Cell Death and DAMPs in Acute Pancreatitis

Abstract

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.

Fine particulate matter potentiates type 2 diabetes development in high-fat diet-treated mice: stress response and extracellular to intracellular HSP70 ratio analysis

“…Administration of recombinant HSP70 to mice aggravates cerulein-induced acute pancreatitis in a TLR4-dependent manner [13]. Thus, the role of iHSP70 and eHSP72 in severe inflammatory pancreatic diseases highlights eHSP72/iHSP70 ratio, expressed as H-Index, as a potential biomarker in these damaging processes.…”

“…Induced expression of iHSP70, by preconditioning animals with either a thermal or chemical stressor, protects against acute pancreatitis [13]. Knocking out heat shock transcription factor-1 (HSF-1) in mice inhibits HSP synthesis leading to more severe acute pancreatitis induced by cerulean, this occurring via upregulation of nuclear factor-kB (NF-kB) signaling, intrapancreatic trypsinogen activation, calcium overload, actin cytoskeleton, apoptosis, and autophagy.…”

“…Knocking out heat shock transcription factor-1 (HSF-1) in mice inhibits HSP synthesis leading to more severe acute pancreatitis induced by cerulean, this occurring via upregulation of nuclear factor-kB (NF-kB) signaling, intrapancreatic trypsinogen activation, calcium overload, actin cytoskeleton, apoptosis, and autophagy. On the other hand, HSP70 is rapidly released following non-programmed cell death [13]. eHSP72 induces immune cell activation and pro-inflammatory response by binding to Toll-like receptor-2 (TLR2), Toll-like receptor-4 (TLR4), and α2-macroglobulin receptor (CD91).…”

Clinical Evaluation of Continuous Renal Replacement Therapy in Combination with Ultrasound-Guided Percutaneous Transhepatic Gallbladder Drainage for Acute Severe Biliary Pancreatitis: a Retrospective Study

“…In the early stage of SAP, the release of a large amount of inflammatory mediators may lead to systemic inflammatory response syndrome (SIRS), inflammatory cell infiltration, etc. in vital organs (such as lung, liver and kidney), which causes tissue edema, aggravates organ damage, and further results in MODS [4-7]. …”

The Receptor for Advanced Glycation End Products Activates the AIM2 Inflammasome in Acute Pancreatitis

“…When released, these mediators gain access to the systemic circulation and play a central role in the progression of systemic inflammatory response syndrome and multisystem organ failure (4). The molecular mechanisms linking the progression of local pancreatic damage to systemic inflammation are still poorly understood (5). …”