Q J Med 2000; 93: 469-476
© 2000 Association of Physicians
Commentary papers |
Mast cell: pivotal player in lethal acute pancreatitis
In association with the Pancreato-Biliary Service, Manchester Royal Infirmary, Manchester, UK
Introduction
The fearful aura of acute pancreatitis stems from the imagery of an organ and organism under threat of cannibalization by pancreatic enzymes that have become active prematurely. This century-old autodigestion theory1 is all too plausible when one is confronted with the necrohaemorrhagic remains of the gland in a patient who succumbs from multisystem organ failure, as do 10–20% of cases. It was challenged2 when the average interval from onset of symptoms to death was found to be shorter (under 48 h) and the degree of initial shock greater with interstitial pancreatitis—which accounts for a quarter of the toll3—than with wholesale coagulative necrosis, an infarct-like lesion associated with hyaline occlusion of venules and capillaries.2
Progress on pathogenesis
The literature is colossal—4844 titles in a Medline search from 1966, and 260 in 1999—but the current position can be gleaned from a recent monograph,4 an assortment of reviews5–11 and supplementary papers. Of necessity, much reliance has been placed on studies of experimental pancreatitis to unravel the earliest aberrations. From these and clinical studies, it is now believed that the ‘attack’ begins in the acinar cell, with a functional blockade in the secretory pathway towards exocytosis of zymogen granules. It is also agreed that multiorgan collapse is primarily due to hyperinflammation, abetted by activation of coagulation, fibrinolytic, kallikrein-kinin and complement enzyme cascades with consumption of 
2 macroglobulin (2M). The debate concerns the nature of the trigger mechanism and why it should evoke an exaggerated inflammatory reaction and cause (subclinical) disturbances in distant organs even when the disease seems to be mild. In the latter context, the injured acinar cell is now known to step up its production of platelet-activating factor (PAF)—a physiological secretagogue but which at high doses inhibits secretion—and to synthesize heat-shock and acute-phase proteins, chemokines, and other cytokines such as tumour necrosis factor alpha (TNF-). However, time-course studies show that these phenotypic changes postdate the microcirculatory alterations which herald inflammation.
There are two main schools of thought. Today's proponents of the autodigestion hypothesis point to active trypsin in the acinar cell from 10–15 min in experimental models, as a result of ‘colocalization’ with lysosomal cathepsin-B and/or autoactivation, and argue that the gamut of trypsin-activated enzymes then goes on to initiate the other disturbances. This notion has received a boost with the discovery that hereditary pancreatitis is due to a mutation in the cationic trypsinogen gene, which in theory could render trypsin resistant to inhibition.7 Nevertheless, the hypothesis remains untenable for many reasons.2,5,10 For example, prospective clinical studies in settings that are conducive to pancreatitis show a rapid (diagnostic) surge in circulating trypsinogen alongside lipase and amylase, but that a clear increase in markers of trypsin is delayed until the inflammatory response is in full swing from 24 h onwards. At this stage the enzyme constitutes a minuscule fraction of the zymogen load, albeit higher in severe than mild disease. A 2–4 h delay occurs in experimental pancreatitis too.12 Therefore the signs are that colocalization and hypertrypsinogenaemia represent homeostatic responses to the secretory blockade.15,10 The first enables unexportable material to be degraded, while the second indicates the diversion of newly synthesized enzymes via the basolateral membrane into venules13 and, after a build-up in the interstitium,14 also into lymphatics.13,14
An alternate viewpoint hinges on oxidative stress.5,6 Heightened free radical activity is recorded from 5 min in experimental models15 and is thought to detonate the attack by interfering with the signal transduction apparatus,4,5 and then to catalyse NF-
B-mediated transformation of the acinar cell into a pro-inflammatory unit.5 The evidence implicates: (i) reactive oxygen species (ROS)—secretagogues at physiological concentrations but inhibitory in excess—when pancreatitis follows ischaemia-reperfusion (as in pancreas transplantation), or transient impedance to ductal drainage with or without bile reflux (as accompanies a migrating gallstone), when xanthine oxidase is the likely source;6 (ii) reactive xenobiotic species (RXS) via pancreatic cytochromes P450 in the best examples of drug or occupational chemical-induced disease;5,9 and (iii) fatty-acid ethyl esters in conjunction with ROS when it is caused by type I hyperlipidaemia or with RXS in alcoholic pancreatitis.9 Preliminary studies suggest that prior insufficiency of micronutrient antioxidants confers susceptibility to pancreatitis among individuals with such diverse risk factors as gallstones,16 alcoholism,9 sodium valproate therapy,17 old age18 or the hereditary pancreatitis gene.19 Also of note, admission blood samples show oxidative stress with an increase in linoleic-acid-derived free radical oxidation products (FROPs) but depletion of thiols, selenium and especially ascorbate.5,9,20–22 These substances interact23 to protect 1 proteinase inhibitor (1PI),24 and likely also 2M,24 plasminogen activator inhibitor (PAI)25 and PAF-acetylhydrolase,26 all of which are vulnerable to neutrophil-derived oxy-radicals. Notwithstanding this evidence, oxidants do not explain the activation of serine protease cascades in acute pancreatitis,5 although they do account for the early phase of interstitial oedema.6 Further, antioxidant supplementation is useful in preventing recurrences in patients with type I hyperlipidaemia and in chronic pancreatitis,5,9 but not in the management of an attack. That is essentially supportive.
Mast cell: the overlooked link
A large body of published evidence is rationalized by perception of the pancreatic mast cell as the ‘stealth bomber’ in lethal acute pancreatitis—operating in an oxidant-charged environment under cover of the autodigestion smokescreen. Although the participation of mast cells in the development of acute pancreatitis and the possibility of an allergic basis to the disease were recognized some time ago,2,3,27,28 only in the past few years has it become possible to appreciate the full pathogenetic potential of the cell.29ndash;34 Three sets of observations have been compelling. The first is the realization that, whereas ROS are involved in the physiological activation of mast cells at the inception of the inflammatory response, certain RXS and also linoleic acid-FROPs elicit a pathological reaction.30 The second is the finding that inactive monomers of the trypsin-like enzyme tryptase reconfigure to the active tetramer spontaneously under acidic conditions,34 as accompany splanchnic ischaemia in acute pancreatitis and worsen in lethal disease.35 The third is the observation that the pool of trypsinogen in the pancreatic interstitium—where mast cells lie27—is the source of circulating trypsin as experimental pancreatitis evolves.14
The abrupt release of mast cell mediators is expected to focus inflammation and the enzymic assault to the gland's interstitium and the peritoneal compartment. It would also be expected to amplify lung damage by way of products with mast cell degranulating capacity that enter lymphatics and venules, and to activate32 the ‘contact system’ of blood coagulation33 (Figure 1
).
|
The evidence in question
Aetiology
The combination of mast cells and aetiogenesis as key words yields only six papers from 1966 in a Medline search. Of these papers, two are in German,36,37 two in Russian by the same authors38,39 and two in English by a group of Swedish investigators.40,41
Yet, there is a striking overlap between agents/manoeuvres that stimulate the mast cell directly and those that are aetiologically related to acute pancreatitis5,9 or (asterisked) believed to aggravate its course:4 in particular, ROS/RXS/linoleic acid-derived FROPs, which perturb glutathione (GSH) homeostasis, emerge as a shared intermediary. The list includes: lipophilic bile acids,42,43 acetaldehyde as from ethanol,44 ischaemia-reperfusion injury,30 imaging media45 as used for endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance scan*46 or angiocomputed tomography,*4 RXS from several drugs that undergo bioactivation30—including opiates,*47 upon which patients with recurrent pancreatitis soon become dependent—as also formaldehyde48,49 and diesel exhaust particulates,49 venoms,50 interferon from viruses,29 endotoxin,51,*4 water immersion stress52 and hyperthermia29 simulating hypothermic and burns-induced pancreatitis, respectively, divalent metals53 which mimic experimental pancreatitis from dibutyltin or from zinc toxicity,9 and a combination of noxae including calcium, lipid and cholinergic stimulation.37
A very large population of mast cells resides in the periacinar space, pancreatic interstitium and mesentery and it degranulates early in acute pancreatitis.27 In three models of necrotizing disease, local increases were noted of mast-cell mediators—prostaglandin (PG)D2,54 its metabolite PGF2,54,55 histamine38 and serotonin.39 These substances, along with bradykinin, are known to be released into ascitic fluid and portal venous blood during acute pancreatitis, and to spill over into the systemic circuit.56 Further, water immersion stress was shown to result in the conversion of hyperstimulation mild pancreatitis into necrohaemorrhagic disease,57 as also when histamine or dimethyl PGE2 were added in a duct hyperpermeability model of mild pancreatitis.58 Studies of the basic hyperstimulation model59 recorded a time-dependent increase in substance P—which is soon released by a histamine-evoked axon reflex29—with augmented expression of its receptor on acinar cells, showing too that whereas mice lacking the receptor suffered less pancreatic and lung injury, mast-cell-deficient animals were not spared the former.60
These reports concur with the new template (Figure 1
), wherein oxidants and PAF in the first wave of diverted secretions from the acinar cell are envisaged as ignitors of inflammation.4–6 They also serve as a reminder of the dual roles, as mast-cell activator and mediator, of ROS, substance P, tryptase, adenosine, complement factor C3a and PGF2: this duality rationalizes the potent histamine-releasing effect of ascitic fluid from dogs with severe pancreatitis.41 In contrast, although the mast cell releases prodigious amounts of PAF within a minute, and PAF-induced sudden death is a model of systemic anaphylaxis,61 PAF does not stimulate mast cells directly, but via neurogenic means.62
Enzyme cascade activation
Mast-cell mediators have long been known to activate components of plasma complement, kallikrein-kinin and intrinsic coagulation cascades,29 but it has recently become clear that fibrinolysis is a major function31—achieved directly by the release of tissue-type and urokinase plasminogen activators (tPA, uPA) without PAI, and indirectly by activation32 of the contact system33—while tryptase leads to fibrinogenolysis. The contact system also has pro-inflammatory, anti-adhesive and anti-coagulant (via thrombin inhibition) properties, but can cause profound hypotension, mainly via bradykinin, and unless intercepted progresses towards hypercoagulability.33 Bradykinin is produced from high-molecular-weight kininogen in a factor-XII-dependent reaction, either directly or via its action in converting prekallikrein to kallikrein.
Several findings in acute pancreatitis now become understandable.
- (i) Mast cells degranulated by 5 min in lethal bile-salt pancreatitis,54 but seemingly not for 3–4 h in the mild hyperstimulation model.59,63 Within 6 h of the former, peritoneal fluid had far higher levels of plasminogen activators, plasmin and kallikrein than plasma.64 Further, the biphasic pattern of plasma TNF in this model, in the absence of endotoxin,65 was noted to resemble that in immune complex peritonitis wherein the first phase was due to the peritoneal mast cell and the second to TNF-elicited neutrophil recruitment. Of interest, a similar pattern of increase in plasma histamine has been recorded upon exposure to water immersion stress.52
- (ii) In bile-trypsin pancreatitis the reported pattern of haemostasis dysregulation66 suggests contact system activation, although trypsin is not known to activate mast cells or the contact system directly and it causes only pancreatic oedema when injected into the duct or gland substance.3 An initial increase in fibrinolytic activity was also noted in venous effluents from human pancreas grafts,67 and in a study of admission samples in Africans with alcoholic pancreatitis wherein trypsin could not be implicated.68
- (iii) Earlier clinical studies showed persistently low
2M in severe pancreatitis, as after therapeutic fibrinolysis but accompanied by prolonged depression of plasminogen too,69 and they also identified depletion of several plasmin inhibitors in peritoneal fluid70—pluripotent 2M and C1-esterase inhibitor (C1-INH), 1-antiplasmin and antithrombin III (AT-III)—although 85% of 1PI was functional.11
- (iv) The finding that among human victims the minority with interstitial pancreatitis died sooner than those with necrotizing disease2 has been baffling. This paradox is rationalized if the former represents a systemic anaphylactoid reaction and the latter a less aggressive reaction which allows time for the contact system to progress to the stage when the capillary-venular network in the gland is occluded by fibrinoid material.
- (v) Thus, mice given an intraperitoneal injection of human serum soon developed complement-dependent pancreatitis and a shock-like state—without trypsin.71
- (ii) In bile-trypsin pancreatitis the reported pattern of haemostasis dysregulation66 suggests contact system activation, although trypsin is not known to activate mast cells or the contact system directly and it causes only pancreatic oedema when injected into the duct or gland substance.3 An initial increase in fibrinolytic activity was also noted in venous effluents from human pancreas grafts,67 and in a study of admission samples in Africans with alcoholic pancreatitis wherein trypsin could not be implicated.68
Collectively these findings, evidence that the mast cell also releases phospholipase A2 (PLA2)72 and elastase,73 and that the cell explodes upon exposure to particular RXS or FROPs30—in contrast to the normal piecemeal pattern of mediator discharge74,75—provide a sufficient explanation for the histological, enzymic and cytokine changes associated with rapidly lethal pancreatitis. Other studies relating to structure-activity relationships76–79 concur with the idea that mast-cell tryptase, which is released some time after the lipid mediators (Figure 1), is responsible for the later activation not only of trypsinogen but also directly of pancreatic procarboxypeptidase B, chymotrypsinogen and proelastase. Unlike trypsin, tryptase is secreted in active form and is not inhibited by 1PI and 2M,80 its bioactivity restricted by the essentiality of a tetramer configuration which is maintained by co-secreted heparin. The speed with which heparin dissipates puts a brake on released tryptase, but recent work shows that this safety device could be brought to nought if tissue pH should fall.34
Inhibitor therapy
Gabexate mesilate (FOY) and similar compounds inhibit all serine proteases and PLA2, complement and immunoglobulin (Ig)E-dependent allergic reactions81 and aberrant neutrophil behaviour;82 they also have antioxidant properties.6 This repertoire rationalizes amelioration of pancreatitis when such compounds were administered prophylactically—for example, in bile salt pancreatitis,6 and in the bile-trypsin variant in which the earliest fibrinolytic phase was abolished.66 The potential implication that the inhibitors curbed ROS and/or complement-evoked mast cell activation and/or mediator release83 is supported clinically by the protection afforded by prophylactic FOY against post-ERCP pancreatitis,84 in which any IgE-dependent component of radiocontrast-induced activation45 is likely to be protease-dependent.85
The control of mast-cell mediators emerges as a common denominator when other interventions conferred benefit. Thus: recipients of stem-cell transplants improved with adjuvant C1-INH;86 clinical trials of a PAF-receptor antagonist showed a reduction in morbidity and circulating interleukin, IL-8, but without any impact on E selectin, IL-6, neutrophil elastase-1PI complexes or C reactive protein;87 combined C1-INH/AT-III ameliorated in bile-salt pancreatitis,88 as did PAF-acetylhydrolase in a duct-obstruction model of severe disease;89 while a bradykinin B2 receptor antagonist90 relieved oedema and hypotension in the hyperstimulation model.
A stabilizing effect on mast cells and/or on venular hyperpermeability caused by mast-cell mediators is the best explanation too for the dramatic amelioration of experimental pancreatitis by pre- or post-induction administration of ß2 adrenergic agonists,58 and from prophylactic use of pancreatic secretory trypsin inhibitor (PSTI),11 antioxidants—GSH precursors, ascorbate, selenium, zinc5,6,9—or heparin,91–93 the last also in patients undergoing ERCP.94 Thus: the life-saving action of ß2 adrenergic agonists in anaphylactic reactions is due in no small part to control of microvascular hyperpermeability;95 trypstatin from rat peritoneal mast cells is of similar size to PSTI, and has been shown to curb both tryptase and trypsin;96 thiols such as GSH, which are known to control serine proteases,97 modulated mast cell sensitization by ROS/RXS83 and inhibited degranulation in a necrohaemorrhagic model;39 ascorbate is highly concentrated in the mast cell and is rapidly consumed by histamine-derived oxidants within the cell and also extracellularly;98,99 selenium and zinc are mast cell stabilizers;100,101 while heparin not only has protease-restraining and anti-inflammatory properties but reduces the cell's production of cytokines.102
Concluding comments
Although the mast cell is a key component of the normal inflammatory response, its vicious potential is demonstrated in anaphylactic/anaphylactoid reactions. Time and further specific investigations will confirm or refute the deduction that lethal acute pancreatitis is a further example of this aggressive role reversal, the local or systemic pattern of anaphylactoid reaction conditioned by the degree of oxidative stress. As has been discussed in this journal in relation to chronic pancreatitis,103 RXS generated by pancreatic cytochromes P450 and any that enter from the liver—in refluxed bile or the bloodstream—seem to be particularly relevant. These arguments, if correct, should simplify prophylaxis in groups at risk. More importantly, they could enable practical measures wherewith to reduce early lethality.
Acknowledgments
I am indebted to Jenny Parr for expert secretarial help, and to Sandra Roe for the Figure. I also thank Ludmilla Speed, Herman Kiboom and Joerg Wilkening for translating papers from the Russian and German literature.
Notes
Address correspondence to Dr J.M. Braganza, c/o the Pancreato-Biliary Service, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL 
References
1. Chiari H. Über die Selbstverdauung des menschlichen Pankreas. Z Heilk1896; 17:69–96.
2. Thal AP, Perry JF, Egner W. A clinical and morphologic study of forty-two cases of fatal acute pancreatitis. Surg Gynecol Obstet1957; 105:191–201.[Web of Science][Medline]
3. Dürr G H-K. Acute pancreatitis. In: Howat HT, Sarles H, eds. The Exocrine Pancreas, London, WB Saunders, 1979:352–402.
4. Büchler MW, Uhl W, Friess, Malfertheiner P, eds. Acute pancreatitis: novel concepts in biology and therapy. Berlin, Blackwell Science, 1999.
5. Braganza JM, Foster JR. Toxicology of the pancreas. In: Ballantyne B, Marrs T, Syverson J, eds. General and Applied Toxicology, 2nd edn. Oxford, MacMillan Reference, 1999:893–936.
6. Schulz H-U, Niederau C, Klonowski-Stumpe H, Halangk W, Luthen R, Lipper H. Oxidative stress in acute pancreatitis. Hepato-Gastroenterology1999; 46:2736–50.[Medline]
7.
Whitcomb DC. Hereditary pancreatitis: new insights into acute and chronic pancreatitis. Gut1999; 45:317–22.
8. Norman J. The role of cytokines in the pathogenesis of acute pancreatitis. Am J Surg1998; 175:76–83.[Web of Science][Medline]
9. Braganza JM, ed. New Developments on the Aetiogenesis of Chronic Pancreatitis: Implications for Treatment and Disease Prophylaxis. Digestion1998; 59 (Suppl. 4).
10. Rinderknecht H. Pancreatic secretory enzymes. In: Go VLW, DiMagno EP, Gardner JD, Lebenthal E, Reber HA, Scheele GA, eds. The Pancreas: Biology, Pathobiology, and Disease, 2nd edn. New York, Raven Press, 1993:219–51.
11. Ohlsson K, Genell S. Role of enzyme inhibitors in acute pancreatitis and rationale for therapeutic use. In: Braganza JM, ed. The Pathogenesis of Pancreatitis. Manchester, Manchester University Press, 1991:198–214.
12. Fernandez-del Castillo C, Schmidt J, Rattner DW, Lewandrowski K, Compton CC, Jehanli A, Patel G, Hermon-Taylor J, Warshaw AL. Generation and possible significance of trypsinogen activation peptides in experimental acute pancreatitis in the rat. Pancreas1992; 7:263–70.[Web of Science][Medline]
13. Cook LJ, Musa OA, Case RM. Intracellular transport of pancreatic enzymes. Scand J Gastroenterol1996; 31 (Suppl. 219):1–5.[Medline]
14. Hartwig W, Jimenez RE, Werner J, Lewandrowski KB, Warshaw AL, Fernandez del Castillo C. Interstitial trypsinogen release and its relevance to the transformation of mild into necrotizing pancreatitis in rats. Gastroenterology1999; 117:717–25.[Web of Science][Medline]
15. Gough DB, Boyle B, Joyce WP, Delaney CP, McGeeney KF, Gorey TF, Fitzpatrick JM. Free radical inhibition and serial chemiluminescence in evolving experimental pancreatitis. Br J Surg1990; 77:1256–9.[Web of Science][Medline]
16. Zaman N, Rameh B, Worthington HV, Rieley F, Schofield D, Braganza JM. Gallstones and acute pancreatitis: more than a mechanistic connection? Biochem Soc Transact1997; 27:A109.
17. Pippenger CE, Meng X, Rothner D, Cruse RP, Erenberg G, Solano R. Free radical scavenging enzyme activity profiles in risk assessment of idiosyncratic drug reactions: probable mechanism for valproate-induced acute pancreatitis and hepatotoxicity. In: Levy RH, Penry JK, eds. Idiosyncratic Reactions to Valproate: Clinical Risk Patterns and Mechanisms of Toxicity. New York, Raven Press, 1991:75–88.
18. Braganza JM, Sharer NM. The pancreas. In: Tallis R, Fillit H, Brocklehurst JC, eds. Geriatric Medicine and Gerentology, 5th edn. London, Churchill Livingstone 1997:827–40.
19. Mathew P, Wyllie R, Van Lente F, Steffen RM, Kay HM. Antioxidants in hereditary pancreatitis. Am J Gastroenterol1996; 91:1558–62.[Web of Science][Medline]
20.
Tsai K, Wang SS, Chen TS, Kong CW, Chang FY, Lee SD, Lu FJ. Oxidative stress: an important phenomenon with pathogenic significance in the progression of acute pancreatitis. Gut1998; 42:850–5.
21. Wereszczynska-Siemiatkowska U, Dabrowski A, Jedynak M, Gabryelewicz A. Oxidative stress as an early prognostic factor in acute pancreatitis (AP): its correlation with serum phospholipase A2 (PLA2) and plasma polymorphonuclear elastase (PMN-E) in different-severity forms of human AP. Pancreas1998; 17:163–8.[Web of Science][Medline]
22. Bonham MJD, Abu-Zidan FM, Simovic MO, Sluis KB, Wilkinson A, Winterbourn CC, Windsor JA. Early ascorbic acid depletion is related to the severity of acute pancreatitis. Br J Surg1999; 86:1296–301.[Web of Science][Medline]
23. Winterbourn CC. Comparative reactivities of various biological compounds with myeloperoxidase-hydrogen peroxide-chloride and similarity of the oxidant to hypochlorite. Biochim Biophys Acta1985; 840:204–10.[Medline]
24. Weiss SJ. Tissue destruction by neutrophils. N Engl J Med1989; 320:365–75.[Web of Science][Medline]
25. Lawrence DA, Loskutoff DJ. Inactivation of plasminogen activator inhibitor by oxidants. Biochemistry1986; 25:6351–5.[Medline]
26. Ambrosio G, Oriente A, Napoli C, et al. Oxygen radicals inhibit human plasma acetylhydrolase, the enzyme that catabolizes platelet-activating factor. J Clin Invest1994; 93:2408–16.
27. Hollender LF, Lehnert P, Wanke M. Acute pancreatitis. Baltimore, Urban & Schwarzenberg, 1983.
28. Braganza JM. Antioxidant therapy for pancreatitis: clinical experience. In: Braganza JM, ed. The Pathogenesis of Pancreatitis. Manchester, Manchester University Press, 1991:178–97.
29. Holgate ST, Church MK, eds. Allergy. London, Gower Medical Publishing, 1993.
30. Mannaioni PF, Masini E. The release of histamine by free radicals. Free Radical Biol Med1988; 5:177–97.[Web of Science][Medline]
31. Valent P, Sillaber C, Baghestanian M, et al. What have mast cells to do with oedema formation, consecutive repair and fibrinolysis? Int Arch Allergy Immunol1998; 115:2–8.[Web of Science][Medline]
32. Brunnee T, Reddigari SR, Shibayama Y, Kaplan AP, Silverberg M. Mast cell derived heparin activates the contact system: a link to kinin generation in allergic reactions. Clin Exp Allergy1997; 27:653–63.[Web of Science][Medline]
33.
Colman RW, Schmaier AH. Contact system: a vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes. Blood1997; 90:3819–43.
34.
Ren S, Sakai K, Schwartz LB. Regulation of human mast cell beta-tryptase: conversion of inactive monomer to active tetramer at acid pH. J Immunol1998; 160:4561–9.
35. Hynninen M, Valtonen M, Markkanen H, Vaara M, Kuusela R, Jousela I, Piilonen A, Takkunen O. Intramucosal pH and endotoxin and cytokine release in severe acute pancreatitis. Shock2000; 13:79–82.[Web of Science][Medline]
36. Wanke M. Morphological findings in experimental acute pancreatitis. Tijdschr Gastroenterol1969; 12:132–46.[Medline]
37. Frick G. Role of mast cells in etiology of pancreatitis. Dtsch Z Verdau Stoffwechselkr1969; 29:237–45.[Medline]
38. Burnazayan RA, Kanayan AS, Mergrabyan VI. Changes in vascular permeability and the state of mesenteric mast cells in acute experimental pancreatitis and following treatment with sodium thiolsulphate. Biull Eksp Biol Med1981; 91:288–90.[Medline]
39.
Alexandrov PN, Simavoryan PS, Burnazayan RA. Effect of prostaglandins E2 and F2 on mast cell serotonin content in experimental pancreatitis. Biull Eksp Biol Med1981; 91:535–7.[Medline]
40. Hagen PO, Ofstad E, Amundsen E. Experimental acute pancreatitis in dogs. IV. The relationship between phospholipase A and the histamine-releasing and hypotensive effects of pancreatic exudate. Scand J Gastroenterol1969; 4:89–96.[Web of Science][Medline]
41. Ofstad E, Amundsen E, Hagen PO. Experimental acute pancreatitis in dogs. II. Histamine release induced by pancreatic exudate. Scand J Gastroenterol1969; 4:75–9.[Web of Science][Medline]
42. Quist RG, Ton-Nu HT, Lillienau J, Hofmann AF, Barrett KE. Activation of mast cells by bile acids. Gastroenterology1991; 101:446–56.[Web of Science][Medline]
43. Peh KH, Wan BY, Assem ES. Characteristics of deoxycholic acid-induced histamine release from mast cells of guinea-pig retrocolonic mucosa and rat peritoneal cavity. Agents Actions1991; 33:76–80.[Web of Science][Medline]
44. Koivisto T, Kaihovaara P, Salaspuro M. Acetaldehyde induces histamine release from purified rat peritoneal mast cells. Life Sci1999; 64:183–90.[Web of Science][Medline]
45. Genovese A, Stellato C, Marsella CV, Adt M, Marone G. Role of mast cells, basophils and their mediators in adverse reactions to general anaesthetics and radiocontrast media. Int Arch Allergy Immunol1996; 110:13–22.[Web of Science][Medline]
46. Terzi C, Sökmen. Acute pancreatitis induced by magnetic-resonance-imaging contrast agent. Lancet1999; 354:1789–90.
47. Famularo G, Pozzessere C, Polchi S, De Simone C. Acute pancreatitis after morphine administration. Ital J Gastroenterol Hepatol1999; 31:522–3.
48. Fujimaki H, Kawagoe A, Bissonnette E, Befus D. Mast cell response to formaldehyde. 1. Modulation of mediator release. Int Arch Allergy Immunol1992; 98:324–31.[Web of Science][Medline]
49. Saneyoshi K, Nohara O, Imai T, Shiraishi F, Moriyama H, Fujimaki H. IL-4 and IL-6 production of bone marrow-derived mast cells is enhanced by treatment with environmental pollutants. Int Arch Allergy Immunol1997; 114:237–45.[Web of Science][Medline]
50. Landucci EC, Castro RC, Pereira MF, et al. Mast cell degranulation induced by two phospholipase A2 homologues: dissociation between enzymatic and biological activities. Eur J Pharmacol1998; 343:257–63.[Web of Science][Medline]
51. Unger LS, Reilly FD. Hepatic microvascular regulatory mechanisms. VII. Effects of endoportally-infused endotoxin on microcirculation and mast cells in rats. Microcirc Endothelium Lymphatics1986; 31:47–74.
52. Huang ZL, Mochizuki T, Watanabe H, Kagoshima M, Maeyama K. Biphasic elevation of plasma histamine induced by water immersion stress, and their sources in rats. Eur J Pharmacol1998; 360:139–46.[Web of Science][Medline]
53. Dastych J, Kolago B, Michon T, Zwolinska A, Wyczolkowska J. Mercuric chloride releases performed mediators from mast cells of the mouse and rat. Inflamm Res1999; 48 Suppl 1:S33–4.
54.
Closa D, Roselló-Catafau J, Fernandez-Cruz L, Gelpí E. Prostaglandin D2, F2, E2 and E1 in early phase of experimental acute necrohemorrhagic pancreatitis in rats. Pancreas1994; 9:73–7.[Web of Science][Medline]
55.
Berger Z, Bàlint GA, Pap A, Karàcsony G, Varro V. Prostaglandin F2 and prostacyclin tissue levels in early phases of trypsin-induced acute pancreatitis in rats. Pancreas1988; 4:295–9.
56. Papp M, Makara GB, Hajtman B, Csáki L. A quantitative study of pancreatic blood flow in experimental pancreatitis. Gastroenterology1996; 51:524–8.[Web of Science][Medline]
57. Yamaguchi H, Kimura T, Nawata H. Does stress play a role in the development of severe pancreatitis in rats? Gastroenterology1990; 98:1682–8.[Web of Science][Medline]
58. Reber A, Adler G, Karanjia N, Widdison A. Permeability characteristics of the main pancreatic duct in cats: models of acute and chronic pancreatitis. In: Go VLW, DiMagno EP, Gardner JD, Lebenthal E, Reber HA, Scheele GA, eds. The Pancreas: Biology, Pathobiology, and Disease, 2nd edn. New York, Raven Press, 1993:527–50.
59.
Bhatia M, Saluja AK, Hofbauer B, Frossard J-L, Lee HS, Castagliuolo I, Wang C-C, Gerard N, Pothaulakis C, Steer ML. Role of substance P and the neurokinin 1 receptor in acute pancreatitis and pancreatitis-associated lung injury. Proc Natl Acad Sci USA1998; 95:4760–5.
60. Bhatia M. Mast cells play a critical role in mediating acute pancreatitis-associated lung injury (abstract). Gastroenterology1999; 16:A1113.
61. Myers AK, Nakanishi T, Ramwell P. Antagonists of PAF-induced death in mice. Prostaglandins1988; 35:447–58.[Web of Science][Medline]
62. Petersen LJ, Church MK, Shov PS. Platelet-activated factor induces histamine release from human skin mast cell? in vivo, which is reduced by local nerve blockade. J Allergy Clin Immunol1997; 99:640–7.[Web of Science][Medline]
63. Shimizu I, Wada S, Okhisa T, Kamamura M, Yano M, Kodaira T, Nishino T, Shima K, Ito S. Radioimmunoreactive plasma bradykinin levels and histological changes during the course of caerulein-induced pancreatitis in rats. Pancreas1993; 8:220–5.[Web of Science][Medline]
64. Etoh Y, Sumi H, Tsushima H, Maruyama M, Mihara H. Fibrinolytic enzymes in ascites during experimental acute pancreatitis in rats. Int J Pancreatol1992; 12:127–37.[Web of Science][Medline]
65. Dolan SJ, Lewis H, McCluggage G, Halliday MI, Rowlands BJ. Systemic endotoxin, antiendotoxin antibodies and proinflammatory cytokines in the taurocholate model of acute pancreatitis. HPB1999; 1:71–7.
66. Satake K, Ha S-S, Hiura A, Nishiwaki H, Haku A, Umeyama K. Effect of a synthetic protease inhibitor (Fut-175) on coagulation abnormalities during experimental acute pancreatitis in dogs. Gastroenterol Jpn1990; 25:720–6.[Medline]
67. Benz S, Keuper H, Kraus M, Heimburger N, Pfeffer F, Büsing M, Becker HD, Hopt UT. Local activation of coagulation initially after repercussion of human pancreas grafts (abstract). Digestion1995; 56:271.
68. Chaloner C, Douglas J, Appelros S, Borgström A, Segal I, Braganza JM. Relationship between trypsinogen burden, activation and fibrinolysis in acute pancreatitis (abstract). Biochem Soc Transact1999; 27:A110.
69. Lasson Å, Ohlsson K. Systemic involvement in pancreatic damage: coagulation and fibrinolysis. Int J Pancreatol1988; S79–86.
70. Lasson Å, Ohlsson K. Protease inhibitors in acute human pancreatitis. Correlation between biochemical changes and clinical course. Scand J Gastroenterol1984; 19:779–86.[Web of Science][Medline]
71. Janigan DT, Nevalainen TJ, MacAuley MA, Vethamany VG. Foreign-serum-induced pancreatitis in mice. Lab Invest1975; 33:591–607.[Web of Science][Medline]
72. De Marino V, Gentile M, Granata F, Marone G, Triggiani M. Secretory phospholipase A2: a putative mediator of airway inflammation. Int Arch Allergy Immunol1999; 118:200–1.[Web of Science][Medline]
73. Meier HL, Heck LW, Schulman ES, MacGlashan DW Jr. Purified human mast cells and basophils release human elastase and cathepsin G by an IgE-mediated mechanism. Int Arch Allergy Appl Immunol1985; 77:179–83.[Web of Science][Medline]
74. Bergstrand H. Mast cells and basophils in inflammation. In: Venge P, Lindbom A, eds. Inflammation: basic mechanisms, tissue injuring principles and clinical models. Stockholm, Almqvist and Wiksell International, 1985:47–84.
75. Dvorak AM, Morgan ES. Diamine oxidase-gold enzyme-affinity ultrastructural demonstration that human gut mucosal mast cells secrete histamine by piecemeal degranulatio? in vivo. J Allergy Clin Immunol1997; 99:812–20.[Web of Science][Medline]
76. Vanderslice P, Craik CS, Nadel JA, Caughey GH. Molecular cloning of dog mast cell tryptase and a related protease: structural evidence of a unique mode of serine protease activation. Biochemistry1989; 28:4148–55.[Medline]
77. Caughey GH, Viro NF, Ramachandran J, Lazarus SC, Borson DB, Nadel JA. Dog mastocytoma tryptase: affinity purification, characterization, and amino-terminal sequence. Arch Biochem Biophys1987; 258:555–63.[Web of Science][Medline]
78. Glasgow RE, Kong W, Corvera CU, Mulvihill SJ, Bunnett NW. Expression and potential functions of proteinase activated receptor-2 (PAR-2) in pancreatic acinar cells (abstract). Gastroenterology1998; 114:A461.
79. Gulberg U, Lindmark A, Lindgren G, Persson AM, Nilsson E, Olsson I. Carboxyl-terminal prodomain-deleted human leukocyte elastase and cathepsin G are efficiently targeted to granules and enzymatically activated in the rat basophilic/mast cell line RBL. J Biol Chem1995; 26:12912–18.
80. Alter SC, Kramps JA, Janoff A, Schwartz LB. Interactions of human mast cell tryptase with biological protease inhibitors. Arch Biochem Biophys1990; 276:26–31.[Web of Science][Medline]
81. Nagai H, Yamada H, Takizawa T, Iwamoto T, Inagaki N, Koda A. the effect of ß-amidino-2-napthyl-4-guanidinobenzoate (FUT-M5) on IgE antibody mediated allergic reactions in experimental animals. Jpn J Allergol1985; 34:962–6.
82. Tamura K, Manabe T, Imanishi K, Nonaka A, Asano N, Yamaki K, Tobe T. Effect of synthetic protease inhibitors on superoxide, hydrogen peroxide and hydroxyl radical production by human polymorphonuclear leukocytes. Hepato-Gastroenterology1992; 39:59–61.[Medline]
83. Wolfreys K, Oliveira DB. Alterations in intracellular reactive oxygen species generation and redox potential modulate mast cell function. Eur J Immunol1997; 27:297–306.[Web of Science][Medline]
84.
Cavallini G, Tittobello A, Frulloni L, Masci E, Mariani A, Di Francesco V, and the Gabexate in Digestive Endoscopy–Italian Group. Gabexate for the prevention of pancreatic damage related to endoscopic retrograde cholangiopancreatography. N Engl J Med1996; 335:919–23.
85. Khiav BE, Pearce FL. Role of serine esterases in mast cell activation. Br J Pharmacol1998; 123:1267–73.[Web of Science][Medline]
86.
Schneider DT, Nurnberger H, Stannigel H, Bonig H, Gobel U. Adjuvant treatment of severe acute pancreatitis with C1 esterase inhibitor concentrate after haematopoietic stem cell transplantation. Gut1999; 45:733–6.
87. Kingsnorth AN, Galloway SY, Formela LJ. Randomised, double blind phase II trial of lexipafant, a platelet activating factor antagonist, in human acute pancreatitis. Br J Surg1995; 82:1414–20.[Web of Science][Medline]
88.
Yamaguchi H, Weidenbach H, Lührs H, Lerch MM, Dickneite G, Adler G. Combined treatment with C1 esterase inhibitor and antithrombin III improves survival in severe acute experimental pancreatitis. Gut1997; 40:531–5.
89. Hofbauer B, Saluja A, Bhatia M, Forssard JL, Lee H, Steer ML. Effect of recombinant platelet-activating factor acetylhydrolase on two models of experimental acute pancreatitis. Gastroenterology1998; 112:960–7.[Web of Science][Medline]
90. Griesbacher T, Tiran B, Lembeck F. Pathological events in experimental acute pancreatitis prevented by the bradykinin antagonist, Hoe 140. Br J Pharmacol1993; 108:405–11.[Web of Science][Medline]
91. Balldin G, Ohlsson K. Studies on the influence of heparin on trypsin-induced shock in dog. Hoppe-Seyler's Z Physiol Chem1981; 362:357–61.[Web of Science][Medline]
92.
Berry AR, Davies GC, Millar AM, Taylor TV. Changes in biophysical properties and ultrastructure of lungs, and intrapulmonary fibrin deposition in experimental acute pancreatitis. Gut1983; 24:929–34.
93. Dryka T, Radwanska-Korzeniowska U, Jesipowicz M, Hermanowicz-Dryka T, Bacher H. The effect of heparin on the course of some organ complications in experimental acute pancreatitis in rats. Wiad Lek1997; 50 (Suppl 1):89–95.
94. Rabenstein T, Framke B, Martus P, Ell C, Hahn EG, Schneider HT. Prevention of post-ERCP pancreatitis (AP) by heparin: a prospective study with respect to risk factors (RF) for AP (abstract) Gastroenterology1999; 16:A1157.
95. Ohuchi K, Watanabe M, Hirasawa N, Yoshizaki S, Mue S, Tsurufuji S. Suppression by adrenoceptor beta-agonists of vascular permeability increase and edema formation induced by arachidonate metabolites, platelet-activating factor and tumour-promoting phorbol ester TPA. Immunopharmacology1990; 20:81–8.[Web of Science][Medline]
96.
Kido H, Yokogoshi Y, Katunuma N. Kunitz-type protease inhibitor found in rat mast cells. Purification, properties, and amino acid sequence. J Biol Chem1988; 263:18104–7.
97. Steven FS, Al-Habib A. Inhibition of trypsin and chymotryspin by thiols: biphasic kinetics of reactivation and inhibition induced by sodium periodate addition. Biochim Biophys Acta1979; 568:408–15.[Medline]
98. Ortner MJ. The oxidation of endogenous ascorbic acid during histamine secretion by rat peritoneal mast cells. Exp Cell Res1980; 129:485–7.[Web of Science][Medline]
99. Subramanian N. Histamine degradative potential of ascorbic acid: considerations and evaluations. Agents Actions1978; 8:484–7.[Web of Science][Medline]
100. Tchoumkeu-Nzouessa GC, Rebel G. Differential effect of ebselen on compound 48/80- and anti-IgE-induced histamine release from rat peritoneal mast cells. Biochem Pharmacol1998; 56:1525–8.[Web of Science][Medline]
101. Pfeiffer CJ, Bulbena O, Esplugues JV, Escolar G, Navarro C, Esplugues J. Anti-ulcer and membrane stabilizing actions of zinc acexamate. Arch Int Pharmacodyn Ther1987; 285:148–57.[Web of Science][Medline]
102. Baram D, Rashkovsky M, Hershkoviz I, Drucker I, Reshef T, Ben-Shitrit S, Mekori YA. Inhibitory effects of low molecular weight heparin on mediator release by mast cells: preferential inhibition of cytokine production and mast cell-dependent cutaneous inflammation. Clin Exp Immunol1997; 110:485–91.[Web of Science][Medline]
103. Braganza JM. The pathogenesis of chronic pancreatitis. Q J Med1996; 89:243–50.[Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||