Mechanisms of polyamine catabolism-induced acute pancreatitis

2007 ◽  
Vol 35 (2) ◽  
pp. 326-330 ◽  
Author(s):  
M.T. Hyvönen ◽  
M. Merentie ◽  
A. Uimari ◽  
T.A. Keinänen ◽  
J. Jänne ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Cathepsin B ◽  
Tissue Injury ◽  
Necrotizing Pancreatitis ◽  
Acinar Cells ◽  
Pancreatic Tissue ◽  
Early Event ◽  
Zymogen Activation ◽  
Polyamine Catabolism ◽  
Trypsinogen Activation

Acute pancreatitis is an autodigestive disease, in which the pancreatic tissue is damaged by the digestive enzymes produced by the acinar cells. Among the tissues in the mammalian body, pancreas has the highest concentration of the natural polyamine, spermidine. We have found that pancreas is very sensitive to acute decreases in the concentrations of the higher polyamines, spermidine and spermine. Activation of polyamine catabolism in transgenic rats overexpressing SSAT (spermidine/spermine-N1-acetyltransferase) in the pancreas leads to rapid depletion of these polyamines and to acute necrotizing pancreatitis. Replacement of the natural polyamines with methylated polyamine analogues before the induction of acute pancreatitis prevents the development of the disease. As premature trypsinogen activation is a common, early event leading to tissue injury in acute pancreatitis in human and in experimental animal models, we studied its role in polyamine catabolism-induced pancreatitis. Cathepsin B, a lysosomal hydrolase mediating trypsinogen activation, was activated just 2 h after induction of SSAT. Pre-treatment of the rats with bismethylspermine prevented pancreatic cathepsin B activation. Analysis of tissue ultrastructure by transmission electron microscopy revealed early dilatation of rough endoplasmic reticulum, probable disturbance of zymogen packaging, appearance of autophagosomes and later disruption of intracellular membranes and organelles. Based on these results, we suggest that rapid eradication of polyamines from cellular structures leads to premature zymogen activation and autodigestion of acinar cells.

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 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.

Subcellular kinetics of early trypsinogen activation in acute rodent pancreatitis

1998 ◽  
Vol 274 (1) ◽  
pp. G71-G79 ◽  
Author(s):  
Kai Mithöfer ◽  
Carlos Fernández-Del Castillo ◽  
David Rattner ◽  
Andrew L. Warshaw
Keyword(s):  
Acute Pancreatitis ◽  
Cathepsin B ◽  
Necrotizing Pancreatitis ◽  
Subcellular Compartment ◽  
Trypsinogen Activation ◽  
Intracellular Compartments ◽  
Trypsinogen Activation Peptide ◽  
Kinetics Of ◽  
Pancreatic Edema

To investigate the debated role of intracellular trypsinogen activation and its relation to lysosomal enzyme redistribution in the pathogenesis of acute pancreatitis, rats were infused with the cholecystokinin analog caerulein at 5 μg ⋅ kg−1⋅ h−1for intervals up to 3 h, and the changes were contrasted with those in animals receiving saline or 0.25 μg ⋅ kg−1⋅ h−1caerulein. Saline or 0.25 μg ⋅ kg−1⋅ h−1caerulein did not induce significant changes. In contrast, 5 μg ⋅ kg−1⋅ h−1caerulein caused significant hyperamylasemia and pancreatic edema within 30 min. Pancreatic content of trypsinogen activation peptide (TAP) increased continuously (significant within 15 min). TAP generation was predominantly located in the zymogen fraction during the first hour but expanded to other intracellular compartments thereafter. Cathepsin B activity in the zymogen compartment increased continuously throughout the experiments and correlated significantly with TAP generation in the same compartment. Total trypsinogen content increased to 143% with marked interstitial trypsinogen accumulation after 3 h. Supramaximal caerulein stimulation causes trypsinogen activation by 15 min that originates in the zymogen compartment and is associated with increasing cathepsin B activity in this subcellular compartment. However, a much larger pool of trypsinogen survives and accumulates in the extracellular space and may become critical in the evolution of necrotizing pancreatitis.

Trimethylamine N-oxide promotes hyperlipidemia acute pancreatitis via inflammatory response

2021 ◽  
pp. 1-7
Author(s):  
Guodong Yang ◽  
Xiaoying Zhang
Keyword(s):  
Acute Pancreatitis ◽  
Inflammatory Response ◽  
Tissue Injury ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Pancreatic Injury ◽  
Pancreatic Tissue ◽  
Lipoprotein Cholesterol ◽  
Model Group ◽  
New Ideas

Trimethylamine N-oxide (TMAO), a metabolite of gut microbiota, is involved in the regulation of lipid metabolism and inflammatory response; however, the role of TMAO in hyperlipidemia acute pancreatitis (HAP) is not clear. In this study, HAP mice were used as an animal model to explore the effects and possible mechanism of TMAO on HAP, which may provide new ideas for the treatment of HAP. Results found that the levels of triglycerides, total cholesterol, low-density lipoprotein cholesterol, nonestesterified fatty acid, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, α-amylase, TMAO, and flavin-containing monooxygenase 3 were significantly increased, the levels of high-density lipoprotein cholesterol and insulin were significantly decreased, and there was an obvious pancreatic injury and inflammatory response in the model group. The choline analogue 3,3-dimethyl-1-butanol (DMB) treatment reversed the changes of serum biochemical parameters, alleviated the pancreatic tissue injury, and reduced the levels of inflammatory cytokines. Further studies of toll-like receptor (TLR)/p-glycoprotein 65 (p65) pathway found that the expressions of TLR2, TLR4, and p-p65/p65 in the model group were significantly increased, which was more obvious after Escherichia coli (Migula) Castellani & Chalmers treatment, while activation of the TLR/p65 pathway was inhibited by DMB. The results indicated that TMAO promotes HAP by promoting inflammatory response through TLR/p65 signaling pathway, suggesting that TMAO may be a potential target of HAP.

scholarly journals Isoliquiritigenin Ameliorates Acute Pancreatitis in Mice via Inhibition of Oxidative Stress and Modulation of the Nrf2/HO-1 Pathway

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Xinnong Liu ◽  
Qingtian Zhu ◽  
Min Zhang ◽  
Tao Yin ◽  
Rong Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Pancreatitis ◽  
Tissue Injury ◽  
Pancreatic Tissue ◽  
Zinc Protoporphyrin ◽  
Dependent Manner ◽  
Protective Effects ◽  
Stress Injury ◽  
Oxidative Stress Injury ◽  
Flavonoid Monomer

Oxidative stress plays a crucial role in the pathogenesis of acute pancreatitis (AP). Isoliquiritigenin (ISL) is a flavonoid monomer with confirmed antioxidant activity. However, the specific effects of ISL on AP have not been determined. In this study, we aimed to investigate the protective effect of ISL on AP using two mouse models. In the caerulein-induced mild acute pancreatitis (MAP) model, dynamic changes in oxidative stress injury of the pancreatic tissue were observed after AP onset. We found that ISL administration reduced serum amylase and lipase levels and alleviated the histopathological manifestations of pancreatic tissue in a dose-dependent manner. Meanwhile, ISL decreased the oxidative stress injury and increased the protein expression of the Nrf2/HO-1 pathway. In addition, after administering a Nrf2 inhibitor (ML385) or HO-1 inhibitor (zinc protoporphyrin) to block the Nrf2/HO-1 pathway, we failed to observe the protective effects of ISL on AP in mice. Furthermore, we found that ISL mitigated the severity of pancreatic tissue injury and pancreatitis-associated lung injury in a severe acute pancreatitis model induced by L-arginine. Taken together, our data for the first time confirmed the protective effects of ISL on AP in mice via inhibition of oxidative stress and modulation of the Nrf2/HO-1 pathway.

Cause-effect relationships between zymogen activation and other early events in secretagogue-induced acute pancreatitis

2007 ◽  
Vol 292 (6) ◽  
pp. G1738-G1746 ◽  
Author(s):  
Gijs J. D. Van Acker ◽  
Eric Weiss ◽  
Michael L. Steer ◽  
George Perides
Keyword(s):  
Acute Pancreatitis ◽  
Transcription Factors ◽  
Acinar Cell ◽  
Cathepsin B ◽  
Cell Injury ◽  
Experimental Pancreatitis ◽  
Causal Relationships ◽  
Zymogen Activation ◽  
Lysosomal Hydrolases ◽  
Early Stages

We have hypothesized that the colocalization of digestive zymogens with lysosomal hydrolases, which occurs during the early stages of every experimental pancreatitis model, facilitates activation of those zymogens by lysosomal hydrolases such as cathepsin B and that this activation triggers acute pancreatitis by leading to acinar cell injury. Some, however, have argued that the colocalization phenomenon may be the result, rather than the cause, of zymogen activation during pancreatitis. To resolve this controversy and explore the causal relationships between zymogen activation and other early pancreatitis events, we induced pancreatitis in mice by repeated supramaximal secretagogue stimulation with caerulein. Some animals were pretreated with the cathepsin B inhibitor CA-074me to inhibit cathepsin B, prevent intrapancreatic activation of digestive zymogens, and reduce the severity of pancreatitis. We show that inhibition of cathepsin B by pretreatment with CA-074me prevents intrapancreatic zymogen activation and reduces organellar fragility, but it does not alter the caerulein-induced colocalization phenomenon or subcellular F-actin redistribution or prevent caerulein-induced activation of NF-κB, ERK1/2, and JNK or upregulated expression of cytochemokines. We conclude 1) that the colocalization phenomenon, F-actin redistribution, activation of proinflammatory transcription factors, and upregulated expression of cytochemokines are not the results of zymogen activation, and 2) that these early events in pancreatitis are not dependent on cathepsin B activity. In contrast, zymogen activation and increased subcellular organellar fragility during caerulein-induced pancreatitis are dependent on cathepsin B activity.

scholarly journals Aspirin Protects against Acinar Cells Necrosis in Severe Acute Pancreatitis in Mice

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Guotao Lu ◽  
Zhihui Tong ◽  
Yanbing Ding ◽  
Jinjiao Liu ◽  
Yiyuan Pan ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Severe Acute Pancreatitis ◽  
Acinar Cell ◽  
Acinar Cells ◽  
Pancreatic Tissue ◽  
Pancreatic Acinar Cell ◽  
Cell Nuclei ◽  
Associated Proteins ◽  
Anti Inflammatory

Aspirin has a clear anti-inflammatory effect and is used as an anti-inflammatory agent for both acute and long-term inflammation. Previous study has indicated that aspirin alleviated acute pancreatitis induced by caerulein in rat. However, the role of aspirin on severe acute pancreatitis (SAP) and the necrosis of pancreatic acinar cell are not yet clear. The aim of this study was to determine the effects of aspirin treatment on a SAP model induced by caerulein combined with Lipopolysaccharide. We found that aspirin reduced serum amylase and lipase levels, decreased the MPO activity, and alleviated the histopathological manifestations of pancreas and pancreatitis-associated lung injury. Proinflammatory cytokines were decreased and the expression of NF-κB p65 in acinar cell nuclei was suppressed after aspirin treatment. Furthermore, aspirin induced the apoptosis of acinar cells by TUNEL assay, and the expression of Bax and caspase 3 was increased and the expression of Bcl-2 was decreased. Intriguingly, the downregulation of critical necrosis associated proteins RIP1, RIP3, and p-MLKL was observed; what is more, we additionally found that aspirin reduced the COX level of pancreatic tissue. In conclusion, our data showed that aspirin could protect pancreatic acinar cell against necrosis and reduce the severity of SAP. Clinically, aspirin may potentially be a therapeutic intervention for SAP.

Cathepsin B inhibition prevents trypsinogen activation and reduces pancreatitis severity

2002 ◽  
Vol 283 (3) ◽  
pp. G794-G800 ◽  
Author(s):  
Gijs J. D. van Acker ◽  
Ashok K. Saluja ◽  
Lakshmi Bhagat ◽  
Vijay P. Singh ◽  
Albert M. Song ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Acinar Cell ◽  
Cathepsin B ◽  
Cell Activation ◽  
Cell Injury ◽  
Critical Role ◽  
Trypsinogen Activation ◽  
Soluble Cell

Intrapancreatic activation of trypsinogen is believed to play a critical role in the initiation of acute pancreatitis, but mechanisms responsible for intrapancreatic trypsinogen activation during pancreatitis have not been clearly defined. In previous in vitro studies, we have shown that intra-acinar cell activation of trypsinogen and acinar cell injury in response to supramaximal secretagogue stimulation could be prevented by the cell permeant cathepsin B inhibitor E64d (Saluja A, Donovan EA, Yamanaka K, Yamaguchi Y, Hofbauer B, and Steer ML. Gastroenterology 113: 304–310, 1997). The present studies evaluated the role of intrapancreatic trypsinogen activation, this time under in vivo conditions, in two models of pancreatitis by using another highly soluble cell permeant cathepsin B inhibitor,l-3-trans-(propylcarbamoyl)oxirane-2-carbonyl-l-isoleucyl-l-proline methyl ester (CA-074me). Intravenous administration of CA-074me (10 mg/kg) before induction of either secretagogue-elicited pancreatitis in mice or duct infusion-elicited pancreatitis in rats markedly reduced the extent of intrapancreatic trypsinogen activation and substantially reduced the severity of both pancreatitis models. These observations support the hypothesis that, during the early stages of pancreatitis, trypsinogen activation in the pancreas is mediated by the lysosomal enzyme cathepsin B. Our findings also suggest that pharmacological interventions that inhibit cathepsin B may prove useful in preventing acute pancreatitis or reducing its severity.

scholarly journals Sulfiredoxin-1 attenuates injury and inflammation in acute pancreatitis through the ROS/ER stress/Cathepsin B axis

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Jun He ◽  
Miaomiao Ma ◽  
Daming Li ◽  
Kunpeng Wang ◽  
Qiuguo Wang ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Inflammatory Response ◽  
Er Stress ◽  
Cathepsin B ◽  
Intraperitoneal Injection ◽  
Inflammatory Responses ◽  
Lentiviral Vector ◽  
Acinar Cells ◽  
Mediated Effects ◽  
Duct Ligation

AbstractAcinar cell injury and the inflammatory response are critical bioprocesses of acute pancreatitis (AP). We investigated the role and underlying mechanism of sulfiredoxin-1 (Srxn1) in AP. Mild AP was induced by intraperitoneal injection of cerulein and severe AP was induced by partial duct ligation with cerulein stimulation or intraperitoneal injection of L-arginine in mice. Acinar cells, neutrophils, and macrophages were isolated. The pancreas was analyzed by histology, immunochemistry staining, and TUNEL assays, and the expression of certain proteins and RNAs, cytokine levels, trypsin activity, and reactive oxygen species (ROS) levels were determined. Srxn1 was inhibited by J14 or silenced by siRNA, and overexpression was introduced by a lentiviral vector. Transcriptomic analysis was used to explore the mechanism of Srxn1-mediated effects. We also evaluated the effect of adeno-associated virus (AAV)-mediated overexpression of Srxn1 by intraductal administration and the protection of AP. We found that Srxn1 expression was upregulated in mild AP but decreased in severe AP. Inhibition of Srxn1 increased ROS, histological score, the release of trypsin, and inflammatory responses in mice. Inhibition of Srxn1 expression promoted the production of ROS and induced apoptosis, while overexpression of Srxn1 led to the opposite results in acinar cells. Furthermore, inhibition of Srxn1 expression promoted the inflammatory response by accumulating and activating M1 phenotype macrophages and neutrophils in AP. Mechanistically, ROS-induced ER stress and activation of Cathepsin B, which converts trypsinogen to trypsin, were responsible for the Srxn1 inhibition-mediated effects on AP. Importantly, we demonstrated that AAV-mediated overexpression of Srxn1 attenuated AP in mice. Taken together, these results showed that Srxn1 is a protective target for AP by attenuating acinar injury and inflammation through the ROS/ER stress/Cathepsin B axis.

PSD-95 protects the pancreas against pathological damage through p38 MAPK signaling pathway in acute pancreatitis

2021 ◽  
pp. 153537022110032
Author(s):  
Yinan Guo ◽  
Weikai Hu ◽  
Xueyan Wang ◽  
Chunyun Li ◽  
Tianyu Cui ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
P38 Mapk ◽  
Cell Model ◽  
Control Cell ◽  
Acinar Cells ◽  
Mapk Signaling ◽  
Pancreatic Tissue ◽  
Pancreatic Acinar Cells ◽  
Ar42j Cells ◽  
Inhibition Group

Acute pancreatitis is one of the leading causes of gastrointestinal disorder-related hospitalizations, yet its pathogenesis remains to be fully elucidated. Postsynaptic density protein-95 (PSD-95) is closely associated with tissue inflammation and injury. We aimed to investigate the expression of PSD-95 in pancreatic acinar cells, and its function in regulating the inflammatory response and pancreatic pathological damage in acute pancreatitis. A mouse model of edematous acute pancreatitis was induced with caerulein and lipopolysaccharide in C57BL/6 mice. Tat-N-dimer was injected to inhibit the PSD-95 activity separately, or simultaneously with SB203580, inhibitor of p38 MAPK phosphorylation. Rat pancreatic acinar cells AR42J were cultured with 1 μM caerulein to build a cell model of acute pancreatitis. PSD-95-knockdown and negative control cell lines were constructed by lentiviral transfection of AR42J cells. Paraffin-embedded pancreatic tissue samples were processed for routine HE staining to evaluate the pathological changes of human and mouse pancreatic tissues. Serum amylase and inflammatory cytokine levels were detected with specific ELISA kits. Immunofluorescence, immunohistochemical, Western-blot, and qRT-PCR were used to detect the expression levels of PSD-95, p38, and phosphorylated p38. Our findings showed that PSD-95 is expressed in the pancreatic tissues of humans, C57BL/6 mice, and AR42J cells, primarily in the cytoplasm. PSD-95 expression increased at 2 h, reaching the peak at 6 h in mice and 12 h in AR42J cells. IL-6, IL-8, and TNF-α increased within 2 h of disease induction. The pancreatic histopathologic score was greater in the PSD-95 inhibition group compared with the control ( P < 0.05), while it was lesser when phosphorylation of p38 MAPK was inhibited compared with the PSD-95 inhibition group ( P < 0.05). Moreover, phosphorylation of p38 MAPK increased statistically after PSD-95 knocked-down. In conclusion, PSD-95 effectively influences the pathological damage of the pancreas in acute pancreatitis by affecting the phosphorylation of p38 MAPK.

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