EMC6 and APAF1 Promote Acinar Cell Injury in Acute and Chronic Pancreatitis

2020 ◽  
Author(s):  
Jie-hui Tan ◽  
Rong-chang Cao ◽  
Lei Zhou ◽  
Zhi-tao Zhou ◽  
Huo-ji Chen ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Acinar Cell ◽  
Cell Injury ◽  
Acute And Chronic Pancreatitis

scholarly journals EMC6 regulates acinar apoptosis via APAF1 in acute and chronic pancreatitis

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Jie-hui Tan ◽  
Rong-chang Cao ◽  
Lei Zhou ◽  
Zhi-tao Zhou ◽  
Huo-ji Chen ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Acinar Cell ◽  
Cell Apoptosis ◽  
Inflammatory Diseases ◽  
Inflammatory Injury ◽  
Proteomic Screen ◽  
Apoptosis Pathways ◽  
Induced Apoptosis ◽  
Acute And Chronic Pancreatitis ◽  
Functional Analyses

Abstract Treatment of acute pancreatitis (AP) and chronic pancreatitis (CP) remains problematic due to a lack of knowledge about disease-specific regulatory targets and mechanisms. The purpose of this study was to screen proteins related to endoplasmic reticulum (ER) stress and apoptosis pathways that may play a role in pancreatitis. Human pancreatic tissues including AP, CP, and healthy volunteers were collected during surgery. Humanized PRSS1 (protease serine 1) transgenic (PRSS1Tg) mice were constructed and treated with caerulein to mimic the development of human AP and CP. Potential regulatory proteins in pancreatitis were identified by proteomic screen using pancreatic tissues of PRSS1Tg AP mice. Adenoviral shRNA-mediated knockdown of identified proteins, followed by functional assays was performed to validate their roles. Functional analyses included transmission electron microscopy for ultrastructural analysis; qRT-PCR, western blotting, co-immunoprecipitation, immunohistochemistry, and immunofluorescence for assessment of gene or protein expression, and TUNEL assays for assessment of acinar cell apoptosis. Humanized PRSS1Tg mice could mimic the development of human pancreatic inflammatory diseases. EMC6 and APAF1 were identified as potential regulatory molecules in AP and CP models by proteomic analysis. Both EMC6 and APAF1 regulated apoptosis and inflammatory injury in pancreatic inflammatory diseases. Moreover, APAF1 was regulated by EMC6, induced apoptosis to injure acinar cells and promoted inflammation. In the progression of pancreatitis, EMC6 was activated and then upregulated APAF1 to induce acinar cell apoptosis and inflammatory injury. These findings suggest that EMC6 may be a new therapeutic target for the treatment of pancreatic inflammatory diseases.

TNF-α Suppresses Autophagic Flux in Acinar Cells in IgG4-Related Sialadenitis

2019 ◽  
Vol 98 (12) ◽  
pp. 1386-1396 ◽  
Author(s):  
X. Hong ◽  
S.N. Min ◽  
Y.Y. Zhang ◽  
Y.T. Lin ◽  
F. Wang ◽  
...  
Keyword(s):  
Acinar Cell ◽  
Cell Injury ◽  
Ex Vivo ◽  
Secretory Granules ◽  
Acinar Cells ◽  
Autophagic Flux ◽  
C6 Cells ◽  
Tnf Α ◽  
Α Level

IgG4-related sialadenitis (IgG4-RS) is a newly recognized immune-mediated systemic fibroinflammatory disease that affects salivary glands and leads to hyposalivation. Tumor necrosis factor–α (TNF-α) is a critical proinflammatory cytokine involved in several salivary gland disorders, but its role and mechanism regarding acinar cell injury in IgG4-RS are unknown. Here, we found that TNF-α level was significantly increased in serum and submandibular gland (SMG) of patients and that serum TNF-α level was negatively correlated with saliva flow rate. Ultrastructural observations of IgG4-RS SMGs revealed accumulation of large autophagic vacuoles, as well as dense fibrous bundles, decreased secretory granules, widened intercellular spaces, swollen mitochondria, and expanded endoplasmic reticulum. Expression levels of LC3 and p62 were both increased in patients’ SMGs. TNF-α treatment led to elevated levels of LC3II and p62 in both SMG-C6 cells and cultured human SMG tissues but did not further increase their levels when combined with bafilomycin A1 treatment. Moreover, transfection of Ad-mCherry-GFP-LC3B in SMG-C6 cells confirmed the suppression of autophagic flux after TNF-α treatment. Immunofluorescence imaging revealed that costaining of LC3 and the lysosomal marker LAMP2 was significantly decreased in patients, TNF-α–treated SMG-C6 cells, and cultured human SMGs, indicating a reduction in autophagosome-lysosome fusion. Furthermore, the ratio of pro/mature cathepsin D was elevated in vivo, ex vivo, and in vitro. TNF-α also appeared to induce abnormal acidification of lysosomes in acinar cells, as assessed by lysosomal pH and LysoTracker DND-26 fluorescence intensity. In addition, TNF-α treatment induced transcription factor EB (TFEB) redistribution in SMG-C6 cells, which was consistent with the changes observed in IgG4-RS patients. TNF-α increased the phosphorylation of extracellular signal–regulated kinase (ERK) 1/2, and inhibition of ERK1/2 by U0126 reversed TNF-α–induced TFEB redistribution, lysosomal dysfunction, and autophagic flux suppression. These findings suggest that TNF-α is a key cytokine related to acinar cell injury in IgG4-RS through ERK1/2-mediated autophagic flux suppression.

scholarly journals Accelerating the Drug Delivery Pipeline for Acute and Chronic Pancreatitis

Pancreas ◽  
2018 ◽  
Vol 47 (10) ◽  
pp. 1200-1207 ◽  
Author(s):  
Christopher E. Forsmark ◽  
Dana K. Andersen ◽  
John T. Farrar ◽  
Megan Golden ◽  
Aida Habtezion ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Chronic Pancreatitis ◽  
Acute And Chronic Pancreatitis

Acute and Chronic Pancreatitis

1964 ◽  
Vol 15 (1) ◽  
pp. 335-356 ◽  
Author(s):  
K W Warren ◽  
W M McDonald
Keyword(s):  
Chronic Pancreatitis ◽  
Acute And Chronic Pancreatitis

scholarly journals Spontaneous pancreatic pseudocyst–portal vein fistula: a rare and potentially life threatening complication of pancreatitis

2013 ◽  
Vol 95 (1) ◽  
pp. e7-e9 ◽  
Author(s):  
SS Raza ◽  
A Hakeem ◽  
M Sheridan ◽  
N Ahmad
Keyword(s):  
Chronic Pancreatitis ◽  
Portal Vein ◽  
Pancreatic Pseudocyst ◽  
Conservative Approach ◽  
Fatal Complication ◽  
Life Threatening ◽  
Life Threatening Complication ◽  
Acute And Chronic Pancreatitis ◽  
Pseudocyst Formation

Pseudocyst formation following acute and chronic pancreatitis is a well known complication. A pancreatic pseudocyst fistulating into the portal vein is a rare and potentially fatal complication. We report a case of pancreatic pseudocyst – portal vein fistula, which was managed with a conservative approach.

Stimulation of stellate cells by injured acinar cells: a model of acute pancreatitis induced by alcohol and fat (VLDL)

2009 ◽  
Vol 297 (6) ◽  
pp. G1163-G1171 ◽  
Author(s):  
Marco Siech ◽  
Zhengfei Zhou ◽  
Shaoxia Zhou ◽  
Bernd Bair ◽  
Andreas Alt ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Pancreatitis ◽  
Acinar Cell ◽  
Cell Injury ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Pancreatic Acinar Cell ◽  
Pancreatic Stellate Cells ◽  
Matrix Synthesis ◽  
Repair Mechanisms

Mechanisms leading to acute pancreatitis after a fat-enriched meal combined with excess alcohol are incompletely understood. We have studied the effects of alcohol and fat (VLDL) on pancreatic acinar cell (PAC) function, oxidative stress, and repair mechanisms by pancreatic stellate cells (PSC) leading to fibrogenesis. To do so, PAC (rat) were isolated and cultured up to 24 h. Ethanol and/or VLDL were added to PAC. We measured PAC function (amylase, lipase), injury (lactic dehydrogenase), apoptosis (TUNEL, Apo2.7, annexin V binding), oxidative stress, and lipid peroxidation (conjugated dienes, malondialdehyde, chemoluminescence); we also measured PSC proliferation (bromodeoxyuridine incorporation), matrix synthesis (immunofluorescence of collagens and fibronectin, fibronectin immunoassay), and fatty acids in PAC supernatants (gas chromatography). Within 6 h, cultured PAC degraded and hydrolyzed VLDL completely. VLDL alone (50 μg/ml) and in combination with alcohol (0.2, 0.5, and 1% vol/vol) induced PAC injury (LDL, amylase, and lipase release) within 2 h through generation of oxidative stress. Depending on the dose of VLDL and alcohol, apoptosis and/or necrosis were induced. Antioxidants (Trolox, Probucol) reduced the cytotoxic effect of alcohol and VLDL. Supernatants of alcohol/VLDL-treated PAC stimulated stellate cell proliferation and extracellular matrix synthesis. We concluded that, in the presence of lipoproteins, alcohol induces acinar cell injury. Our results provide a biochemical pathway for the clinical observation that a fat-enriched meal combined with excess alcohol consumption can induce acinar cell injury (acute pancreatitis) followed by repair mechanisms (proliferation and increased matrix synthesis in PSC).

scholarly journals Sex-Related Differences of Acute and Chronic Pancreatitis in Adults

2021 ◽  
Vol 10 (2) ◽  
pp. 300
Author(s):  
Madeline Drake ◽  
Shah-Jahan M. Dodwad ◽  
Joy Davis ◽  
Lillian S. Kao ◽  
Yanna Cao ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
The United States ◽  
Prevention Strategies ◽  
Endoscopic Retrograde ◽  
Effective Prevention ◽  
Type 1 Autoimmune Pancreatitis ◽  
Acute And Chronic Pancreatitis ◽  
Effective Prevention Strategies

The incidence of acute and chronic pancreatitis is increasing in the United States. Rates of acute pancreatitis (AP) are similar in both sexes, but chronic pancreatitis (CP) is more common in males. When stratified by etiology, women have higher rates of gallstone AP, while men have higher rates of alcohol- and tobacco-related AP and CP, hypercalcemic AP, hypertriglyceridemic AP, malignancy-related AP, and type 1 autoimmune pancreatitis (AIP). No significant sex-related differences have been reported in medication-induced AP or type 2 AIP. Whether post-endoscopic retrograde cholangiopancreatography pancreatitis is sex-associated remains controversial. Animal models have demonstrated sex-related differences in the rates of induction and severity of AP, CP, and AIP. Animal and human studies have suggested that a combination of risk factor profiles, as well as genes, may be responsible for the observed differences. More investigation into the sex-related differences of AP and CP is desired in order to improve clinical management by developing effective prevention strategies, diagnostics, and therapeutics.

scholarly journals Accelerating the Drug Delivery Pipeline for Acute and Chronic Pancreatitis

Pancreas ◽  
2018 ◽  
Vol 47 (10) ◽  
pp. 1185-1192 ◽  
Author(s):  
Maisam Abu-El-Haija ◽  
Anna S. Gukovskaya ◽  
Dana K. Andersen ◽  
Timothy B. Gardner ◽  
Peter Hegyi ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Chronic Pancreatitis ◽  
Acute And Chronic Pancreatitis

Computerized Tomography in Acute and Chronic Pancreatitis

1984 ◽  
Vol 77 (11) ◽  
pp. 1393-1396 ◽  
Author(s):  
JOHN A. KALMAR ◽  
CHARLES C. MATTHEWS ◽  
LAURIE A. BISHOP
Keyword(s):  
Chronic Pancreatitis ◽  
Computerized Tomography ◽  
Acute And Chronic Pancreatitis
Sign in / Sign up

Export Citation Format

Share Document