TLR4 but not TLR2 regulates inflammation and tissue damage in acute pancreatitis induced by retrograde infusion of taurocholate

Awla, Darbaz; Abdulla, Aree; Regnér, Sara; Thorlacius, Henrik

doi:10.1007/s00011-011-0370-1

Cited by 53 publications

(42 citation statements)

References 27 publications

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“…The inflammasome is activated in macrophages that infiltrate the pancreas; its blockade, by deletion of caspase-1 or components of inflammasome (such as the nucleotide binding domain leucine-rich repeat [NLR] family, pyrin domain containing-3 [NLRP3]), ameliorates cerulein pancreatitis in mice. 7,24 The beneficial effect of deletion of Toll-like receptor-4 in AP models 44,45 also can be mediated through inflammasome inhibition. Mechanisms of inflammasome activation in pancreatitis likely involve reactive oxygen species (ROS) (eg, resulting from mitochondrial damage) or damage/danger-associated molecular pattern molecules (DAMPs)–cellular components, such as high-mobility group box-1 protein, released from necrotic cells.…”

Section: Role Of Inflammation In Pancreatitismentioning

confidence: 99%

“…These studies used various approaches to inhibit inflammation: inactivation or neutralization of cytokines, chemokines, adhesion molecules, and other mediators of inflammation 13,14,34,47–53 ; deletion of Toll-like receptors to decrease the innate immune response 44,45 ; blockade of neutrophil recruitment with neutralizing antibodies 47,53–56 or genetic deletion of specific integrins 48,57 ; inhibition of complement 58 ; or multidrug strategies. 59 Conversely, acinar cell-specific overexpression of IL-1 β causes spontaneous pancreatitis.…”

Section: Role Of Inflammation In Pancreatitismentioning

confidence: 99%

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Inflammation, Autophagy, and Obesity: Common Features in the Pathogenesis of Pancreatitis and Pancreatic Cancer

et al. 2013

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Inflammation and autophagy are cellular defense mechanisms. When these processes are deregulated (deficient or overactivated) they produce pathologic effects, such as oxidative stress, metabolic impairments, and cell death. Unresolved inflammation and disrupted regulation of autophagy are common features of pancreatitis and pancreatic cancer. Furthermore, obesity, a risk factor for pancreatitis and pancreatic cancer, promotes inflammation and inhibits or deregulates autophagy, creating an environment that facilitates the induction and progression of pancreatic diseases. However, little is known about how inflammation, autophagy, and obesity interact to promote exocrine pancreatic disorders. We review the roles of inflammation and autophagy, and their deregulation by obesity, in pancreatic diseases. We discuss the connections among disordered pathways and important areas for future research.

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Section: Role Of Inflammation In Pancreatitismentioning

confidence: 99%

Section: Role Of Inflammation In Pancreatitismentioning

confidence: 99%

Inflammation, Autophagy, and Obesity: Common Features in the Pathogenesis of Pancreatitis and Pancreatic Cancer

et al. 2013

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“…Extracellular DAMPs may exert synergistic effects to accelerate the development of AP. The role of DAMP receptors such as TLR2 and TLR4 in AP appears complex and even contradictory (159)(160)(161). The existence of multiple DAMP receptors likely provides distinct control mechanisms for expanding or diminishing inflammation at different stages of AP.…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

Cell Death and DAMPs in Acute Pancreatitis

Kang

Lotze

Zeh

et al. 2014

Mol Med

129

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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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“…JAK/STAT signaling pathway is involved in the regulation of many inflammatory responses 38 . Toll-like receptor signaling pathway belongs to innate immune responses, which plays an important role in pancreatitis 39, 40 . The over-activation of the above pathways in APFL group suggests that fatty liver may aggravate pancreatitis through JAK/STAT and Toll-like receptor signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

RNA sequence analysis of rat acute experimental pancreatitis with and without fatty liver: a gene expression profiling comparative study

Wang

Yan

Wang

et al. 2017

Sci Rep

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Fatty liver (FL) is one of the risk factors for acute pancreatitis and is also indicative of a worse prognosis as compared to acute pancreatitis without fatty liver (AP). The aim of the present study was to analyze, at the hepatic level, the differentially expressed genes (DEGs) between acute pancreatitis with fatty liver (APFL) rats and AP rats. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analyses of these DEGs indicated that PPARα signalling pathway and fatty acid degradation pathway may be involved in the pathological process of APFL, which indicated that fatty liver may aggravate pancreatitis through these pathways. Moreover, the excessive activation of JAK/STAT signaling pathway and toll-like receptor signaling pathway was also found in APFL group as shown in heat map. In conclusion, the inhibition of PPARα signaling pathway and the fatty acid degradation pathway may lead to the further disorder of lipid metabolism, which can aggravate pancreatitis.

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TLR4 but not TLR2 regulates inflammation and tissue damage in acute pancreatitis induced by retrograde infusion of taurocholate

Abstract: Our data suggest a role for TLR4 but not TLR2 in the pathogenesis of severe AP in mice.

Cited by 53 publications

References 27 publications

Inflammation, Autophagy, and Obesity: Common Features in the Pathogenesis of Pancreatitis and Pancreatic Cancer

Inflammation, Autophagy, and Obesity: Common Features in the Pathogenesis of Pancreatitis and Pancreatic Cancer

Cell Death and DAMPs in Acute Pancreatitis

RNA sequence analysis of rat acute experimental pancreatitis with and without fatty liver: a gene expression profiling comparative study

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