Pathophysiology of Pancreatitis

Acute PancreatitisNew Approaches for the Management of Acute Pancreatitis

Digestion 1999;60(suppl 1):27–33

Pathophysiology of PancreatitisRole of Cytokines and Other Mediators of Inflammation

Ashok K. Saluja Michael L. Steer

Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, Mass., USA

Ashok K. Saluja, PhDHarvard Medical School and Beth Israel Deaconess Medical CenterBoston MA 02215 (USA)Tel. +1 617 667 5369, Fax +1 617 667 8679, E-Mail [email protected]

ABCFax + 41 61 306 12 34E-Mail [email protected]

© 1999 S. Karger AG, Basel0012–2823/99/0607–0027$17.50/0

Accessible online at:http://BioMedNet.com/karger

Key WordsAcinar cells W Caerulein W Platelet-activating factor W Ca5 W

Substance P W Lung injury

AbstractAcute pancreatitis is an inflammatory disease, which var-

ies in severity from mild to severe. Factors determining

the severity of pancreatitis are not known. It is generally

believed that the earliest events in the evolution of acute

pancreatitis lead to premature intra-acinar cell activation

of digestive zymogens and that those enzymes, once

activated cause acinar cell injury. Recent studies have

suggested that the ultimate severity of resulting pancre-

atitis may be determined by events which occur subse-

quent to acinar cell injury. These include inflammatory

cell recruitment and activation as well as the generation

and release of cytokines and other chemical mediators of

inflammation. Recently, we have undertaken studies to

elucidate the role of various inflammatory agents in

determining the severity of pancreatitis. Results from

these ongoing studies indicate that substance P acting

via neurokinin-1 (NK1) receptors, chemokines interacting

with CCR1 receptors and platelet activating factor play an

important pro-inflammatory role in regulating the severi-

ty of pancreatitis and associated lung injury. On the other

hand, complement factor 5a (C5a) acts as an anti-inflam-

matory agent during the development of pancreatitis.

Acute pancreatitis is an inflammatory disease thatoccurs in varying degrees of severity, the determinants ofwhich are not known. The belief generally prevalent todayis that pancreatitis begins with the activation inside theacinar cells of digestive zymogens which, once activated,cause acinar cell injury. Recent studies have suggestedthat the ultimate severity of the resulting pancreatitis maybe determined by events which occur subsequent to aci-nar cell injury. These include inflammatory cell recruit-ment and activation as well as the generation and releaseof cytokines and other chemical mediators of inflamma-tion (fig. 1). This article reviews some of our recent workdealing with the steps involved in the initiation of pancre-atitis and factors which determine its severity.

Events Leading to the Onset of Pancreatitis

The exocrine pancreas must function in the unenviablesituation of producing several enzymes that are potential-ly injurious to itself. The modus operandi it has evolved toprevent self-digestion is to assemble, intracellularly, trans-port and secrete to the outside the inactive precursors ofthese enzymes, which are called proenzymes or zymogens.Their activation occurs safely in the duodenum, where thebrush-border enzyme enteropeptidase activates the tryp-sinogen, and the resulting trypsin then activates the otherzymogens in a cascade reaction. It is generally believed

28 Digestion 1999;60(suppl 1):27–33 Saluja/Steer

Fig. 1. Schematic representation of the mechanism of pathogenesisof acute pancreatitis.

Insult

Block in secretion

Colocalization of zymogens and lysosomal enzymes

Activation of trypsinogen

Activation of other zymogens

Cell injury

Release of chemokines, cytokines and PAF

Leukocyte infiltration

Increased release of cytokines

Severe pancreatitis

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Fig. 2. Protein synthesis and discharge during secretagogue-inducedpancreatitis. Rats were preinfused with saline alone ([) or with cae-rulein (P; 5 Ìg/kg/h) and given a pulse of [3H]phenylalanine followedby a nonradioactive bolus of phenylalanine. At selected times, ratswere sacrificed and TCA precipitable radioactivity in pancreashomogenates was measured. Saluja et al. [7].

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that acute pancreatitis occurs when this process goes awryand the gland is injured by the erroneously activatedenzymes that it normally produces. There are three rea-sons for believing that this is so: (a) the pancreas is digest-ible by the activated enzymes of the duodenum; (b) acti-vated digestive enzymes are found within the pancreasduring pancreatitis, and (c) the histology of pancreatitis issuggestive of a coagulative necrosis [1–3]. However, themechanism of erroneous activation has been cloaked inconjecture until rather recently.

Using several different models, our research has fo-cused intensively upon the etiology of that activationmechanism [4–6]. It was seen that the synthesis and intra-cellular transport of digestive enzymes are not affectedduring the development of pancreatitis in these models,but that the secretory output of enzymes from the pan-creas is markedly reduced (fig. 2) [7]. Very early in thedevelopment of the disease (shortly after the onset butbefore morphological or biochemical changes are appar-ent), digestive enzymes are localized in cytoplasmic va-cuoles that also contained the lysosomal hydrolase cathep-sin B, which, it is known, can activate trypsinogen. Fur-thermore, we found evidence of intracellular trypsinogenactivation synchronously with the co-localization phe-

nomenon [8, 9]. When we inhibited the cathepsin B invitro using the highly specific, cell-permeant inhibitorE64D, we could prevent the supramaximal secretagogue-induced activation of trypsinogen (fig. 3) [10]. We con-clude from these studies that trypsinogen is activatedbecause it erroneously colocalizes in cytoplasmic vacuoleswith cathepsin B. The path is now open for autodigestion,because this activated trypsin, when released into thecytoplasm, can cause injury, and additionally it may acti-vate other enzymes capable of causing autodigestive cellinjury [11].

Factors Determining the Severity ofPancreatitis

Clinically, the severity of acute pancreatitis varies sig-nificantly. Some patients experience the milder form ofthe disease which is self-limiting, while others suffer moresevere, frequently lethal attacks.

Pathophysiology of Pancreatitis Digestion 1999;60(suppl 1):27–33 29

Fig. 3. Effect of E64-d on cathepsin B activity and caerulein-inducedactivation of trypsinogen. After a 30-min preincubation with 1 mME64-d, rat pancreatic acini were incubated with 0.1 ÌM caeruleinalong with E64-d for 30 min and cathepsin B (X) and trypsin (i)activities in the homogenates was measured. Results are expressed aspercent of activity obtained with caerulein alone. Values are ex-pressed as means B SEM obtained from at least three experiments.Saluja et al. [10].

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Fig. 4. Effect of rPAF-AH on the acinar cell injury/necrosis in opos-sum following CPBD ligation. CPBD ligation was performed inAmerican opossums followed by treatment with PAF-AH (5 mg/kg/day). Acinar cell injury/necrosis was quantitated as a percent of totalarea in pancreas HE sections.

The factors determining the severity of pancreatitis arenot known, but it is obvious that their identification is ofconsiderable therapeutic importance, since their manipu-lation may decrease the morbidity and mortality associat-ed with the disease. It is generally recognized that the ini-tial events in the development of acute pancreatitis occurwithin the acinar cells, resulting in acinar cell injury asdescribed in the preceding section. This initial injurycauses the release of several factors from both acinar cellsand leukocytes, though an additional, yet uncharacterizedsource of these factors cannot be ruled out. Release ofthese factors could result in recruitment of inflammatorycells and generation of other mediators which can furtherinfluence the severity of acute pancreatitis. Several recentstudies have identified these agents, though their natureand action remain to be understood. These determinantsinclude oxygen-derived free radicals, pancreatic gluta-thione, ischemia, mode of acinar cell death (apoptosis vs.necrosis), cytokines, chemokines and neurokines [12–19].Recently, our group has undertaken a number of studies

to evaluate the role of many of these factors in regulatingthe severity of pancreatitis. A brief review of some ofthese ongoing studies follows.

Platelet-activating factor (PAF) is a potent pro-inflam-matory lipid mediator released by a number of cell typesincluding epithelial cells, mast cells, macrophages, andendothelial cells [20]. PAF has also been linked to thepathogenesis of several inflammatory diseases includingpancreatitis. In our recent studies [18], we have evaluatedthe role of PAF in the pathogenesis of acute pancreatitisby terminating its action with recombinant PAF-acetylhy-drolase (rPAF-AH, ICOS Corp, Bothell, Wash., USA) in asevere form of pancreatitis induced by obstruction of thecommon pancreatic bile duct in opossums – a situationsimilar to that observed during biliary pancreatitis. Thismodel of pancreatitis is associated with hyperamylasemiaand extensive pancreatic necrosis, which increase with theduration of duct obstruction. This model is also associat-ed with lung injury which can be quantitated by measur-ing changes in microvascular permeability and histologi-cal evaluation of lung tissue. The results obtained in thisstudy indicate that rPAF-AH given 2 days after duct liga-tion resulted in significant amelioration of acinar cellinjury and necrosis (fig. 4) [18]. Furthermore, treatmentwith rPAF-AH almost totally prevented lung injury.These results suggest that PAF plays an important pro-inflammatory role in the development of pancreatitis, andthat rPAF-AH may be of therapeutic rather than prophy-lactic value in the management of acute pancreatitis and


Fig. 5. Effects of NK1R deletion on caerulein-induced pancreatitis.Mice were given 12-hourly injections of caerulein (50 Ìg/kg i.p.). Onehour after the last caerulein injection, mice were sacrificed andserum amylase activity, serum lipase activity, pancreatic MPO activ-ity and acinar cell necrosis were measured as described in the text.Values are expressed as a percent of the values obtained for wild-type animals given caerulein. These values (100%) were as follows:serum amylase: 32,865 B 4,064 U/l; serum lipase: 4,074 B 380 U/l;pancreas MPO: 1.73 B 0.18-fold increase over saline-treated con-trols; acinar cell injury/necrosis: 31.3 B 3.64. Results shown aremean B SEM for 10 or more animals in each group. * p ! 0.05 whenNK1R–/– animals were compared to NK1R+/+ animals. Bhatia etal. [23].

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Fig. 6. Effects of NK1R receptor deletion on pancreatitis-associat-ed lung injury. Mice were given 12-hourly injections of caerulein(50 Ìg/kg i.p.). One hour after the last caerulein injection, mice weresacrificed and capillary leakage of FITC-albumin and lung MPOactivity were measured as described in the text. Values are expressedas a percent of the value obtained for wild type animals given caeru-lein. These values (100%) were as follows: lung MPO activity 3.06 B0.37; FITC-albumin bronchoalveolar lavage fluid to serum ratio 2.13B 0.24. Results shown are mean B SEM for 10 or more animals ineach group. * p ! 0.05 when NK1R–/– animals were compared toNK1R+/+ animals. Bhatia et al. [23].

associated lung injury. Clinical studies on rPAF-AH’seffectiveness in patients with pancreatitis are indicated inthe light of these observations.

Substance P is a neuropeptide released from sensoryafferent nerve endings [21]. Once released, substance Phas two major effects: it binds to the NK-1 receptor on thesurface of the effector cells and it increases the permeabil-ity of vascular endothelium. Several studies have shownthat substance P plays an important role in regulating theextent of inflammation in many diseases including arthri-tis, immune complex-mediated lung injury, asthma, andinflammatory bowel disease [22]. Recently, we have un-dertaken studies to evaluate the role of substance P and itsreceptor (NK-1R) in regulating the severity of pancreatitis[23]. We induced pancreatitis in mice by giving 12-hourlyinjections of a supramaximally stimulatory dose of thesecretagogue caerulein. This model of pancreatitis is char-acterized by massive hyperamylasemia, pancreatic ede-ma, sequestration of neutrophils in the pancreas and mor-

phological evidence of acinar cell necrosis/injury. Thepancreatitis observed in this model is also associated withlung injury evidenced by increased microvascular perme-ability, increased sequestration of neutrophils in the lungsand morphological evidence of alveolar membrane thick-ening. Our studies show that the total quantity of sub-stance P is increased in the pancreas during episodes ofacute pancreatitis, and that the acinar cell expression ofNK-1 receptors is also markedly upregulated. Further-more, genetic deletion of NK-1R (NK-1R knockout) inmice resulted in a marked decrease in the parameters thatcharacterize the severity of pancreatitis induced by ad-ministration of caerulein. We have found that the geneticlack of NK-1 receptors confers partial protection againstpancreatitis (fig. 5), and markedly protects against pan-creatitis-associated lung injury (fig. 6) in mice. We inter-pret these findings to indicate that substance P, acting viaNK-1 receptors, is a powerful pro-inflammatory mediatorof both pancreatitis and pancreatitis-associated lung inju-


Fig. 7. Effects of CCR1 deletion on caerulein-induced pancreatitis.Mice were given 12-hourly injections of caerulein (50 Ìg/kg i.p.). Onehour after the last caerulein injection, mice were sacrificed andserum amylase activity, serum lipase activity, pancreatic MPO activ-ity and acinar cell necrosis were measured as described in the text.Values are expressed as a percent of the values obtained for wild-typeanimals given caerulein. Results shown are mean B SEM for 10 ormore animals in each group. * p ! 0.05 when CCR1–/– animals werecompared to CCR1+/+ animals. Gerard et al. [28].

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ry. The mechanism(s) by which substance P exerts its pro-inflammatory effects and increases the severity of pancre-atitis are not yet understood.

In another study we have evaluated the role of comple-ment in regulating the severity of pancreatitis. The com-plement system consists of several different proteins,which are activated by the classical and alternative path-ways [24]. This activation process involves a cascade ofenzymatic steps in which various peptides are cleaved,resulting in activated factors. Many of these fragmentsplay an important role in the regulation of different bio-logical processes. One of the most potent of these frag-ments is C5a which is generated during the cleavage offactor C5. C5a is a powerful anaphylatoxin and is be-lieved to be a pro-inflammatory mediator because it stim-ulates smooth muscle contraction, increases blood flowand enhances vascular permeability [25]. Consideringthese well-established roles of C5a, we had expected thatC5a would act as a pro-inflammatory agent in pancreatitisand that mice which genetically lack C5a receptors wouldhave decreased severity of pancreatitis. However, we were

surprised to find that pancreatitis was more severe inmice lacking genes for C5a receptors. A worsening wasobserved for each of the parameters used to evaluate theseverity of caerulein-induced pancreatitis, i.e. serum amy-lase, neutrophil sequestration in the pancreas (quanti-tated by the MPO activity) and acinar cell necrosis [26].The severity of pancreatitis-associated lung injury (in-creased microvascular permeability, lung MPO activity)was also increased in knockout mice incapable of re-sponding to C5a. Similar results were observed when pan-creatitis was induced in mice which do not express C5.These observations led us to the surprising conclusionthat C5a, acting via the C5a receptor, is actually an anti-inflammatory factor at least during caerulein-inducedpancreatitis. However, the mechanisms responsible forthis effect are not obvious. One possible explanation forthis effect could be that C5a might act in pancreatitis bypromoting the release of IL-10. Indeed, several recentreports have suggested that exogenously-administered IL-10 reduces the severity of pancreatitis [19]. We tested thispossibility by neutralizing endogenous IL-10 by adminis-tration of IL-10 antibody to wild-type mice. However, theresults of these experiments indicate that IL-10 neutrali-zation had no effect on the severity of caerulein-inducedpancreatitis or pancreatitis-associated lung injury. Thus,the mechanisms responsible for the anti-inflammatoryeffect of C5a during pancreatitis remain unknown, al-though it is possible that C5a acts by releasing yet anotheranti-inflammatory agent.

Chemokines are chemoattractant cytokines that areinvolved in the activation and trafficking of variousinflammatory cells [27]. An array of chemokine receptorshas been characterized. Several of these receptors arecapable of recognizing many different chemokines. Oneof these chemokine receptors, CCR1, recognizes chemo-kine MIP1a, RANTES and MCP-3 among others. Wehave recently evaluated the role of these chemokines inregulating the severity of acute pancreatitis and associatedlung injury [28]. For these studies we have used knockoutmice that lacked the CCR1 receptors. Administration ofsupramaximally stimulatory doses of caerulein to wild-type mice results in acute pancreatitis which is character-ized by an increase in serum amylase, pancreatic edema,acinar cell necrosis as well as infiltration of various leuko-cytes into the pancreatic tissue. Similar changes wereobserved when caerulein was administered to mice thatlacked CCR1 receptors (fig. 7). These findings suggestthat chemokines acting via CCR1 receptors have little, ifany, role in determining the severity of pancreatitis. Incontrast to its effects on pancreatitis, deletion of CCR1


Fig. 8. Effects of CCR1 deletion on pancreatitis-associated lung inju-ry. Mice were given 12-hourly injections of caerulein (50 Ìg/kg i.p.).One hour after the last caerulein injection, mice were sacrificed andcapillary leakage of FITC-albumin and lung MPO activity were mea-sured as described in the text. Values are expressed as a percent of thevalue obtained for wild type animals given caerulein. Results shownare mean B SEM for 10 or more animals in each group. * p ! 0.05when CCR1–/– animals were compared to CCR1+/+ animals. Ger-ard et al. [28].

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receptors had a significant effect on pancreatitis-associat-ed lung injury. Caerulein-induced pancreatitis in wild-type mice resulted in lung injury which was manifested byan increase in microvascular permeability, rise in lungMPO (a measure of neutrophil sequestration) and thick-ening of alveolar membranes. In CCR1 receptor-deficient

Table 1. Cytokines, chemokines and neuropeptides in acute pancre-atitis

Pro-inflammatory Anti-inflammatory

IL-1 C5aIL-6 IL-10TNF-· IL-11 (?)PAFMIP1-·Substance P

mice, these changes in lung injury were significantlyattenuated (fig. 8). These mice also showed a markeddecrease in pulmonary levels of TNF-· during episodes ofexperimentally induced pancreatitis.

These observations indicate that genetic deletion ofCCR1 receptors dramatically reduces the severity of lunginjury associated with caerulein-induced pancreatitis.Furthermore, the results of this study indicate that activa-tion of CCR1 receptors resulting in TNF-· release is anearly event in the systemic inflammatory response ob-served during pancreatitis.

Table 1 shows several factors that play active roles inpancreatitis as pro- or anti-inflammatory agents, and webelieve that more will be discovered in the near future. Assuch, we are hopeful that drugs or other interventionsdesigned to favor anti-inflammatory events or counteractpro-inflammatory events will prove useful in treating clin-ical pancreatitis. We believe that the identification ofthese factors is but a preliminary step in the developmentof interventions that will reduce the severity of pancreaticinjury in pancreatitis and associated systemic manifesta-tions, e.g. lung injury.

References

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3 Acosta JL, Ledesma CL: Gallstone migrationas a cause for acute pancreatitis. N Engl J Med1974;190:484–487.

4 Lerch MM, Saluja AK, Runzi M, Dawra R,Saluja M, Steer ML: Pancreatic duct obstruc-tion triggers acute necrotizing pancreatitis inthe opossum. Gastroenterology 1993;104:853–861.

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8 Grady T, Saluja A, Kaiser A, Steer M: Pan-creatic edema and intrapancreatic activation oftrypsinogen during secretagogue-induced pan-creatitis precedes glutathione depletion. Am JPhysiol 1996;271:G20–26.


9 Hofbauer B, Saluja AK, Lerch MM, Bhagat L,Bhatia M, Lee HS, Frossard J-L, Adler G, SteerML: Intra-acinar cell activation of trypsinogenduring caerulein-induced pancreatitis in rats.Am J Physiol 1998;275:G352–362.

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19 Rongione AJ, Kusske AM, Kwan K, AshleySW, Reber HA, McFadden DW: Interleukin 10reduces the severity of acute pancreatitis inrats. Gastroenterology 1997;112:960–967.

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22 Bowden JJ, Garland AM, Baluk P, Lefevre P,Grady EF, Vigna SR, Bunnett NW, McDonaldDM: Direct observation of substance P-in-duced internalization of neurokinin 1 (NK1)receptors at sites of inflammation. Proc NatlAcad Sci USA 1994;91:8964–8968.

23 Bhatia M, Saluja AK, Hofbauer B, Frossard JL,Lee HS, Castagliuolo I, Wang CC, Gerard N,Pothoulakis C, Steer ML: Role of substance Pand the NK1 receptor in acute pancreatitis andpancreatitis-associated lung injury. Proc NatlAcad Sci USA 1998;95:4760–4765.

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Pathophysiology of Pancreatitis