Cell Death and Damps in Acute Pancreatitis

Cell Death and DAMPs in Acute Pancreatitis Rui 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 cor- relate 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. Online address: http://www.molmed.org doi: 10.2119/molmed.2014.00117 INTRODUCTION tion of comorbid disease (4). About one- This triggers downstream signaling and Acute pancreatitis (AP) is inflamma- third of patients with AP develop severe manifests as sterile inflammation tion of the pancreas that can become a necrotizing pancreatitis with persistent (9,12,14). In this review, we outline the fatal disease or lead to severe complica- MOF and a high mortality rate. The main pathogenesis of AP, discuss the relation- tions (1). It is characterized clinically by goals in the clinical management of AP ship between cell death and AP, and abdominal pain and by increased pancre- are adequate fluid resuscitation and the highlight the latest exciting advances in atic enzyme levels in the blood or urine. prevention of MOF (6,7). Both genetic the pathogenic role of DAMPs in AP. Gallstone migration and alcohol abuse and environmental factors affect the de- are the two major risk factors for AP in velopment and severity of pancreatitis PATHOGENESIS OF ACUTE humans (2,3). According to the updated (8). Although the pathogenic mecha- PANCREATITIS Atlanta classification, AP is generally di- nisms remain largely unknown, increas- The pancreas is a dual-purpose gland vided into mild, moderate or severe pan- ing evidence suggests that damage- with exocrine and endocrine functions. creatitis according to the presence or ab- associated molecular pattern molecules The exocrine pancreas produces digestive sence of multiple organ failure (MOF) or (DAMPs) play a central role in the patho- proteases in inactive proenzyme form, local or systemic complications (4). Mild genesis of AP. DAMPs link local tissue namely zymogens. The pancreas is nor- pancreatitis has a good prognosis with damage to systemic inflammation re- mally able to protect itself from zymogen rapid recovery. The late consequences of sponse syndrome (SIRS), which, if severe activation by synthesis of protease in- AP include impaired pancreatic exocrine or sustained, can lead to subsequent hibitors such as pancreatic secretory function and glucose tolerance, diabetes MOF and even death (9,11) (Figure 1). trypsin inhibitor and serine protease in- and development of chronic pancreatitis Most DAMPs are recognized by mem- hibitor (for example, SPINK1/Spink3). By (5). Moderately severe AP is character- brane-bound and cytosolic pattern recog- contrast, pancreatic autodigestion and ized by the presence of transient organ nition receptors (PRRs) expressed by subsequent AP is initiated once these de- failure, local complications or exacerba- both immune and nonimmune cell types. fenses are impaired. In studies of rodent models (for example, repetitive cerulein or L-arginine injections, choline-deficient ethionine supplementation [CDE] diet, Address correspondence to Rui Kang or Daolin Tang, Department of Surgery, University of perfusion of taurocholate into the biliary Pittsburgh, 5117 Centre Ave, Hillman Cancer Center, Pittsburgh, Pennsylvania, 15213. Phone: or pancreatic duct and surgical ligation or 412-623-1211; Fax: 412-623-1212: E-mail: [email protected] or [email protected]. infusion of pancreatic duct models), some Submitted June 11, 2014; Accepted for publication August 4, 2014; Epub essential pathogenic AP events have been (www.molmed.org) ahead of print August 5, 2014. 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- 466 | KANG ET AL. | MOL MED 20:466-477, 2014 REVIEW ARTICLE [NF-κB], mitogen-activated protein ki- nase [MAPK], signal transducer and acti- vator of transcription 3 [STAT3] and in- flammasome). Of these, NF-κB appears to the main inflammatory pathway in pancreatitis, although conflicting reports have been published (27–30). Recruitment and activated innate immune cells at the site of injury lead to further acinar cell injury and increase the levels of circulating DAMPs. It is important to note that neu- trophil depletion markedly reduces tissue damage severity in AP, suggesting a criti- cal role for tissue infiltration of neu- trophils in AP (31). DAMPs ultimately are the mediators of the systemic inflammatory response and cause further pancreatic damage, as well as MOF. In particu- lar, acute lung injury and adult respiratory distress syndrome are the leading causes of death in patients with AP (6). More recently, myeloid NF-κB activation was found to contribute to IL-6 synthesis and IL-6 transsignaling, which promotes pancreatitis-associated lung injury and lethality (32). A better under- Figure 1. Emerging role of DAMPs in acute pancreatitis. A number of rodent models have standing of the relationship between local proven useful for studying the pathogenic mechanisms of acute pancreatitis. Increasing tissue injury and systemic inflammation evidence indicates that DAMPs such as HMGB1, DNA, HSPs, histones and ATP play a cen- syndrome in the development of AP may tral role in the pathogenesis of acute pancreatitis because DAMPs link local tissue dam- provide more targeted therapeutic op- age and death to systemic inflammation response syndrome, which leads to subsequent tions (see Figure 1). MOF and even death. CELL DEATH AND ACUTE PANCREATITIS creatic acini, which then permits the leak- reticulum, can cause mitochondrial cal- The severity of experimental AP corre- age of active pancreatic enzymes includ- cium overload, which leads to enhanced lates with the extent and type of cell in- ing amylolytic, lipolytic and proteolytic generation of mitochondrial ROS and mi- jury and death. Although multiple forms enzymes that destroy local tissues. This tochondrial membrane permeabilization. of cell death exist in physiological and results in edema, vascular damage, hem- Mitochondria dysfunction-mediated ox- pathological conditions (33), necrosis and orrhage and cell death (18,19). In addition idative injury results in endoplasmic apoptosis are the most widely studied to oxidative stress (20) and calcium over- reticulum stress, lysosomal damage and types in both clinical and experimental load (21), hypotension (22) and low aci- the release of proteases (for example, AP (34,35). Necrotic cells are capable of nar pH (23) contribute to these initiation cathepsin and trypsin) to degrade cytoso- activating proinflammatory and im- processes. After initial production of ac- lic proteins that cause pancreatic acinar munostimulatory responses by releasing tive pancreatic enzymes, local cell death cell death (25,26). Dead, dying and in- DAMPs and other molecules, whereas and systemic inflammation ensue. Mito- jured pancreatic acinar cells release intra- apoptosis is usually considered immuno- chondria, the energy factories of cells, cellular contents, including DAMPs (for logically silent because the cytoplasmic regulate pancreatic cell death through example, high mobility group box 1 content is packaged in apoptotic bodies control of the production of adenosine [HMGB1], DNA, histones and ATP), and these membrane-bound cell frag- triphosphate (ATP) and reactive oxygen which in turn promote infiltration of vari- ments are rapidly taken up and de- species (ROS), as well as calcium (24). ous immune cells (for example, neu- graded by phagocytes or autophagy (36). Dysfunction of mitochondrial calcium trophils, monocytes and macrophages) However, excessive apoptotic cells can uptake and efflux, including elevation of and activation of inflammatory signaling activate the inflammatory and immune cytosolic calcium from the endoplasmic pathways (for example, nuclear factor-κB responses by releasing nuclear DAMPs MOL MED 20:466-477, 2014 | KANG ET AL. | 467 DAMPs AND ACUTE PANCREATITIS served in necrosis, whereas pyknosis and karyorrhexis occur in apoptotic cells. A number of observations have indi- cated that necrosis is the major type of pancreatic acinar cell death (34,41). Al- though some data clearly implicates that the release of DAMPs from necrosis is responsible for the inflammatory response, much less is known about the signaling mechanisms responsible for this function. A good example of such a mechanism is derived from the study of poly (ADP-ribose) polymerase (PARP) in necrosis. PARP-1 activation during DNA damage induces energy failure by de- pleting NAD+; the cell consumes ATP to replete the NAD+ level, ultimately re- sulting in energy

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