and trypsin activity, in the same cerulein-processed cells. More importantly, the trypsinogen activation in this model could be ameliorated by 3-Methyladenine(3-MA), an autophagy inhibitor. Thus, this study revealed, possibly for the first time, that SPINK1 greatly blocked the trypsinogen activation possibly through the modulation of impaired autophagy in cerulein-induced in vitro model of acute pancreatitis.

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Recent Insights Into the Pathogenic Mechanism of Pancreatitis

Cited by 49 publications

References 137 publications

Management of severe acute pancreatitis

Management of severe acute pancreatitis

Yes-Associated Protein 1 Plays Major Roles in Pancreatic Stellate Cell Activation and Fibroinflammatory Responses

SPINK1-induced amelioration of impaired autophagy contributes to suppression of trypsinogen activation in a model of acute pancreatitis

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