Role of Intrapancreatic SPINK1/Spink3 Expression in the Development of Pancreatitis

Ohmuraya, Masaki; Sugano, Aki; Hirota, Masahiko; Takaoka, Yutaka; Yamamura, Ken Ichi

doi:10.3389/fphys.2012.00126

Cited by 27 publications

(25 citation statements)

References 78 publications

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“…Further, alternate mechanisms other than trypsinogen activation may be responsible for these associations. For example, PSTI and SPINK proteins have been shown to be important in cell death regulation (50), autophagy (51), growth (50, 52) and inflammation (52, 53). Such effects may explain amelioration of pancreatitis with PSTI overexpression (54, 55).…”

Section: Discussionmentioning

confidence: 99%

Cerulein-Induced Chronic Pancreatitis Does Not Require Intra-Acinar Activation of Trypsinogen in Mice

et al. 2013

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Background & Aims Premature activation of trypsinogen activation can cause pancreatic injury and has been associated with chronic pancreatitis (CP). Mice that lack intra-acinar activation of trypsinogen, such as trypsinogen-7–null (T−/−) and cathepsin B-null (CB−/−) mice, have been used to study trypsin-independent processes of CP development. We compared histological features and inflammatory response of pancreatic tissues from these mice to those from wild-type after development of CP. Methods CP was induced in wild-type, T−/−, and CB−/− mice by twice-weekly induction of acute pancreatitis for 10 weeks; acute pancreatitis was induced by hourly intraperitoneal injections of caerulein (50 μg/kg ×6). Pancreatic samples were collected and evaluated by histologic and immunohistochemical analyses. Normal human pancreas samples, obtained from the islet transplant program at the University of Minnesota, were used as controls and CP samples were obtained from surgical resections. Results Compared with pancreatic tissues from wild-type mice, those from T−/− and CB−/− mice had similar levels of atrophy, histo-morphologic features of CP, and chronic inflammation. All samples had comparable intra-acinar activation of nuclear factor (NF)-κB, a transcription factor that regulates the inflammatory response, immediately after injection of caerulein. Pancreatic tissues samples from patients CP had increased activation of NF-B (based on nuclear translocation p65 in acinar cells) compared with controls. Conclusion Induction of CP in mice by caerulein injection does not require intra-acinar activation of trypsinogen. Pancreatic acinar cells of patients with CP have increased levels of NF-κB activation, compared with controls; regulation of the inflammatory response by this transcription factor might be involved in pathogenesis of CP.

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Section: Discussionmentioning

confidence: 99%

Cerulein-Induced Chronic Pancreatitis Does Not Require Intra-Acinar Activation of Trypsinogen in Mice

et al. 2013

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“…Loss of LAMP-2 impairs autophagosome-lysosome fusion and promotes necrosis and inflammation, which is associated with HMGB1 release in AP (70). Interestingly, autophagosomes are increased significantly in trypsin inhibitor SPINK1/Spink3-deficient pancreatic acinar cells (75). However, it is unclear how SPINK1 regulates autophagy flux and zymophagy.…”

Section: Autophagymentioning

confidence: 94%

Cell Death and DAMPs in Acute Pancreatitis

Kang

Lotze

Zeh

et al. 2014

Mol Med

123

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The pancreas is a dual-purpose gland with exocrine and endocrine functions. The exocrine pancreas produces digestive proteases in inactive proenzyme form, namely zymogens. The pancreas is normally able to protect itself from zymogen activation by synthesis of protease inhibitors such as pancreatic secretory trypsin inhibitor and serine protease inhibitor (for example, SPINK1/Spink3). By contrast, pancreatic autodigestion and subsequent AP is initiated once these defenses are impaired. In studies of rodent models (for example, repetitive cerulein or L-arginine injections, choline-deficient ethionine supplementation [CDE] diet, perfusion of taurocholate into the biliary or pancreatic duct and surgical ligation or infusion of pancreatic duct models), some essential pathogenic AP events have been identified (see Figure 1) (15,16).The development of AP involves a complex cascade of events (17), which start with injury or disruption of the pan- Cell Death and DAMPs in Acute PancreatitisRui Kang, Michael T Lotze, Herbert J Zeh, Timothy R Billiar, and Daolin Tang Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America Cell death and inflammation are key pathologic responses of acute pancreatitis (AP), the leading cause of hospital admissions for gastrointestinal disorders. It is becoming increasingly clear that damage-associated molecular pattern molecules (DAMPs) play an important role in the pathogenesis of AP by linking local tissue damage to systemic inflammation syndrome. Endogenous DAMPs released from dead, dying or injured cells initiate and extend sterile inflammation via specific pattern recognition receptors. Inhibition of the release and activity of DAMPs (for example, high mobility group box 1, DNA, histones and adenosine triphosphate) provides significant protection against experimental AP . Moreover, increased serum levels of DAMPs in patients with AP correlate with disease severity. These findings provide novel insight into the mechanism, diagnosis and management of AP . DAMPs might be an attractive therapeutic target in AP.

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“…The inappropriate increase in pancreatic trypsin activity is a hallmark of both human and experimental pancreatitis1718. We find that pancreatic trypsin activity was dramatically upregulated in Spink3 −/− mice at P0.5 (compared to wild type or Spink3 + / − mice) and that this increase was ~3 times less in Spink3 −/− ;XX SPINK1 mice (Fig.…”

Section: Resultsmentioning

confidence: 65%

Novel method to rescue a lethal phenotype through integration of target gene onto the X-chromosome

Sakata

Araki

Nakano

et al. 2016

Sci Rep

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The loss-of-function mutations of serine protease inhibitor, Kazal type 1 (SPINK1) gene are associated with human chronic pancreatitis, but the underlying mechanisms remain unknown. We previously reported that mice lacking Spink3, the murine homologue of human SPINK1, die perinatally due to massive pancreatic acinar cell death, precluding investigation of the effects of SPINK1 deficiency. To circumvent perinatal lethality, we have developed a novel method to integrate human SPINK1 gene on the X chromosome using Cre-loxP technology and thus generated transgenic mice termed “X-SPINK1“. Consistent with the fact that one of the two X chromosomes is randomly inactivated, X-SPINK1 mice exhibit mosaic pattern of SPINK1 expression. Crossing of X-SPINK1 mice with Spink3+/− mice rescued perinatal lethality, but the resulting Spink3−/−;XXSPINK1 mice developed spontaneous pancreatitis characterized by chronic inflammation and fibrosis. The results show that mice lacking a gene essential for cell survival can be rescued by expressing this gene on the X chromosome. The Spink3−/−;XXSPINK1 mice, in which this method has been applied to partially restore SPINK1 function, present a novel genetic model of chronic pancreatitis.

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Role of Intrapancreatic SPINK1/Spink3 Expression in the Development of Pancreatitis

Cited by 27 publications

References 78 publications

Cerulein-Induced Chronic Pancreatitis Does Not Require Intra-Acinar Activation of Trypsinogen in Mice

Cerulein-Induced Chronic Pancreatitis Does Not Require Intra-Acinar Activation of Trypsinogen in Mice

Cell Death and DAMPs in Acute Pancreatitis

Novel method to rescue a lethal phenotype through integration of target gene onto the X-chromosome

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