Acute Pancreatitis: Bench to the Bedside

Abstract

Acute pancreatitis is an acute inflammatory process of the pancreas that frequently involves peripancreatic tissues and at times remote organ systems. The severity of the disease varies widely from mild forms only affecting the pancreas to severe disease with multisystemic organ failure and death. In this review, a synopsis of our current understanding of the pathobiologic processes that underlie pancreatitis and its sequelae is provided; and a current approach to the management of patients with this disorder is reviewed. We conclude this review with suggestions for future directions for research to improve outcomes for patients who have acute pancreatitis. The major pathobiologic processes underlying acute pancreatitis are inflammation, edema, and necrosis of pancreatic tissue as well as inflammation and injury of extrapancreatic organs. The overall mortality in patients with acute pancreatitis is approximately 5%.1Banks P.A. Freeman M.L. Practice guidelines in acute pancreatitis.Am J Gastroenterol. 2006; 101: 2379-2400Crossref PubMed Scopus (696) Google Scholar Mortality is higher in patients with necrotizing pancreatitis compared with those with interstitial pancreatitis in which there is little necrosis (approximately 17% vs 3%, respectively). Among patients with necrotizing pancreatitis, mortality is greater in patients with infected necrosis than in those with sterile necrosis (approximately 30% vs 12%, respectively). The prevalence of infected necrosis in patients with necrotizing pancreatitis now appears to be approximately 15%–20% compared with approximately 35% several years ago. Far more patients have interstitial pancreatitis than necrotizing pancreatitis (approximately 85% vs 15%, respectively). Organ failure occurs more commonly in patients with necrotizing pancreatitis compared with those with interstitial pancreatitis (approximately 50% vs 5%–10%, respectively). In necrotizing pancreatitis, mortality is very low in the absence of organ failure (close to 0%); in the presence of single organ failure, mortality is generally less than 10%; with multisystem organ failure, mortality is in the range of 35%–50%. Approximately half of deaths in acute pancreatitis occur within the first 2 weeks of illness and are generally attributed to organ failure. The remainder of deaths occurs weeks to months after this interval, and death is generally related to organ failure associated with infected necrosis or complications of sterile necrosis. Although alcohol abuse and gallstone disease account for 70%–80% of the cases of acute pancreatitis, the exact mechanisms by which these factors initiate acute pancreatitis are presently unknown. In addition, because of the rapid course of the disease and the relative inaccessibility of pancreatic tissue for examination during pancreatitis, investigations of the mechanisms underlying these pathobiologic processes have been hampered. Considering these obstacles, investigators have turned to animal models of acute pancreatitis to reveal the molecular steps initiating these pathobiologic responses to identify potential targets for therapeutic intervention. The premise underlying this approach is that, although the exact triggering mechanism(s) for acute pancreatitis caused by alcohol and gallstones in humans is not established, key steps in mediating the pathobiologic processes that define acute pancreatitis can be identified from animal models, and used to develop therapies that can be ultimately tested in human pancreatitis. In this article, we will first describe our current state of knowledge about the mechanisms of pancreatitis, which are largely based on studies in animal models, followed by a discussion of the clinical disorder and its management, especially related to issues that give rise to severe disease. Finally, in the last section, we will provide our perspective about future research directions needed to improve outcome in this group of patients. Figure 1 represents an overview of processes that need to be considered. This figure illustrates unique extrapancreatic and intrapancreatic cellular events/factors involved in disease pathogenesis. Examples of extracellular factors include vascular and neural participation in pancreatitis. Examples of intracellular events/factors are activation of digestive enzymes, inhibition of secretion, cell calcium, heat shock proteins, inflammatory signaling pathways, and cell death pathways. Figure 1 suggests that these factors/events all have important roles in regulating inflammation, edema, and cell death responses as well as the systemic inflammatory response and multisystem organ failure in severe disease. There are 2 principal functions for animal model research in acute pancreatitis. These are investigations of the molecular mechanisms underlying the pathobiologic responses and testing of potential therapies before human trials. At present, only animal models provide the ability to reveal the sequence of initiating molecular steps resulting in the pathobiologic processes of acute pancreatitis. Moreover, there are considerable difficulties in designing human clinical trials related to the fact that the disease varies widely in course and severity. In addition, there is a low incidence of the most severe forms of pancreatitis in which testing agents for therapeutic benefit would have the most value. Thus, testing a large number of agents is not feasible. Animal models of acute pancreatitis can be used to screen potential therapies so that only the most promising ones advance to human testing. There have been several animal models of acute pancreatitis developed.2Foitzik T. Hotz H.G. Eibl G. Buhr H.J. Experimental models of acute pancreatitis: are they suitable for evaluating therapy?.Int J Colorectal Dis. 2000; 15: 127-135Crossref PubMed Scopus (33) Google Scholar, 3Hegyi P. Rakonczay Jr, Z. Sari R. Gog C. Lonovics J. Takacs T. Czako L. L-arginine-induced experimental pancreatitis.World J Gastroenterol. 2004; 10: 2003-2009Crossref PubMed Google Scholar, 4Pastor C.M. Frossard J.L. Are genetically modified mice useful for the understanding of acute pancreatitis?.FASEB J. 2001; 15: 893-897Crossref PubMed Scopus (45) Google Scholar, 5Pandol S.J. Gukovsky I. Satoh A. Lugea A. Gukovskaya A.S. Emerging concepts for the mechanism of alcoholic pancreatitis from experimental models.J Gastroenterol. 2003; 38: 623-628Crossref PubMed Scopus (29) Google Scholar, 6Schneider A. Whitcomb D.C. Singer M.V. Animal models in alcoholic pancreatitis—what can we learn?.Pancreatology. 2002; 2: 189-203Abstract Full Text PDF PubMed Scopus (63) Google Scholar, 7Pandol S.J. Gukovsky I. Satoh A. Lugea A. Gukovskaya A.S. Animal and in vitro models of alcoholic pancreatitis: role of cholecystokinin.Pancreas. 2003; 27: 297-300Crossref PubMed Scopus (30) Google Scholar, 8Kaiser A.M. Saluja A.K. Sengupta A. Saluja M. Steer M.L. Relationship between severity, necrosis, and apoptosis in five models of experimental acute pancreatitis.Am J Physiol. 1995; 269: C1295-C1304PubMed Google Scholar, 9Gukovskaya A.S. Perkins P. Zaninovic V. Sandoval D. Rutherford R. Fitzsimmons T. Pandol S.J. Poucell-Hatton S. Mechanisms of cell death after pancreatic duct obstruction in the opossum and the rat.Gastroenterology. 1996; 110: 875-884Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar The more commonly used models are listed in Table 1. The specific animal model selected for an experiment depends upon the specific goals of the experiment. For example, for testing a potential therapy, animal models with more severe pancreatitis and systemic inflammatory response should be used because this is the type of disease in which therapy will likely have the greatest benefit in humans. For studies designed to reveal the molecular signals underlying a particular pathobiologic response such as inflammation, cell death, or systemic inflammatory response, the most important issue in selection pertains to whether the particular animal model expresses the pathobiologic response under investigation. As Table 1 indicates, there are significant differences in the pathobiologic responses among species and among models in 1 species that must be considered to choose a model appropriate to address the response under investigation.8Kaiser A.M. Saluja A.K. Sengupta A. Saluja M. Steer M.L. Relationship between severity, necrosis, and apoptosis in five models of experimental acute pancreatitis.Am J Physiol. 1995; 269: C1295-C1304PubMed Google Scholar, 9Gukovskaya A.S. Perkins P. Zaninovic V. Sandoval D. Rutherford R. Fitzsimmons T. Pandol S.J. Poucell-Hatton S. Mechanisms of cell death after pancreatic duct obstruction in the opossum and the rat.Gastroenterology. 1996; 110: 875-884Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 10Mareninova O.A. Sung K.F. Hong P. Lugea A. Pandol S.J. Gukovsky I. Gukovskaya A.S. Cell death in pancreatitis: caspases protect from necrotizing pancreatitis.J Biol Chem. 2006; 281: 3370-3381Crossref PubMed Scopus (145) Google Scholar A recent mouse model of acute necrotizing pancreatitis has been introduced by the group of Saluja using intraperitoneal applications of L-arginine.11Dawra R. Sharif R. Phillips P. Dudeja V. Dhaulakhandi D. Saluja A.K. Development of a new mouse model of acute pancreatitis induced by administration of L-arginine.Am J Physiol Gastrointest Liver Physiol. 2007; 292: G1009-G1018Crossref PubMed Scopus (67) Google ScholarTable 1Models of Experimental Acute PancreatitisModelsSpeciesFeaturesCholecystokinin analogues (parenteral)RatPancreatic inflammation, apoptosis, mild necrosis. Systemic inflammationCholecystokinin analogues (parenteral)MousePancreatic inflammation, severe necrosis. Systemic inflammationPancreatic duct obstructionRatPancreatic apoptosisPancreatic duct obstructionOpossumPancreatic inflammation, severe necrosis. Systemic inflammationBile acid perfusion of pancreatic ductRatPancreatic inflammation, severe necrosis. Systemic inflammationCholine-deficient, ethionine-supplemented dietMousePancreatic inflammation, severe necrosis. Systemic inflammationArginine (parenteral)RatPancreatic inflammation, severe necrosis. Systemic inflammationAlcohol diet and cholesystokinin analogues (parenteral)RatPancreatic inflammation, mild necrosis. Systemic inflammation Open table in a new tab Of particular note, none of the models are caused by factors that we currently believe cause human pancreatitis. Thus, considerable caution should be used when applying the results from experimental animal models to designing therapies for humans. A judicious approach should include focus on treating a specific pathobiologic response; showing that the mechanism of the pathobiologic response is similar across several animal models; and that a proposed treatment is effective in attenuating the pathobiological response across several animal models. Of note, because genetically modified mice are becoming widely available, experimental models of acute pancreatitis are now often used to test the participation of specific biochemical pathways.4Pastor C.M. Frossard J.L. Are genetically modified mice useful for the understanding of acute pancreatitis?.FASEB J. 2001; 15: 893-897Crossref PubMed Scopus (45) Google Scholar It is generally believed that the severity of pancreatitis might be determined by events that occur after acinar cell injury. Pancreatic acinar cells also synthesize and release cytokines and chemokines, resulting in the recruitment of inflammatory cells such as neutrophils and macrophages. Recruitment and activation of various inflammatory cells leads to further acinar cell injury and causes an elevation of various proinflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1, IL-2, IL-6, and other chemokines and anti-inflammatory factors such as IL-10 and IL-1 receptor antagonist.12Davies M.G. Hagen P.O. Systemic inflammatory response syndrome.Br J Surg. 1997; 84: 920-935Crossref PubMed Scopus (297) Google Scholar, 13Makhija R. Kingsnorth A.N. Cytokine storm in acute pancreatitis.J Hepatobiliary Pancreat Surg. 2002; 9: 401-410Crossref PubMed Scopus (191) Google Scholar The role of some of these cytokines in disease severity has been demonstrated for some including TNF-α and IL-1 using animals with genetic deletions for receptors for these cytokines.14Denham W. Yang J. Fink G. Denham D. Carter G. Ward K. Norman J. Gene targeting demonstrates additive detrimental effects of interleukin 1 and tumor necrosis factor during pancreatitis.Gastroenterology. 1997; 113: 1741-1746Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar These inflammatory cells and mediators play a role in the systemic manifestations besides modulating pancreatic acinar cell injury. In most patients, the acinar cell damage and local inflammation associated with pancreatitis will resolve, but, in some cases, the disease progresses to systemic illness. Systemic inflammatory response syndrome (SIRS) is a result of uncontrolled local inflammation and predisposes to multiple organ failure. Pancreatitis-associated lung injury (adult respiratory distress syndrome [ARDS]) is frequently a factor in the early death of patients with severe acute pancreatitis.15Robertson C.S. Basran G.S. Hardy J.G. Lung vascular permeability in patients with acute pancreatitis.Pancreas. 1988; 3: 162-165Crossref PubMed Google Scholar Several key inflammatory mediators including platelet-activating factor (PAF) and substance P have been identified to play a key role in experimental cholecystokinin (CCK)-induced pancreatitis as well as in human disease. Inhibition of PAF by either accelerating its degradation by recombinant PAF acetylhydrolase16Hofbauer B. Saluja A.K. Bhatia M. Frossard J.L. Lee H.S. Bhagat L. Steer M.L. Effect of recombinant platelet-activating factor acetylhydrolase on two models of experimental acute pancreatitis.Gastroenterology. 1998; 115: 1238-1247Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar or PAF antagonists17Ais G. Lopez-Farre A. Gomez-Garre D.N. Novo C. Romeo J.M. Braquet P. Lopez-Novoa J.M. 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Zaninovic V. Gorelick F.S. Lusis A.J. Brennan M.L. Holland S. Pandol S.J. Neutrophils and NADPH oxidase mediate intrapancreatic trypsin activation in murine experimental acute pancreatitis.Gastroenterology. 2002; 122: 974-984Abstract Full Text Full Text PDF PubMed Google Scholar, 28Frossard J.L. Saluja A. Bhagat L. Lee H.S. Bhatia M. Hofbauer B. Steer M.L. The role of intercellular adhesion molecule 1 and neutrophils in acute pancreatitis and pancreatitis-associated lung injury.Gastroenterology. 1999; 116: 694-701Abstract Full Text Full Text PDF PubMed Google Scholar In addition to the involvement of extracellular signaling in the inflammatory response described above, mechanisms of intracellular signaling have also been identified that mediate the inflammatory response in the pancreas and are systemically.29Singh V.P. Saluja A.K. Bhagat L. van Acker G.J. Song A.M. Soltoff S.P. Cantley L.C. Steer M.L. Phosphatidylinositol 3-kinase-dependent activation of trypsinogen modulates the severity of acute pancreatitis.J Clin Invest. 2001; 108: 1387-1395Crossref PubMed Google Scholar, 30Gukovsky I. Reyes C.N. Vaquero E.C. Gukovskaya A.S. Pandol S.J. Curcumin ameliorates ethanol and nonethanol experimental pancreatitis.Am J Physiol Gastrointest Liver Physiol. 2003; 284: G85-G95Crossref PubMed Google Scholar, 31Vaquero E. Gukovsky I. Zaninovic V. Gukovskaya A.S. Pandol S.J. Localized pancreatic NF-kappaB activation and inflammatory response in taurocholate-induced pancreatitis.Am J Physiol Gastrointest Liver Physiol. 2001; 280: G1197-G1208PubMed Google Scholar, 32Gukovsky I. Gukovskaya A.S. Blinman T.A. Zaninovic V. Pandol S.J. Early NF-kappaB activation is associated with hormone-induced pancreatitis.Am J Physiol. 1998; 275: G1402-G1414PubMed Google Scholar, 33Gukovsky I. Cheng J.H. Nam K.J. Lee O.T. Lugea A. Fischer L. Penninger J.M. Pandol S.J. Gukovskaya A.S. Phosphatidylinositide 3-kinase gamma regulates key pathologic responses to cholecystokinin in pancreatic acinar cells.Gastroenterology. 2004; 126: 554-566Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar These signaling systems include nuclear factor-κB (NF-κB) activator protein-1 (AP-1), MAPK-modules, Stat3, and phosphatidylinositol-3 kinase (PI-3 kinase). Inhibition of these signals has been demonstrated to decrease inflammation and improve the severity of pancreatitis in most cases.29Singh V.P. Saluja A.K. Bhagat L. van Acker G.J. Song A.M. Soltoff S.P. Cantley L.C. Steer M.L. Phosphatidylinositol 3-kinase-dependent activation of trypsinogen modulates the severity of acute pancreatitis.J Clin Invest. 2001; 108: 1387-1395Crossref PubMed Google Scholar, 30Gukovsky I. Reyes C.N. Vaquero E.C. Gukovskaya A.S. Pandol S.J. Curcumin ameliorates ethanol and nonethanol experimental pancreatitis.Am J Physiol Gastrointest Liver Physiol. 2003; 284: G85-G95Crossref PubMed Google Scholar, 31Vaquero E. Gukovsky I. Zaninovic V. Gukovskaya A.S. Pandol S.J. Localized pancreatic NF-kappaB activation and inflammatory response in taurocholate-induced pancreatitis.Am J Physiol Gastrointest Liver Physiol. 2001; 280: G1197-G1208PubMed Google Scholar, 32Gukovsky I. Gukovskaya A.S. Blinman T.A. Zaninovic V. Pandol S.J. Early NF-kappaB activation is associated with hormone-induced pancreatitis.Am J Physiol. 1998; 275: G1402-G1414PubMed Google Scholar, 34Chen X. Ji B. Han B. Ernst S.A. Simeone D. Logsdon C.D. NF-kappaB activation in pancreas induces pancreatic and systemic inflammatory response.Gastroenterology. 2002; 122: 448-457Abstract Full Text Full Text PDF PubMed Google Scholar Studies of NF-κB have demonstrated that it is activated in the pancreatic acinar cell early before the influx of inflammatory cells into the tissue.32Gukovsky I. Gukovskaya A.S. Blinman T.A. Zaninovic V. Pandol S.J. Early NF-kappaB activation is associated with hormone-induced pancreatitis.Am J Physiol. 1998; 275: G1402-G1414PubMed Google Scholar Intraductal adenoviral gene transfer of the activating subunit RelAp65 was sufficient to induce acute pancreatitis with systemic complications.34Chen X. Ji B. Han B. Ernst S.A. Simeone D. Logsdon C.D. NF-kappaB activation in pancreas induces pancreatic and systemic inflammatory response.Gastroenterology. 2002; 122: 448-457Abstract Full Text Full Text PDF PubMed Google Scholar However, pharmacological strategies to inhibit NF-κB activation revealed mixed results. Most studies suggest a harmful role of NF-κB activation with one exception proposing a protective role.35Steinle A.U. Weidenbach H. Wagner M. Adler G. Schmid R.M. NF-kappaB/Rel activation in cerulein pancreatitis.Gastroenterology. 1999; 116: 420-430Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar Furthermore, pharmalogical inhibition of MAPK-modules during the onset of acute pancreatitis resulted in mixed outcomes as well.36Wagner A.C. Mazzucchelli L. Miller M. Camoratto A.M. Goke B. CEP-1347 inhibits caerulein-induced rat pancreatic JNK activation and ameliorates caerulein pancreatitis.Am J Physiol Gastrointest Liver Physiol. 2000; 278: G165-G172PubMed Google Scholar, 37Fleischer F. Dabew R. Goke B. Wagner A.C. Stress kinase inhibition modulates acute experimental pancreatitis.World J Gastroenterol. 2001; 7: 259-265Crossref PubMed Scopus (33) Google Scholar Interestingly, blocking PI3-Kinase activation resulted in amelioration of pancreatitis in 2 rodent models without affecting NF-κB activation. The interaction and cross talk of these signaling pathways is not well understood. Thus, a better understanding of the signaling network is mandatory for the identification of therapeutic targets. Activation of acinar cell CCK and TNF-α receptors through effects on protein kinase C isoforms can cause the NF-κB activation in acinar cells.38Han B. Logsdon C.D. CCK stimulates mob-1 expression and NF-kappaB activation via protein kinase C and intracellular Ca(2+).Am J Physiol Cell Physiol. 2000; 278: C344-C351PubMed Google Scholar, 39Satoh A. Gukovskaya A.S. Nieto J.M. Cheng J.H. Gukovsky I. Reeve Jr, J.R. Shimosegawa T. Pandol S.J. PKC-delta and -epsilon regulate NF-kappaB activation induced by cholecystokinin and TNF-alpha in pancreatic acinar cells.Am J Physiol Gastrointest Liver Physiol. 2004; 287: G582-G591Crossref PubMed Scopus (104) Google Scholar, 40Satoh A. Gukovskaya A.S. Edderkaoui M. Daghighian M.S. Reeve Jr, J.R. Shimosegawa T. Pandol S.J. Tumor necrosis factor-alpha mediates pancreatitis responses in acinar cells via protein kinase C and proline-rich tyrosine kinase 2.Gastroenterology. 2005; 129: 639-651Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 41Satoh A. Gukovskaya A.S. Reeve Jr, J.R. Shimosegawa T. Pandol S.J. Ethanol sensitizes NF-kappaB activation in pancreatic acinar cells through effects on protein kinase C-epsilon.Am J Physiol Gastrointest Liver Physiol. 2006; 291: G432-G438Crossref PubMed Scopus (44) Google Scholar, 42Tando Y. Algul H. Wagner M. Weidenbach H. Adler G. Schmid R.M. Caerulein-induced NF-kappaB/Rel activation requires both Ca2+ and protein kinase C as messengers.Am J Physiol. 1999; 277: G678-G686PubMed Google Scholar In addition to up-regulating proinflammatory cytokines, NF-κB can increase adhesion molecule ICAM-1 effect in the pancreas.43Zaninovic V. Gukovskaya A.S. Gukovsky I. Mouria M. Pandol S.J. Cerulein upregulates ICAM-1 in pancreatic acinar cells, which mediates neutrophil adhesion to these cells.Am J Physiol Gastrointest Liver Physiol. 2000; 279: G666-G676PubMed Google Scholar NF-κB is also involved in the systemic inflammatory response of acute pancreatitis. The involvement of the pancreatic enzymes themselves in the systemic inflammatory response of acute pancreatitis has been proposed. For example, pancreatic elastase but not amylase and lipase causes the pulmonary injury of the adult respiratory distress syndrome by activating NF-κB in pulmonary tissue.44Jaffray C. Yang J. Carter G. Mendez C. Norman J. Pancreatic elastase activates pulmonary nuclear factor kappa B and inhibitory kappa B, mimicking pancreatitis-associated adult respiratory distress syndrome.Surgery. 2000; 128: 225-231Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar Pancreatic elastase causes liver injury through increasing cytokine production in Kupffer cells utilizing NF-κB signaling.45Murr M.M. Yang J. Fier A. Kaylor P. Mastorides S. Norman J.G. Pancreatic elastase induces liver injury by activating cytokine production within Kupffer cells via nuclear factor-Kappa B.J Gastrointest Surg. 2002; 6: 474-480Crossref PubMed Scopus (45) Google Scholar However, recent data question this concept since various elastase preparations were found to be contaminated with LPS, and low endotoxin elastase failed to induce proinflammatory effects in vivo and in vitro.46Geisler F. Algul H. Riemann M. Schmid R.M. Questioning current concepts in acute pancreatitis: endotoxin contamination of porcine pancreatic elastase is responsible for experimental pancreatitis-associated distant organ failure.J Immunol. 2005; 174: 6431-6439Crossref PubMed Google Scholar Although less well investigated, stress kinases Erk and p38 are also activated in experimental pancreatitis and may play a role in pathogenesis.47Samuel I. Zaheer A. Fisher R.A. In Vitro Evidence for Role of ERK, p38, and JNK in Exocrine Pancreatic Cytokine Production.J Gastrointest Surg. 2006; 10: 1376-1383Crossref PubMed Scopus (17) Google Scholar, 48Pereda J. Sabater L. Cassinello N. Gomez-Cambronero L. Closa D. Folch-Puy E. Aparisi L. Calvete J. Cerda M. Lledo S. Vina J. Sastre J. Effect of simultaneous inhibition of TNF-alpha production and xanthine oxidase in experimental acute pancreatitis: the role of mitogen activated protein kinases.Ann Surg. 2004; 240: 108-116Crossref PubMed Scopus (82) Google Scholar, 49Blinman T.A. Gukovsky I. Mouria M. Zaninovic V. Livingston E. Pandol S.J. Gukovskaya A.S. Activation of pancreatic acinar cells on isolation from tissue: cytokine upregulation via p38 MAP kinase.Am J Physiol Cell Physiol. 2000; 279: C1993-C2003PubMed Google Scholar Of particular interest are observations that during pancreatitis, there is up-regulation of an anti-inflammatory system that is probably protective. This system includes a transcriptional regulator called p8, and it is one of its regulated genes, pancreatitis-associated protein I (PAPI).50Vasseur S. Folch-Puy E. Hlouschek V. Garcia S. Fiedler F. Lerch M.M. Dagorn J.C. Closa D. Iovanna J.L. p8 improves pancreatic response to acute pancreatitis by enhancing the expression of the anti-inflammatory protein pancreatitis-associated protein I.J Biol Chem. 2004; 279: 7199-7207Crossref PubMed Scopus (97) Google Scholar, 51Hoffmeister A. Ropolo A. Vasseur S. Mallo G.V. Bodeker H. Ritz-Laser B. Dressler G.R. Vaccaro M.I. Dagorn J.C. Moreno S. Iovanna J.L. The HMG-I/Y-related protein p8 binds to p300 and Pax2 trans-activation domain-interacting protein to regulate the trans-activation activity of the Pax2A and Pax2B transcription factors on the glucagon gene promoter.J Biol Chem. 2002; 277: 22314-22319Crossref PubMed Scopus (52) Google Scholar Both p8 and PAPI are rapidly induced during pancreatitis. Animals with genetic deletions of p8 have a markedly augmented pancreatic inflammatory response during pancreatitis,50Vasseur S. Folch-Puy E. Hlouschek V. Garcia S. Fiedler F. Lerch M.M. Dagorn J.C. Closa D. Iovanna J.L. p8 improves pancreatic response to acute pancreatitis by enhancing the expression of the anti-inflammatory protein pancreatitis-associated protein I.J Biol Chem. 2004; 279: 7199-7207Crossref PubMed Scopus (97) Google Scholar and antibodies to PAPI injected into animals with experimental pancreatitis also markedly augmented pancreatic inflammation.50Vasseur S. Folch-Puy E. Hlouschek V. Garcia S. Fiedler F. Lerch M.M. Dagorn J.C. Closa D. Iovanna J.L. p8 improves pancreatic response to acute pancreatitis by enhancing the expression of the a