scholarly journals Involvement of autophagy in trypsinogen activation within the pancreatic acinar cells

2008 ◽  
Vol 181 (7) ◽  
pp. 1065-1072 ◽  
Author(s):  
Daisuke Hashimoto ◽  
Masaki Ohmuraya ◽  
Masahiko Hirota ◽  
Akitsugu Yamamoto ◽  
Koichi Suyama ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Knockout Mice ◽  
Early Stage ◽  
Acinar Cells ◽  
Conditional Knockout ◽  
Pancreatic Acinar Cells ◽  
Trypsinogen Activation ◽  
Conditional Knockout Mice ◽  
Cellular Environment

Autophagy is mostly a nonselective bulk degradation system within cells. Recent reports indicate that autophagy can act both as a protector and killer of the cell depending on the stage of the disease or the surrounding cellular environment (for review see Cuervo, A.M. 2004. Trends Cell Biol. 14:70–77). We found that cytoplasmic vacuoles induced in pancreatic acinar cells by experimental pancreatitis were autophagic in origin, as demonstrated by microtubule-associated protein 1 light chain 3 expression and electron microscopy experiments. To analyze the role of macroautophagy in acute pancreatitis, we produced conditional knockout mice lacking the autophagy-related 5 gene in acinar cells. Acute pancreatitis was not observed, except for very mild edema in a restricted area, in conditional knockout mice. Unexpectedly, trypsinogen activation was greatly reduced in the absence of autophagy. These results suggest that autophagy exerts devastating effects in pancreatic acinar cells by activation of trypsinogen to trypsin in the early stage of acute pancreatitis through delivering trypsinogen to the lysosome.

scholarly journals Absence of the neutrophil serine protease cathepsin G decreases neutrophil granulocyte infiltration but does not change the severity of acute pancreatitis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ali A. Aghdassi ◽  
Daniel S. John ◽  
Matthias Sendler ◽  
Christian Storck ◽  
Cindy van den Brandt ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Serine Protease ◽  
Acinar Cells ◽  
Neutrophil Infiltration ◽  
Cathepsin G ◽  
Pancreatic Acinar Cells ◽  
Neutrophil Granulocyte ◽  
Zymogen Activation ◽  
Trypsinogen Activation ◽  
Extracellular Matrix Components

AbstractAcute pancreatitis is characterized by an early intracellular protease activation and invasion of leukocytes into the pancreas. Cathepsins constitute a large group of lysosomal enzymes, that have been shown to modulate trypsinogen activation and neutrophil infiltration. Cathepsin G (CTSG) is a neutrophil serine protease of the chymotrypsin C family known to degrade extracellular matrix components and to have regulatory functions in inflammatory disorders. The aim of this study was to investigate the role of CTSG in pancreatitis. Isolated acinar cells were exposed to recombinant CTSG and supramaximal cholezystokinin stimulation. In CTSG−/− mice and corresponding controls acute experimental pancreatitis was induced by serial caerulein injections. Severity was assessed by histology, serum enzyme levels and zymogen activation. Neutrophil infiltration was quantified by chloro-acetate ersterase staining and myeloperoxidase measurement. CTSG was expessed in inflammatory cells but not in pancreatic acinar cells. CTSG had no effect on intra-acinar-cell trypsinogen activation. In CTSG−/− mice a transient decrease of neutrophil infiltration into the pancreas and lungs was found during acute pancreatitis while the disease severity remained largely unchanged. CTSG is involved in pancreatic neutrophil infiltration during pancreatitis, albeit to a lesser degree than the related neutrophil (PMN) elastase. Its absence therefore leaves pancreatitis severity essentially unaffected.

scholarly journals CaMKII/proteasome/cytosolic calcium/cathepsin B axis was present in tryspin activation induced by nicardipine

2019 ◽  
Vol 39 (7) ◽  
Author(s):  
Juan Xiao ◽  
Houmin Lin ◽  
Binggang Liu ◽  
Junfei Jin
Keyword(s):  
Acute Pancreatitis ◽  
Calcium Channel ◽  
Cathepsin B ◽  
Acinar Cells ◽  
Proteasome Inhibition ◽  
Cytosolic Calcium ◽  
Pancreatic Acinar Cells ◽  
Prolonged Treatment ◽  
Early Event ◽  
Trypsinogen Activation

Abstract Premature trypsinogen activation is the early event of acute pancreatitis. Therefore, the studies on the processes of trypsinogen activation induced by compounds are important to understand mechanism underly acute pancreatitis under various conditions. Calcium overload in the early stage of acute pancreatitis was previously found to cause intracellular trypsinogen activation; however, treatment of acute pancreatitis using calcium channel blockers did not produced consistent results. Proteasome activity that could be inhibited by some calcium channel blocker has recently been reported to affect the development of acute pancreatitis; however, the associated mechanism were not fully understood. Here, the roles of nicardipine were investigated in trypsinogen activation in pancreatic acinar cells. The results showed that nicardipine could increase cathepsin B activity that caused trypsinogen activation, but higher concentration of nicardipine or prolonged treatment had an opposite effect. The effects of short time treatment of nicardipine at low concentration were studied here. Proteasome inhibition was observed under nicardipine treatment that contributed to the up-regulation in cytosolic calcium. Increased cytosolic calcium from ER induced by nicardipine resulted in the release and activation of cathepsin B. Meanwhile, calcium chelator inhibited cathepsin B as well as trypsinogen activation. Consistently, proteasome activator protected acinar cells from injury induced by nicardipine. Moreover, proteasome inhibition caused by nicardipine depended on CaMKII. In conclusion, CaMKII down-regulation/proteasome inhibition/cytosolic calcium up-regulation/cathepsin B activation/trypsinogen activation axis was present in pancreatic acinar cells injury under nicardipine treatment.

scholarly journals Mechanisms of damage of acinar pancreatic cells in acute alcohol pancreatitis

2019 ◽  
Vol 16 (1) ◽  
pp. 108-116
Author(s):  
L. A. Mozheiko
Keyword(s):  
Molecular Level ◽  
Early Stage ◽  
Acinar Cells ◽  
Current Data ◽  
Cellular Damage ◽  
Pancreatic Acinar Cells ◽  
Atp Production ◽  
Functional Changes ◽  
Trypsinogen Activation ◽  
Pancreatic Cells

The review analyzes the current data on the main mechanisms of toxic effects of alcohol and its metabolites on pancreatic acinar cells in acute pancreatitis. It is shown that the mechanisms of cellular damage are multicomponent and closely linked by the regulatory factors of the molecular level. At the early stage of the disease, they lead to the following structural and functional changes in acinar cells that promote the premature intracellular trypsinogen activation and autoaggression: sustained rise of cytosolic Ca2+ and excess of mitochondrial matrix Ca2+; destabilization due to lysosomes and zymogen granules; debective autophagy; mitochondrial depolarization; decreased ATP production and necrosis.

scholarly journals The role of Ca2+ influx in endocytic vacuole formation in pancreatic acinar cells

2015 ◽  
Vol 465 (3) ◽  
pp. 405-412 ◽  
Author(s):  
Svetlana Voronina ◽  
David Collier ◽  
Michael Chvanov ◽  
Ben Middlehurst ◽  
Alison J. Beckett ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Vacuole Formation

Endocytic vacuoles are ‘initiating’ organelles in the development of acute pancreatitis. In the present study, we identified the important roles of store-operated Ca2+ influx and Ca2+-dependent proteases (calpains) in the formation of these organelles.

scholarly journals Important role of hypothalamic Y2 receptors in body weight regulation revealed in conditional knockout mice

2002 ◽  
Vol 99 (13) ◽  
pp. 8938-8943 ◽  
Author(s):  
A. Sainsbury ◽  
C. Schwarzer ◽  
M. Couzens ◽  
S. Fetissov ◽  
S. Furtinger ◽  
...  
Keyword(s):  
Body Weight ◽  
Knockout Mice ◽  
Conditional Knockout ◽  
Weight Regulation ◽  
Body Weight Regulation ◽  
Conditional Knockout Mice

A facile one-step strategy for the generation of conditional knockout mice to explore the role of Notch1 in oroesophageal tumorigenesis

2016 ◽  
Vol 469 (3) ◽  
pp. 761-767 ◽  
Author(s):  
Masita Mandasari ◽  
Wanlada Sawangarun ◽  
Ken-ichi Katsube ◽  
Kou Kayamori ◽  
Akira Yamaguchi ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Conditional Knockout ◽  
Conditional Knockout Mice ◽  
One Step

Pancreatic gene expression during the initiation of acute pancreatitis: identification of EGR-1 as a key regulator

2003 ◽  
Vol 14 (1) ◽  
pp. 59-72 ◽  
Author(s):  
Baoan Ji ◽  
Xue-qing Chen ◽  
David E. Misek ◽  
Rork Kuick ◽  
Samir Hanash ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Rt Pcr ◽  
Novel Genes ◽  
In Vivo Models ◽  
Severity Of The Disease ◽  
Deficient Mice

We hypothesized that genes expressed in pancreatic acinar cells during the initiation of acute pancreatitis determine the severity of the disease. Therefore, we utilized microarrays to identify those genes commonly induced in rat pancreatic acinar cells within 1–4 h in two in vivo models, caerulein and taurocholate administration. This strategy yielded 51 known genes representing a complex array of molecules, including those that are likely to either reduce or increase the severity of the disease. Novel genes identified in the current study included ATF3, BRF1, C/EBPβ, CGRP, EGR-1, ephrinA1, villin2, ferredoxin, latexin, lipocalin, MKP-1, NGFI-B, RhoA, tissue factor (TF), and syndecan. To validate these microarray results, the role of EGR-1 was further investigated using quantitative RT-PCR, Western blotting, and immunocytochemistry. EGR-1 expression occurred within acinar cells and correlated with the development of caerulein-induced acute pancreatitis in rats. Furthermore, the levels of the inflammation-related genes MCP-1, PAI, TF, IL-6, and ICAM-1 and the extent of lung inflammation were reduced during the initiation of caerulein-induced acute pancreatitis in EGR-1-deficient mice. Thus this study identified EGR-1 and several other novel genes likely to be important in the development and severity of acute pancreatitis.

scholarly journals Elevated p62/SQSTM1 determines the fate of autophagy-deficient neural stem cells by increasing superoxide

2016 ◽  
Vol 212 (5) ◽  
pp. 545-560 ◽  
Author(s):  
Chenran Wang ◽  
Song Chen ◽  
Syn Yeo ◽  
Gizem Karsli-Uzunbas ◽  
Eileen White ◽  
...  
Keyword(s):  
Stem Cells ◽  
Superoxide Dismutase ◽  
Neural Stem Cells ◽  
Knockout Mice ◽  
Critical Role ◽  
Conditional Knockout ◽  
Biological Processes ◽  
Aggregate Formation ◽  
Conditional Knockout Mice

Autophagy plays important roles in many biological processes, but our understanding of the mechanisms regulating stem cells by autophagy is limited. Interpretations of earlier studies of autophagy using knockouts of single genes are confounded by accumulating evidence for other functions of many autophagy genes. Here, we show that, in contrast to Fip200 deletion, inhibition of autophagy by deletion of Atg5, Atg16L1, or Atg7 does not impair the maintenance and differentiation of postnatal neural stem cells (NSCs). Only Fip200 deletion, but not Atg5, Atg16L1, or Atg7 deletion, caused p62/sequestome1 aggregates to accumulate in NSCs. Fip200 and p62 double conditional knockout mice demonstrated that p62 aggregate formation triggers aberrant superoxide increases by impairing superoxide dismutase functions. By comparing the inhibition of autophagy by deletion of Atg5, Atg16L1, or Atg7 with Fip200 deletion, we revealed a critical role of increased p62 in determining the fate of autophagy-deficient NSCs through intracellular superoxide control.

scholarly journals UBIAD1 Plays an Essential Role in the Survival of Pancreatic Acinar Cells

2019 ◽  
Vol 20 (8) ◽  
pp. 1971 ◽  
Author(s):  
Kimie Nakagawa ◽  
Kiyomi Fujiwara ◽  
Akihiro Nishimura ◽  
Chinami Murakami ◽  
Kanaha Kawamoto ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Apoptotic Cell ◽  
Biological Effects ◽  
Acinar Cells ◽  
Vitamin K2 ◽  
Pancreatic Acinar Cells ◽  
Biosynthetic Enzyme ◽  
Knockout Mouse Model ◽  
Adult Mice

UbiA prenyltransferase domain-containing protein 1 (UBIAD1) is a vitamin K2 biosynthetic enzyme. We previously showed the lethality of this enzyme in UBIAD1 knockout mice during the embryonic stage. However, the biological effects of UBIAD1 deficiency after birth remain unclear. In the present study, we used a tamoxifen-inducible systemic UBIAD1 knockout mouse model to determine the role of UBIAD1 in adult mice. UBIAD1 knockout resulted in the death of the mice within about 60 days of administration of tamoxifen. The pancreas presented with the most prominent abnormality in the tamoxifen-induced UBIAD1 knockout mice. The pancreas was reduced remarkably in size; furthermore, the pancreatic acinar cells disappeared and were replaced by vacuoles. Further analysis revealed that the vacuoles were adipocytes. UBIAD1 deficiency in the pancreatic acinar cells caused an increase in oxidative stress and autophagy, leading to apoptotic cell death in the tamoxifen-induced UBIAD 1 knockout mice. These results indicate that UBIAD1 is essential for maintaining the survival of pancreatic acinar cells in the pancreas.

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