Early Intra-Acinar Events in Pathogenesis of Pancreatitis

Saluja, Ashok K.; Dudeja, Vikas; Dawra, Rajinder; Sah, Raghuwansh P.

doi:10.1053/j.gastro.2019.01.268

Cited by 177 publications

(171 citation statements)

References 165 publications

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“…Injured acinar cells initiate inflammatory responses by releasing proinflammatory cytokines, digestive enzymes, and nuclear damage-associated molecular patterns molecules, which attract and activate immune cell to exacerbate tissue injury 20, 21 . It has been demonstrated that pancreatic acinar cells undergo necrosis when exposed to supraphysiological cerulein in vitro 22 .…”

Section: Resultsmentioning

confidence: 99%

PRDM3 attenuates pancreatitis and pancreatic tumorigenesis by regulating inflammatory response

Huang

Wang

et al. 2019

Preprint

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2Pancreatic ductal adenocarcinoma (PDAC) is associated with metaplastic changes in the 3 pancreas but the transcriptional program underlying these changes is incompletely understood. 4The zinc finger transcription factor, PRDM3, is lowly expressed in normal pancreatic acini and 5 its expression increases during tumorigenesis. Although PRDM3 promotes proliferation and 6 migration of PDAC cell lines, the role of PRDM3 during tumor initiation from pancreatic acinar 7 cells in vivo is unclear. In this study, we showed that high levels of PRDM3 expression in human 8 pancreas was associated with pancreatitis, and well-differentiated but not poorly differentiated 9 carcinoma. We examined PRDM3 function in pancreatic acinar cells during tumor formation and 10 pancreatitis by inactivating Prdm3 using a conditional allele (Ptf1a CreER ;Prdm3 flox/flox mice) in the 11 context of oncogenic Kras expression and supraphysiological cerulein injections, respectively. In 12Prdm3-deficient mice, Kras G12D -driven preneoplastic lesions were more abundant and progressed 13 to high-grade precancerous lesions more rapidly. This is consistent with our observations that 14 low levels of PRDM3 in human PDAC was correlated significantly with poorer survival in patient. 15Moreover, loss of Prdm3 in acinar cells elevated exocrine injury, enhanced immune cell 16 activation and infiltration, and greatly increased acinar-to-ductal cell reprogramming upon 17 cerulein-induced pancreatitis. Whole transcriptome analyses of Prdm3 knockout acini revealed 18 that pathways involved in inflammatory response and Hif-1 signaling were significantly 19 upregulated in Prdm3-depleted acinar cells. Taken together, our results suggest that Prdm3 20 favors the maintenance of acinar cell homeostasis through modulation of their response to 21 inflammation and oncogenic Kras activation, and thus plays a previously unexpected suppressive 22 role during PDAC initiation. 23

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Section: Resultsmentioning

confidence: 99%

PRDM3 attenuates pancreatitis and pancreatic tumorigenesis by regulating inflammatory response

Huang

Wang

et al. 2019

Preprint

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“…Immune-related digestive system inflammation, including colitis, hepatitis, pancreatitis, can be caused by a variety of pathogenic factors, such as genetic abnormality, autoimmune factors, immune-related drugs, viral infections, and so on (1)(2)(3)(4). PD-L1(B7-H1) is thought to be involved in the regulation of cellular and humoral immune responses through the PD-1 receptor on activated T and B cells (5,6).…”

Section: Introductionmentioning

confidence: 99%

The Risk Ratio of Immune-Related Colitis, Hepatitis, and Pancreatitis in Patients With Solid Tumors Caused by PD-1/PD-L1 Inhibitors: A Systematic Review and Meta-Analysis

et al. 2020

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Purpose: The meta-analysis was put into practice in evaluating the risk ratio of immune-related digestive system inflammation in patients with solid tumors caused by PD-1/PD-L1 inhibitors.Method: The process of the meta-analysis was performed by us according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.Results: After screening and eligibility assessment, a total of 26 clinical trials involving 16,409 patients were selected for the final quantitative synthesis. Immune-related digestive system inflammations, including colitis, hepatitis, pancreatitis, were evaluated separately. Compared with chemotherapy, PD-1/PD-L1 inhibitors led to an increase in the incidence risk of all grade colitis (RR = 2.43, 95% CI: [1.23, 4.82], P = 0.01). Similar incidence trend could also be seen when PD-1/PD-L1 inhibitors were combined with chemotherapy (RR = 2.62, 95% CI: [1.25, 5.48], P = 0.01). Whether compared with Nivolumab plus Ipilimumab or Ipilimumab alone, the incidence risk of colitis in the Nivolumab group was significantly lower than that of the control group. Similar analysis results could also be seen in the incidence risk of hepatitis. We did not find a statistically significant effect on the incidence of immune-related pancreatitis after the use of PD-1/PD-L1 inhibitors.Tian et al.Inflammation and Anti-PD-1/PD-L1 Therapy Conclusion: The use of PD-1/PD-L1 inhibitors increased the incidence risk of immune-related colitis and hepatitis, but this potential to increase the incidence risk of the disease was weaker than Ipilimumab.

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“…The mechanisms in the pathogenesis of acute pancreatitis (AP) remains incompletely understood. SPINK1, serine protease inhibitor Kazal-type 1, was originally identified as a reversible inhibitor of accumulated active trypsin produced in the triggering step of AP [1].…”

Section: Introductionmentioning

confidence: 99%

“…Thus, the occurrence of autophagy in AP was likely associated with activation of the zymogen granules, while SPINK1's presence was possibly related to regulation of the autophagic event of the disease [8]. In acute pancreatitis, it is generally accepted that the premature and intrapancreatic activation of trypsinogen is an early triggering step for the disease [1,4]. However, the mechanisms or intermediate links by which SPINK1 blocks trypsin activation in the pancreas remains largely unknown.…”

Section: Introductionmentioning

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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Early Intra-Acinar Events in Pathogenesis of Pancreatitis

Cited by 177 publications

References 165 publications

PRDM3 attenuates pancreatitis and pancreatic tumorigenesis by regulating inflammatory response

PRDM3 attenuates pancreatitis and pancreatic tumorigenesis by regulating inflammatory response

The Risk Ratio of Immune-Related Colitis, Hepatitis, and Pancreatitis in Patients With Solid Tumors Caused by PD-1/PD-L1 Inhibitors: A Systematic Review and Meta-Analysis

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

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