Arachidonic acid metabolites in hepatobiliary physiology and disease

GASTROENTEROLOGY

SPECIAL

REPORTS

AND

Arachidonic Hepatobiliary DONALD Department Missouri

1989:97:781-92

REVIEWS

Acid Metabolites in Physiology and Disease

L. KAMINSKI of Surgery, The University

Hospital, St. Louis University

Arachidonic acid metabolites are involved in a wide spectrum of hepatobiliary physiologic functions and disease. Prostanoids alter hepatic bile flow. Prostaglandins with a C, ketooxygen stimulate a bicarbonate-rich choleresis and those with a C, hydroxyloxygen produce a chloride-rich choleresis. Prostaglandin F,, stimulates the release of the potent choleretic glucagon and the stimulatory effect of prostaglandin F,, on bile flow is inhibited by cyclooxygenase inhibitors, suggesting that prostaglandins play a role in the release of choleretic hormones as well as in their action. Prostanoids are involved in gallbladder contraction and water absorption. Prostaglandins produce gallbladder contraction in various species and cause gallbladder relaxation in other species. Prostaglandins also may be mediators of cholecystokinetic hormone action: however, cyclooxygenase inhibitors do not inhibit the effect of cholecystokinetic hormones in all species. Prostanoids alter the normal process of water absorption by gallbladder mucosa and induce net water secretion. The inflamed gallbladder secretes rather than absorbs fluid. The demonstration that prostaglandin E, inhibits gallbladder fluid absorption has led to subsequent studies that demonstrated that the secretion of fluid into the inflamed gallbladder lumen may be mediated by prostanoids. In cholecystitis, the prostanoids may mediate the distention produced by mucosal fluid secretion and the contraction of the diseased gallbladder. The inflammatory changes produced in various experimental models of cholecystitis can be prevented by cyclooxygenase inhibitors. Cyclooxygenase inhibitors decrease gallbladder prostaglandin formation and are effective in producing relief of the symptoms of gallbladder disease. In experimental cholesterol gallstone formation, prostaglandins are involved in the production of mucin, which acts as a nidus for stone formation, and cyclooxygenase inhibitors prevent the formation of experimental cholesterol gallstones. Prostaglandins have been shown to be cyto-

Medical Center, St. Louis,

protective in various types of experimental hepatic injury and leukotrienes have been shown to be injurious to hepatocytes and biliary tract tissues. Specific prostanoids and lipoxygenase inhibitors may be valuable in treating patients with various acute hepatic inflammatory disease processes. Continued evaluation of the role of arachidonic acid metabolites in heptobiliary physiology and disease may lead to important new therapeutic modalities. he historical information concerning the identification and subsequent isolation of the prostaglandins, leukotrienes, and lipoxins has recently been reviewed (l-5). Although the formation of prostanoids is a continually evolving subject, the current status of arachidonic acid metabolism is outlined in Figure 1 (3~). The eicosanoids are a unique group of mediators derived from arachidonic acid. Arachidonic acid is a polyunsaturated fatty acid found in phospholipids in cell membranes. After inflammatory or other stimuli, it is converted to prostaglandins through the action of the cyclooxygenase enzyme system or to leukotrienes through the action of the lipoxygenase enzymes. The enzymes, 12-, 15-, and 5-lipoxygenase, produce ll-, 12-,15-, and 5-hydroperoxyeicosatetranoic acids. The hydroperoxyeicosatetranoic acid compounds can then be converted either to the corresponding hydroeicosatetranoic acids or to the unstable epoxide intermediate, leukotriene A, (5). One biosynthetic pathway of lipoxins A and B is from conversion of 15hydroeicosatetranoic acid to a 5 (6)-epoxide tetraene that is enzymatically transformed to lipoxin A and B (4). Prostaglandins (PGs), leukotrienes, and lipoxins are produced by inflammatory cells and a large number of other tissues (1,3-5). These substances are important mediators of inflammation and are in-

T

0

1989 by the American Gastroenterological 0016-5085/89/$3.50

Association

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GASTROENTEROLOGY Vol. 97. No. 3

Phospholipids 1 l-,12- or 15. HPETE 15 HETE

LTB4

PhospholipaseA 2

ll-. 12 HETE 4

t

Arachidonicacid p

Lipoxygenase

5-HPETE--.-+

/

LTA4 1

1 Llpoxln / A

‘xI”B/7f
Prostacyclin

PGF2,

PGE2

PGDs

6-KETOPGF 1a Figure

1. Schematic illustration of arachidonic hydroperoxyeicosatetranoic acid.

ThromboxaneA2

TXB2 acid metabolism

volved in numerous physiologic activities and pathologic disease states (l-5). Prostaglandins are present in most gastrointestinal tissues and have been shown to affect many gastrointestinal tract functions (6) and to alter or mimic the action of many gastrointestinal hormones (7-11). Cyclooxygenase and lipoxygenase inhibitors are an important class of drugs that are efficacious in the treatment of a variety of diseases (3). In this review, the term “eicosanoid” refers to arachidonic acid and all its metabolites including PGs, leukotrienes, and lipoxins. “Prostanoids” refer to the metabolites of arachidonic acid produced via the cyclooxygenase pathway. The term “leukotrienes” collectively refers to the arachidonic acid metabolites produced via the lipoxygenase pathway. The initial recognition of the relationship of the prostanoids to biliary tract function and pathology occurred in 1973 with the demonstration that certain PGs had cholecystokinetic activity and were capable of producing gallbladder contraction (12). In 1974, it was demonstrated that PGs altered hepatic bile flow with certain PGs stimulating bile flow and others inhibiting bile flow (13). The possible role of PGs in cholecystitis and gallstone disease was initially proposed by Wood and Stamford in 1977 (14) when they demonstrated large amounts of PGs in diseased gallbladder by bioassay. Evaluation of the potential role of prostanoids in various liver disorders has been stimulated by the presence of relatively large amounts of PGs (15) and leukotrienes (16) in bile. Bile Flow Three components of hepatic bile flow are presently recognized (17). There is a bile salt-depen-

(from References

3

and 4). HETE, hydroeicosatetranoic

acid, HPETE,

dent component and bile flow rates increase with bile salt infusion with a discernible D,, and transport maximum (17,18). A ductular component is well recognized as the bile duct mucosa secretes fluid and is responsive to hormonal stimulation (1920). It is believed that secretin stimulates bile duct mucosa to secrete a bicarbonate-rich fluid (2O), possibly mediated by cyclic nucleotides (21). The canalicular membranes that anatomically form the terminal ends of the biliary tract are believed to contribute to bile formation (22,231. As measurement of the volume and composition of this component has always been indirect because of the inaccessibility of the bile canaliculus (24), concern has existed related to the relative importance of this component of hepatic bile (25-27). It presently seems reasonable to consider that the bile canaliculus produces a component of bile independent of bile salts. Glucagon is a choleretic agent that may stimulate a chloride-rich canalicular bile flow (28) through a cyclic nucleotide-mediated process (29-31). Exogenous administration of prostanoids alters hepatic bile flow. The term “hepatic bile flow” indicates that the gallbladder has been removed and gallbladder contraction does not contribute to the change in bile flow that is produced. Information concerning the administration of PGs, both naturally occurring and synthetic, on bile salt and hormonally stimulated hepatic bile flow is summarized in Table 1. The bile volume and electrolyte changes produced are identified and, as is evident, the prostanoids are primarily choleretics. The more recently identified endoperoxide metabolites (42,43), prostacyclin and thromboxane B,, are choleretics (40). We know of no

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1989

PROSTAGLANDINS

IN THE BILIARY

TRACT

783

Table 1. Effect of Exogenous Prostaglandins on Bile Flow Stimulant Bile saltsa

Prostanoid PGA, PGE, PGE,

Secretin Glucagon CCK

16,16-Dimethyl

PGE,

PGF,, 16,16-Dimethyl Prostacylin

PGF,,,

6-Keto PGF,, Thromboxane PGA, PGE, PGF,, PGA, PGE,

B,

Species

Bile flow change

Dog Rat

r

Bile electrolyte change

13,32 33 32 34 35 33 34 36 37 36,38,39 36 40 41 35 40 13,32 13.32 39 13,32 13,32

? HCO, t H:O,

Dog Cat Dog Rat Cat Dog Man Dog Dog Dog Rat

r 0 0

t HCO, 0

t 0

t H:O, 0

t

+I

r 0

t HCO,

Dog Dog Dog Dog

r :

& t cl4 HCO,

Dog Dog Dog

t 0 0

r:10 0

CCK, cholecystokinin; PG, prostaglandin. ’ Bile salt indicates that prostaglandins were administered enterohepatic circulation interrupted with or without intravenous bile salt infusion. Bile salts were secretin, glucagon, and CCK. t indicates increase; & , decrease; 0, no change; ?, response not evaluated.

information concerning the effect of leukotrienes or lipoxins on bile flow. The choleretic response produced by various prostanoids is characterized by increased bile chloride or bicarbonate secretion [Table 1). A discernible pattern of effect of the prostanoids on bile flow is evident based on their structural characteristics. The PGE compounds in dogs (32) and cats (34) and prostacyclin in dogs stimulate a bicarbonate-rich choleresis comparable to the ductular component produced by secretin (44). These prostanoids are structurally similar with a ketooxygen present in the C, position rather than the hydroxyloxygen (Figure 2). Although the PGA compounds may not exist naturally and may only represent artifacts of the extraction process (45) the PGA compounds similarly have a C, ketooxygen and increase bile flow in rats (33) and dogs (32) primarily by stimulating bicarbonate secretion. The presence of the hydroxyl group in the C, position in PGF,, and thromboxane B, (Figure 2) stimulates chloride secretion in bile (36,38-40), a phenomenon otherwise peculiar to the choleretic hormone glucagon (17). Both PGF,, (39) and glucagon (28) increase the clearance of [14C]erythritol in bile, suggesting that they both stimulate canalicular bile flow. Although the bisenoic prostanoids appear to be

References

Bile Chloride Stimulants

during bile flow with the also administered along with

Bile Bicarbonate Stimulants

HO

,

OH

,

TX&

PGA

HO Figure

dH

2. Structure-function relationships of the prostaglandins in bile flow. Prostaglandins are primarily choleretics. Prostaglandins with a hydroxyl group in the C, position appear to stimulate a chloride-rich bile, whereas prostaglandins with a C, ketooxygen produce a bicarbonaterich choleresis.

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Endogenous Stimulation

1

Islet Cells

Bile Chloride Secretion

Cell Membrane

~

ATP Mg#

! /

Figure 3. Prostaglandin F,, is involved in glucagon-stimulated bile flow. Prostaglandin F,, appears to be a mediator of the response of the biliary tract receptor to glucagon. The prostaglandins may act by increasing cyclic AMP formation. ATP, adenosine triphosphate.

predominant in nature (45), the C, and C,, cis double bonds are not essential to stimulate bile flow, as the keto group present in 6 keto-PGF,, does not eliminate the choleretic response (35). This would suggest that PFG,, may also be a choleretic substance. This information is summarized in Figure 2. The physiologic significance of the broad effects of the prostanoids on bile flow is unknown. The possible physiologic role of PGF,, in bile flow has recently been determined. Both glucagon (46) and PGF,, (36,38,39,46) stimulate a chloride-rich choleresis. The hypothesis was made that PGF,, was a hormone receptor mediator of the choleresis produced by glucagon. The cyclooxygenase inhibitor indomethacin inhibited glucagon-stimulated bile flow (46). This was associated with a marked inhibition of PGF concentration in bile but not in venous blood. This response suggests that the activity of glucagon on the biliary tract membrane may be mediated by PGF,,. Prostaglandin F,, administration increased bile flow and serum glucagon concentrations and this response was inhibited by somatostatin, a universal inhibitor of hormone release (46). Prostaglandin F,, may mediate hormone release as well as hormone receptor stimulation (Figure 3) (46). In the endocrine system, a unifying mechanism of action of the PGs related to the cyclic nucleotides has been proposed (47). Hormones stimulate cell membrane receptors and initiate prostanoid formation. Increased prostanoids stimulate the intracellular adenylate cyclase, cyclic nucleotide system that initiates a response (Figure 3) (47). Large amounts of cyclic nucleotides are present in bile (48) and these levels change in response to choleretic hormones (21,29,49) and PGs (38). It has been difficult, by determination of cyclic nucleotides in bile, to determine the role these substances play in hormonal or prostanoid-stimulated responses. The cyclic nucleotide present in bile may arise from an unrelated hepatogenous or systemic pool and be excreted in

bile (29-31). Glucagon stimulates increased cyclic nucleotide content in liver tissue (50) and it is presently not possible to separate the hepatogenous cyclic adenosine monophosphate (AMP) response from that associated with glucagon stimulating bile flow through PGF,, formation. Proof of the role of cyclic AMP in glucagon-stimulated bile flow (Figure 3) will require experiments utilizing isolated biliary cells (51). Prostacyclin is a choleretic agent in dogs (40) and in other systems its function is mediated by cyclic nucleotides (45). Prostacyclin was evaluated to ascertain if cyclic AMP acted as a mediator of the stimulatory effect of the prostanoid. Bile flow and bile cyclic AMP increased in response to prostacyclin, whereas significant systemic arterial and hepatic tissue cyclic AMP changes did not occur, indicating that the activity of prostacyclin in increasing bile flow was mediated by cyclic AMP formation (40). It is unlikely that prostacyclin functions as a membrane mediator of secretin stimulation, although it stimulates bicarbonate secretion in bile. Cyclooxygenase inhibition with indomethacin failed to alter the choleresis produced by intraduodenal acid stimulation of secretin release (40). Prostanoid synthesis and activity may have a physiologic role in mediating hormone-stimulated bile formation; however, cyclooxygenase inhibition does not alter basal bile flow rates (39). An important experiment to determine a potential physiologic role of the prostanoids in bile flow would be to evaluate the effects of cyclooxygenase inhibition on the choleresis produced by a meal. Additionally, limited information has been produced related to the effects of the prostanoids on bile secretion in humans (37).

Gallbladder Physiology The gallbladder concentrates bile by fluid and electrolyte transport (52) and contracts during digestion to provide bile for fat digestion (53). Gallbladder water absorption is due to a coupled, carrier-mediated transport of Na+ and Cl- from the lumen into the mucosal cell and into the intercellular spaces. An osmotic gradient is established, driving water into the spaces, producing an isotonic fluid that moves through the open basal end of the intracellular spaces (54,55). Although several hormones such as secretin and vasoactive intestinal peptide can stimulate gallbladder mucosal water secretion (56), we do not know of any hormones that enhance fluid absorption. Indomethacin, an inhibitor of cyclooxygenase activity (Figure l), has no effect on basal gallbladder absorptive function (57). Prostaglandin E, inhibits fluid absorption from the gallbladder and induces net secretion in some species (58-60).

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Again, we know of no information that prostanoids stimulate gallbladder water absorption. Gallbladder contraction is stimulated by cholecystokinin released from intestinal mucosa in response to contact with fat and protein (53,61). The PGs alter gallbladder contraction. In dogs, PGF administration produces a cholecystokinetic response and PGE proIn guinea pigs (63) duces gallbladder relaxation (62). and cats (57), PGE compounds produce gallbladder contraction. Cyclooxygenase inhibition eliminates the activity of pentagastrin on canine gallbladder contraction, suggesting that the PGs may be mediators of the effect of the cholecystokinetic hormone (62).Cyclooxygenase inhibitors do not alter the cholecystokinetic effect of cholecystokinin in the isolated, ex vivo, guinea pig gallbladder (63). Human gallbladder muscle strips in vitro contract in response to PGE,. Indomethacin produced a decrease in baseline contractions, suggesting that intrinsic spontaneous tone in human gallbladder musInformation cle is dependent on PG production (64). concerning the effect of cyclooxygenase inhibition of cholecystokinin-induced human gallbladder contraction is not available but could readily be produced utilizing radionucleotide cholecystoscintography. Normal gallbladder mucosa and muscle tissue from cats, dogs, guinea pigs, opossums, and humans, unspiked by arachidonic acid, produce prostanoids (65). The above evidence suggests that PCs may play a role in the physiologic functions of gallbladder mucosal water transport and muscle contraction. Cholecystitis In view of the prevalence of gallstone disease, the prevention of cholecystitis would benefit a large number of people. Gallbladder disease is a major health problem. It is estimated that -15 million people in the United States have calculous biliary disease; 100,000new cases are detected each year; more than 300,000people are operated on per year in the United States to remove the gallbladder; and 6000 people per year die of complications of biliary tract disease (66).Three processes that develop in the diseased gallbladder resulting in symptoms and morbidity are fluid secretion by inflamed gallbladder mucosa, muscular contraction resulting in colicky pain, and inflammation (57). All three processes have direct relationships to prostanoid formation. The proinflammatory prostanoids (2) normally present in the gallbladder and involved in physiologic functions may incite inflammation and the development of cholecystitis. Also, the tissue concentrations of eicosanoids change during the development of inflammation (2). The changes may adversely affect

PROSTAGLANDINS

IN THE BILIARY TRACT

785

the symptoms by enhancing gallbladder contraction, resulting in pain and, by increasing fluid accumulation in the gallbladder, producing distention. Pharmacologic control of gallbladder mucosal water secretion, muscular contraction, and inflammation may decrease pain and the morbidity associated with this disease. Nonoperative management of gallstones by shock-wave lithotripter therapy and gallstone dissolution are therapeutic modalities that would benefit considerably from drugs controlling gallbladder inflammation and the symptoms of gallbladder disease (67). Gallbladder disease is usually associated with stone formation. Recent information has developed implicating the prostanoids in gallstone formation. Several animals, notably the prairie dog, form cholesterol gallstones when fed high-cholesterol diets (68,69). Gallstone formation from cholesterol crystals, formed in the presence of bile supersaturated with cholesterol, is enhanced in the presence of nucleating agents (70).Gallbladder mucin is the nidus for some human gallstones (71). In cholesterolfed animal models with cholesterol gallstone formation, mucin production increased before stone formation (72). In addition to mucin production, gallbladder bile stasis has been implicated in the formation of cholesterol gallstones in prairie dogs (73), as has increased lysolecithin concentrations found to be present in gallbladder bile of cholesterolfed prairie dogs (74). Lysolecithin is possibly a mucin secretagogue (75). The role of the prostanoids in this process was discovered in a circuitous fashion. Mucin production by gastric mucosa has been evaluated extensively in relationship to the effect of ulcerogenic drugs, such as aspirin, on mucin production. Aspirin inhibits mucin production (76).As mucin production precedes cholesterol gallstone formation in animal models (721, experiments were performed that demonstrated that the cyclooxygenase inhibitor aspirin decreased mucin production and prevented gallstone formation in cholesterol-fed prairie dogs (73,77). Subsequent studies have demonstrated that in vitro gallbladder mucin secretion is stimulated by arachidonic acid and the response is inhibited by indomethacin. The primary prostanoid produced was prostacyclin, suggesting that gallbladder mucin secretion may be regulated by endogenous prostacyclin (78). During cholesterol feeding and induction of mucin secretion and subsequent cholesterol gallstone formation, significant increases in PG formation occurred before the development of the changes in mucin secretion (79). Increases in PGF, PGE, prostacyclin, and thromboxane occurred in association with increases in lysolecithin formation as well

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KAMINSKI

ASA lndomethacin

Figure 4. The role of prqstaglandins in experimental cholesterol gallstone formation. A cholesterol-rich diet increases biliary cholesterol. The increased cholesterol is associated with increased production by the gallbladder of lysolecithin and prostanoids. Both substances promote increased gallbladder mucin production. Mucin acts as a nidus for gallstone formation. Aspirin has been shown to prevent the formation of gallstones in prairie dogs fed high-cholesterol diets and indomethacin prevents mucin production by gallbladder tissue. -

as mucin secretion in gallbladders during cholesterol feeding. The increased lysolecithin caused an increase in mucin production (79). As seen in Figure 4, increased cholesterol in bile results in increased prostanoid and lysolecithin formation and mucin production, leading to the nucleation of cholesterol and gallstone formation. Aspirin prevents stone formation (77) and indomethacin can inhibit mucin production (78). Limited information currently exists relating human cholesterol gallstone formation to eicosanoid metabolism. It should be determined whether lysolecithin stimulates mucin secretion by human gallbladder mucosa through a prostanoid-mediated process that could be prevented by cyclooxygenase inhibitors (Figure 4). Preliminary attempts to evaluate cyclooxygenase inhibitors in gallstone prevention in high-risk patients revealed that aspirin decreased glycoprotein formation in bile but did not reduce the incidence of cholelithiasis. Aspirin administration in obese patients undergoing dietary weight loss failed to prevent gallstone formation. However, the number of patients was small, and the dose of aspirin used was low (80). Further controlled trials should be established to determine if cyclooxygenase inhibitors prevent gallstone formation in other high-risk groups such as patients who have undergone gallstone lithotripter therapy (67). Normal gallbladder mucosa absorbs water and concentrates bile, whereas an inflamed gallbladder secretes fluid into the lumen (81,82). Recent studies have demonstrated that experimental production of gallbladder inflammation by lysolecithin perfusion is associated with the secretion of a protein-rich fluid (83). Lysolecithin is an agent destructive to the cell wall (84) that is present in gallbladder bile (85) and has been identified as an important causative agent in cholecystitis (86). It has recently been shown to produce experimental cholecystitis (75). Evidence that the fluid secretion produced by inflamed gallbladder mucosa is mediated by pros-

tanoid continues to develop. Gallbladders perfused with lysophosphatidyl-choline secreted fluid; indomethacin decreased this secretion (87). Prostaglandin E concentrations in gallbladder perfusates were increased by lysolecithin compared with control perfusate levels; this increase was inhibited by indomethacin (87). These studies suggest that the secretion of fluid associated with mucosal inflammation may be mediated by PGE compounds. A similar process occurred in gallbladder contraction. Gallbladders perfused with lysolecithin contracted; this contraction was prevented by intravenous indomethacin (57). When intraluminal pressure was artificially increased by the restriction of perfusate efflux, increased pressure was produced: this increase was also inhibited by indomethacin (57). These results suggest that pain associated with gallbladder contraction in biliary tract disease may be mediated by prostanoids and relieved by cyclooxygenase inhibitors. The cascade of local morphologic and chemical events that occur in association with the development of inflammation has been presented by Vinegar et al. (88). The role of the eicosanoids in this process has been reviewed (89), as has the action of antiinflammatory drugs (3). Inflammation can be pharmacologically altered by preventing eicosanoid formation (3). Corticosteroids prevent the formation of both PGs and leukotrienes by causing the release of lipocortin, which by inhibiting phospholipase A,, decreases arachidonic acid release (3). Nonsteroidal antiinflammatory drugs inhibit the cyclooxygenase enzyme and decrease PG formation (Figure 1) (3). Specific 5-lipoxygenase inhibitors prevent leukotriene formation and eicosanoid receptor antagonists have recently been described that decrease the inflammatory responses mediated by the eicosanoids (3). Gallbladder disease can be classified on the basis of its clinical presentation as acute or chronic, acalculous or calculous. It is possible that the different

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1989

types of gallbladder inflammation will manifest varying levels of mediator eicosanoids. Acute disease processes would be more likely to have discernible patterns of eicosanoid formation than would be found in chronically diseased, fibrotic gallbladders with mucosal effacement. In search of an appropriate animal model of acute cholecystitis, it was found that normal animal and human gallbladders formed and released relatively large amounts of PGE and PGF from mucosa and muscle in the concentration range of 3-12 ng/mg cell protein. A 4: 1 ratio of PGE to PGF was present in both animal and human gallbladders (65,90,91). Cat gallbladders produced large amounts of PGs and were of satisfactory size to yield adequate amounts of tissue for evaluation (65). To produce acute cholecystitis over a relevant interval of time, 4% carrageenan-soaked, sterile polyester sponges were placed in cat gallbladders for 5 days. This resulted in acutely inflamed gallbladders grossly and histologically indistinguishable from those of humans with acute cholecystitis. The inflamed feline gallbladder muscle and mucosa had very specific PG changes in blood cell free homogenates and in tissue culture media. Increased PG formation was evident when inflamed gallbladders were compared with normal gallbladders. The PG increases and the inflammatory changes were inhibited by indomethacin (65). Evaluation of the role of the prostanoids in human gallbladder disease has revealed that large amounts of PGE and PGF are present in human gallbladders (91). The amount of PGE produced by inflamed gallbladder muscle and mucosa in tissue culture media, and in mucosal cell and muscle tissue homogenates, increases with the severity of the inflammatory process (91). Treatment of patients with cyclooxygenase inhibitors decreases PG formation (92). It is not possible to determine if cyclooxygenase or lipoxygenase inhibition decreases inflammation in human gallbladder disease, as no reliable means of nonoperatively ascertaining the degree of inflammation present in the gallbladder currently exists (92). In a feline model of experimental cholecystitis, cyclooxygenase inhibition decreased the inflammatory response (65). Acalculous gallbladder disease occurs as an acute inflammatory process in patients ill from other diseases (93) and as a painful chronic disorder with minimal inflammation (94). It was postulated that both disease processes were the result of abnormal or increased prostanoid formation. Comparison of gallbladder PGE and PGF mucosal cell and muscle tissue concentrations in gallbladders from patients with chronic acalculous gallbladder disease with those that were normal demonstrated no differences.

PROSTAGLANDINS

IN THE BILIARY TRACT

787

No evidence was found that these prostanoids were involved in the development of chronic acalculous gallbladder disease (95). In acute acalculous cholecystitis, tissue PGE concentrations were increased compared with normal gallbladders, and the increase in PGE levels corresponded to the severity of inflammation (95). A role for these prostanoids in acute acalculous cholecystitis seems possible. Human gallbladders with and without gallstones readily become inflamed and cause symptoms (96). This may be due to the large amounts of proinflammatory prostanoids present in gallbladder tissue being involved in gallbladder mucosal transport and muscle contraction. In response to a variety of stimuli including stones, trauma, cystic duct obstruction, shock, and lysolecithins, the arachidonic acid present in gallbladder tissue is metabolized to proinflammatory prostanoids. Inflammatory mediators are released from accumulating white blood cells and the released eicosanoids, particularly the leukotrienes, function as chemoattractants (97,981 for additional white blood cells, resulting in additional proinflammatory substances being released. As the histologic inflammation increases, so does the prostanoid production by gallbladder tissue (91,95). Prostanoid formation and release by isolated mucosal cells and muscle tissue of diseased gallbladders, relatively free of blood cells, has been demonstrated (91,951. Accumulating inflammatory cells (97,98) and vascular endothelium (43) also contribute to the prostanoid levels present in gallbladder homogenates. Based on the previous discussion of the role of prostanoids in gallbladder mucosal fluid secretion, muscular contraction, and inflammation, it can be assumed that prostaglandin synthetase inhibitors have the potential to relieve gallbladder pain. Comparison of cyclooxygenase inhibitors with placebo has uniformly demonstrated the effectiveness of these drugs in treating pain associated with gallbladder disease (92,99,100). We know of no information related to the produc(2) or lition of the proinflammatory leukotrienes poxins (4) by gallbladder tissue. Leukotrienes are recognized as proinflammatory compounds whose production by inflammatory cells may increase in the presence of cyclooxygenase inhibitors (2). Inhibition of cyclooxygenase activity may increase lipoxygenase activity. In gallbladder tissue, it will be important to determine if cyclooxygenase inhibition stimulates leukotriene and lipoxin formation. Nonsteroidal antiinflammatory agents also have effects in inflammation other than cyclooxygenase inhibition, including inhibition of neutrophil activation, decreasing cellular calcium movement, and increasing intracellular cyclic AMP levels, all of which may be important in their therapeutic activity (101). En-

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hanced therapeutic efficacy in the pharmacologic control of the pain and inflammation of cholecystitis may be possible by delineation of specific prostanoids or leukotrienes that mediate the response and treatment with specific inhibitors (102,103)or receptor antagonists (104).

GASTROENTEROLOGYVol. 97,No.3

and galactosamineand endotoxin and amanitininduced hepatic damage, inhibitors of leukotriene synthesis decreased the necrosis in the liver as evaluated histologically, and reduced the amount of hepatic enzymes released into the circulation (120). In experimental viral hepatitis in rats, cysteinyl leukotrienes increased in bile and specific inhibitors of leukotriene formation decreased the hepatocelluLiver lar injury as judged by hepatic enzyme release (121). The interest in evaluating the role of the There is presently limited information available concerning the relationship of eicosanoids to cholestasis eicosanoids in acute inflammatory processes of the and hepatic inflammation in humans. For example, liver (105) is related to the presence in bile of relatively large amounts of arachidonic acid (106), it is not known if leukotrienes are secreted in human occur prostaglandins (15),and leukotrienes (16,107,108). bile and if increased systemic concentrations in the presence of liver disease. Initially, studies with PGE and PGF compounds Whereas leukotrienes appear harmful to the liver, indicated that these substances, present in bile, were some PGs have been shown to be cytoprotective not the secretory products of systemic PGs (109,110). Recently, it has been shown that prostacyclin (6-keto during various types of experimental liver injury (122). The concept that prostanoids protect gastroinPGF,,) (111) and PGF (112) undergo biliary excretestinal mucosa from various damaging agents has tion and enterohepatic recirculation. Heptocytes metabolize and secrete leukotrienes in bile (16,107, been well established (123).The first evidence that prostanoids may be cytoprotective in solid gastroin108).The liver is the primary organ involved in the catabolism of the cysteinyl-containing leukotrienes testinal viscera was the demonstration that pretreatLTC, and LTD, (113). In addition to the liver parenment with PGE compounds protected rats from the (124,125). chymal cells, blood vessels and white blood cells are hepatotoxic effect of carbon tetrachloride other potential sources of eicosanoids in bile. As Prostanoids, primarily PGE compounds, are also with other mononuclear phagocytosing cells, the cytoprotective in experimental galactosamine (126), lipopolysaccharide (127),and nutritional (128)and function of Kupffer cells is affected by eicosanoids. The relationship of Kupffer cell function to eiviral (129) liver injury. This protective effect has cosanoid metabolism has been previously reviewed been demonstrated to occur in some experimental models when prostanoids were administered as late (113). Attempts to implicate bile PGs and leukoas 48 h after the production of the liver injury (129). trienes as being important in hepatic disease should Prostacyclin has been shown to be cytoprotective in include measurement of systemic and hepatogenous liver injury produced by hypoxia (130-132). eicosanoid concentrations. A unifying concept concerning the cytoprotective Endotoxin administration produces hepatic necroeffects of the prostanoids has been proposed suggestsis (114) and cholestasis (115) and is associated with ing that the prostanoids act by eliminating the inincreased production of systemic leukotrienes and decreased secretion of leukotrienes in bile (116). creased procoagulant activity associated with various agents or manipulations that produce liver Cholestasis produced by bile duct ligation produces damage (129). The prostanoids may prevent the impairment of biliary excretion of leukotrienes, changes in the microcirculation of the liver caused which results in increased systemic (105) and heby the hepatotoxins by preventing the induction of patic (16)leukotriene concentrations. The increased procoagulant activity (129). concentrations of leukotrienes may be harmful to Preliminary studies performed in a nonrandomhepatocytes (117,118)and the biliary tract (16).Heized manner found that treatment of 10 patients with patocytes exposed to LTC, are killed if they are acute or subacute fulminant hepatitis with PGE was hypoxic (118). The leukotrienemia associated with associated with a marked improvement (133). Conendotoxin-produced shock may contribute to the associated hepatocellular damage and subsequent trolled randomized trials will need to be performed cholestasis (116). to ascertain the exact role of prostanoids in the management of acute hepatic injury. Isolated rat hepatocytes in primary culture produce LTB, in response to exposure to ethanol. This response may be very important in explaining ethaSummary nol-associated hepatic inflammation (119). Evaluation of specific inhibitors of leukotriene The information concerning the PGs and leukotrienes in biliary tract and hepatic physiology and formation in experimental liver injury has demonstrated protective effects (105).In both endotoxin disease does not presently allow the presentation of

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a unifying concept concerning their function or mode of action. In some circumstances, such as in bile flow, these substances are involved in mediating hormone action. In the gallbladder, they independently promote inflammation and gallstone formation, and in the liver, leukotrienes appear to be hepatotoxins whereas prostanoids are cytoprotective. Although a unifying concept of the function of these agents is not possible, enough information has been accumulated for an important role to be attributed to these substances in gallbladder, biliary tract, and hepatic physiology and disease. The rapidly improving methodology of the measurement and knowledge of metabolism and the function of arachidonic metabolites will stimulate continued research into their role in hepatobiliary disease. The prospects for improved specific knowledge concerning the role of arachidonic acid metabolites in bile flow are augmented by the possibility of quantitating these substances in blood, hepatic tissue, and bile. New methodologies in bile flow research have resulted in the exciting capability of studying the bile canaliculus (134) and isolated bile duct mucosal cells (135), permitting the direct evaluation of the interaction of hormones and prostanoids. The therapeutic implications of prostanoid research in cholecystitis are already practically applied with drugs to treat biliary pain. The potential for decreasing mucin availability as a nucleating factor in gallstone formation utilizing cyclooxygenase inhibitors may decrease gallstone formation rates in high-risk patient populations. Hepatic cholestasis and acute inflammatory liver disease may be accentuated by leukotrienes and other arachidonic acid metabolites in liver tissue, and preventing their accumulation by specific inhibitors may be beneficial in these disorders. Conversely, the use of prostanoids to protect the liver in a variety of acute hepatic disease stages may also be beneficial. Continued evaluation of the role of leukotrienes and PGs in hepatobiliary physiology and disease has evident therapeutic potential.

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structures,

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logical effects. Science 1987;237:1171-6. 5. Ford-Hutchinson AW. Leukotrienes: their formation and role as inflammatory mediators. FASEB Mongr 1985;44: 25-9. 6. Robert A. Prostaglandins and the digestive system. In: Ramwell PW, ed. The prostaglandins. New York: Plenum, 1977: 225-66. 7. Bennett A, Fleshler B. Prostaglandins and the gastrointestinaI tract.

Gastroenterology

1970;59:790-800.

8. Robert A, Nezamis JE, Phillips JP. Inhibition of gastric secretion by prostaglandins. Am J Dig Dis 1967;12:1073-6. 9. Rudick J, Gondu M, Dreiling DA. Effects of prostaglandins E, and E, on pancreatic exocrine function. Gastroenterology 1971;60:272-8. 10. Case RM, Scratcherd T. Prostaglandin action on pancreatic blood flow and on electrolyte and enzyme secretion by exocrine pancreas in vivo and in vitro. J Physiol 1972; 226:393-405. 11

Goyal RJ, Rattan S. Mechanism of lower esophageal sphincter relaxation. J Clin Invest 1973;52:337-41. 12 Andersson KE, Andersson R, Hedner P, Persson CGA. Parallelism between mechanical and metabolic responses to cholecystokinin and prostaglandin E, in extrahepatic biliary tract. Acta Physiol Stand 1973;89:571-9. Kaminski DL, Jellinek M. The effect of prostaglandin A, (PGA,) and E, (PGE,) on canine hepatic bile flow. Clin Res 1974:22:361A. IF. Prostaglandins in chronic cholecys14 Wood JR, Stamford titis. Prostaglandins 1977;13:97-104. YG, Kaminski DL. Identification and quantifica15. Deshpande tion by radioimmunoassay of prostaglandin F compounds in bile. Prostaglandins 1980;20:373-6. W, Denzlinger C, Keppler D. Role of peptide 16 Hagmann leukotrienes and hepatobiliary elimination in endotoxin 13

17

18. 19 20 21 22.

23 24.

References 25 Lewis RA, Drazen JM, Figueiredo JC, Corey EJ, Austen KF. A review of recent contributions of biologically active products of arachidonic acid conversion. Int J Immunopharmacol 1982;4:85-99. Samuelsson B. Leukotrienes. Mediators of immediate hypersensitivity reactions and inflammation. Science 1982:220: 568-75. Vane J, Botting R. Inflammation and the mechanism of action of anti-inflammatory drugs. FASEB Monogr 1987:1:89-96. Samuelsson B, Dahlen S, Lindgren J, Rouzel C, Serhan C.

and lipoxins:

IN THE BILIARY

26.

27.

28.

shock. Circ Shock 1984;14:223-5. Kaminski DL. Nahrwold DL. Neurohormonal control of biliary secretion and gallbladder function. World J Surg 1979;3:449-556. Wheeler HO, Pier L. Mancusi-Ungaro PL, Whitlock RT. Bile salt transport in the dog. J Clin Invest 1970;39:1039-40. Chenderovitch J. Secretory function of the rabbit common bile duct. Am J Physiol 1972;223:695-706. Nahrwold DL. Secretion by the common duct in response to secretin. Surg Forum 1971;22:386-7. Levine RA. Hall RC. Cyclic AMP in secretin choleresis. Gastroenterology 1976:70:537-44. Forker EL. Two sites of bile formation as determined by mannitol and erythritol clearance in the guinea pig. J Clin Invest 1967;46:1189-95. Wheeler HO, Ross ED, Bradley SE. Canalicular bile production in dogs. Am J Physiol 1968;214:866-74. Gautam A. Ng 0. Boyer JL. Isolated rat hepatocyte couplets in short term culture: structural characteristics and plasma membrane reorganization. Hepatology 1987;7:21623. Smith ND, Boyer JL. Permeability characteristics of bile duct in the rat. Am J Physiol 1982;242:G52-7. Lewis MHA, Baker AL, Moossa AR. Secretin enhances “C-erythritol clearance in unanesthetized dogs (abstr). Gastroenterology 1979:76:1290. Balabaud C. Kron KA, Gumcio JJ. The assessment of the bile salt nondependent fraction of canalicular bile water in the rat. J Lab Clin Med 1977;89:393-9. Khedis A, Dumont M. Duval M. Erlinger S. Influence of glucagon on canalicular bile production in the dog. Biomedicine 1974;21:176-81.

790

KAMINSKI

GASTROENTEROLOGY

Vol. 97. No. 3

29. Kaminski DL, Brown W, Deshpande YG. Effect of glucagon on bile CAMP secretion. Am J Physiol 1980;128:G119-23. 30. Poupon RE, Do1 ML, Dumont M, Erlinger S. Evidence against a physiologic role of CAMP in choleresis in dogs and rats.

biliary cells isolated by centrifugal elutriation from normal and paraneoplastic livers. Cancer Res 1984;44:332-8. 52. Rose RC. Electrolyte absorption by gallbladders: models of transport. Life Sci 1978;23:1517-32.

Biochem Pharmacol 1978;27:2413-6. 31. Larsen JA, Krarup N, Thomsen 0. The effect of glucagon and theophylline and dibutycyclic AMP on bile production in the cat. Acta Physiol Stand 1979;106:23-7. 32. Kaminski DL, Ruwart MJ, Willman VL. The effect of prostaglandin A, and E, on canine hepatic bile flow. J Surg Res 1975;18:391-7. 33. Lauterburg B, Baumgartner G, Preisig R. Prostaglandininduced choleresis in the rat. Experientia 1975:31:1191-3. 34. Krarup N, Larsen JA, Munck A. Secretin-like choleretic effects of prostaglandins E, and E, in cats. J Physiol 1976; 254:813-20. 35. Deshpande YG, Kaminski DL. The effect of prostanoids on hepatic bile flow (abstr). Fed Proc 1982;41:1704. 36. Kaminski DL, Ruwart MJ. Deshpande YG. The effects of synthetic prostaglandin analogs on canine hepatic bile flow. Prostaglandins 1979;18:73-80. 37. Ekelund K, Johansson C, Nylander B. Effects of 16. 16dimethyl prostaglandin E, on food-stimulated pancreatic secretion and output of bile in man. Stand J Gastroenterol 1977;12:457-60. 38. Kaminski DL, Deshpande YG, Ruwart MJ. The effect of prostaglandin F,, on canine hepatic bile flow and biliary cyclic AMP secretion. J Surg Res 1977:22:545-53. 39. Kaminski DL, Deshpande YG. Evaluation of the role of the F prostaglandins in canine bile flow. Prostaglandins 1980: 20:367-72. 40. Kaminski DL, Deshpande YG. The effects of prostacyclin on canine hepatic bile flow. Hepatology 1984:4:644-50. 41. Fukumoto Y, Hughes RD, Guarner PF. Williams R. Effects of intraportal prostacyclin on hepatic bile flow in the rat. Prostaglandins Leukotrienes Med 1986:22:35-43. 42. Hamberg M, Svensson J. Samuelsson B. Detection and isolation of an endoperoxide intermediate in prostaglandin biosynthesis. Proc Nat1 Acad Sci USA 1973;70:899-903. 43. Moncada SR, Gryglewski R, Bunting S. Vane JR. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature 1976;263:663-5. 44. Kaminski DL, Deshpande YG. The effect of somatostatin and bombesin on secretin-stimulated ductular bile flow in dogs. Gastroenterology 1983:85:1239947. 45. Feigen L. Hyman AL. Vascular influences of prostaglandins. Fed Proc 1981;40:1985-6. 46. Kaminski DL, Deshpande YG. The relationship between glucagon and prostaglandin F in stimulating canine hepatic bile flow. Hepatology 1986;6:265-81. 47. Kenimer JG, Goldberg V, Blecher M. The endocrine system. Interaction of prostanglandins with adenylyi cyclase-cyclic AMP systems. In: Ramwell PW, ed. The prostaglandins. New York: Plenum, 1977:77. 48. Ruwart MJ. Kaminski DL. Isolation, purification and quantitation of cyclic AMP and cyclic GMP in canine bile. Anal Biochem 1977:81:130-5. 49. Kaminski DL, Ruwart MJ, Desphande YG. Role of cyclic AMP in canine secretin-stimulated bile flow. J Surg Res 1979;27:57-61. 50. Levine RA. The role of cyclic AMP and prostaglandins in hepatic and gastrointestinal functions. In: Kahn RH. Lands WEM, eds. Prostaglandins and cyclic AMP. New York: Academic, 1973:75-118. 51. Hayner NT, Braun L. Yaswen P. Brooks M. Faust0 N. Isoenzyme profiles of oval cells, parenchymal cells and

53. Lin TM. Actions of gastrointestinal hormones and related peptides on the motor function of the biliary tract. Gastroenterology 1975;69:1006-22. 54. Diamond JM. Standing gradient model of fluid transport in epithelia. Fed Proc 1971;30:6-13. 55. Frizzell RA, Dugas MC, Schultz SG. Sodium chloride transport by rabbit gallbladder. J Gen Physiol 1975;65:769-95. 56. Morton IKM, Phillips SJ, Saverymuttu SH, Wood JR. Secretin and vasoactive intestinal peptide inhibit fluid absorption and induce secretion in the isolated gallbladder of the guinea pig. J Physiol 1977;266:65-6P. 57. Thornell E. Mechanisms in the development of acute cholecystitis and biliary pain. Stand J Gastroenterol 1982;17 (Suppl 76):1-31. 58. Leyssac PP. Bukhave K, Fredericksen 0. Inhibitory effect of prostaglandins on isosmotic fluid transport by rabbit gallbladder in vitro and its modification by blockage of endogenous PGE biosynthesis with indomethacin. Acta Physiol Stand 1974:92:496-507. 59. Morton IKM, Saverymuttu SM, Wood JR. Inhibition by prostaglandins of fluid transport in the isolated gallbladder of the guinea pig. Br J Pharmacol 1974;50:46OP. 60. Heintze K, Leinesser W, Peterssen KU, Heidenreich 0. Triphasic effect of prostaglandins E,, E, and F,, on the fluid transport of isolated gallbladder of guinea pigs. Prostaglandins 1975;9:309-22. 61. Malagelada JR, Go VLW. DiMagno EP, Summerskill WHJ. Interactions between intraluminal bile acids and digestive products on pancreatic and gallbladder function. J Clin Invest 1973:52:2160-5. 62. Nakano J. McCloy RF. Gin AC, Nakano SK. Effect of prostaglandins E,. E, and F,,,, and pentagastrin on gallbladder pressure in dogs. Eur ) Pharmacol 1975;30:107-12. 63. Andersson KE. Hedner P, Persson CGA. Differentiation of the contractile effects of prostaglandins E, and the C terminal octapeptide of cholecystokinin in isolated guinea pig gallbladder. Acta Physiol Stand 1974:90:657-63. 64. Kotwall CA, Scott GW. Effects of prostaglandins on motility of gallbladders removed from patients with gallstones. Arch Surg 1984;119:709-12. 65. Kaminski DL, Deshpande YG, Qualy J, Thomas L. The role of prostaglandins in feline experimental cholecystitis. Surgery 1985:98:760-8. 66. Javitt NB, McSherry CK. Pathogenesis of cholesterol gallstones. Hosp Prac [Off] 1973;8:39-48. 67. Sackmann M. Delius M. Sauerbruch T. et al. Shockwave lithotripsy of gallbladder stones. N Engl J Med 1988;318: 393-7. 68. Brenneman DE, Conner WE, Forker EL, Den Besten L. The formation of abnormal bile and cholesterol gallstones from dietary cholesterol in the prairie dog. J Clin Invest 1972; 51:1495-503. 69. Chang SH, Ho KJ. Taylor CB. Cholesterol gallstone formation and its regression in prairie dog. Arch Path01 1973;96: 417-26. 70. Small DM. Cholesterol nucleation and growth in gallstone formation. N Engl J Med 1980;302:1305-7. 71. Womack NA. Zeppa R. Irvin GL. The anatomy of gallstones. Ann Surg 1963;157:670-86. 72. Lee SP. LaMont JT, Carey MC. Role of gallbladder mucus hypersecretion in the evolution of cholesterol gallstones. J Clin Invest 1981;67:1712-23. 73. Kuckenbecker SL. Doty JE. Pitt HA, Denbesten L. Salicylate

September

74.

75.

76.

77.

78.

79.

80.

81.

82.

83. 84.

85.

86.

87.

88.

89.

90.

91.

92.

1989

prevents gallbladder stasis and cholesterol gallstones in the prairie dog. Surg Forum 1981;32:154-5. Rutledge FA, Hickman DM, Dunn JJ, Frey CF, Matson RS. Lysophosphatidylcholine acyltransferase activity during experimental cholelithiasis. Lipids 1981;16:714-20. Neiderhiser D, Thornell E, Bjorck S, Svanvik J. The effect of lysophosphatidylcholine on gallbladder function in the cat. J Lab Clin Med 1983;101:699-707. Lukie BE, Forstner GC. Synthesis of intestinal glycoproteins: inhibition of 1% glucosamine incorporation by sodium salicylate in vitro. Biochem Biophys Acta 1972;273:380-4. Lee SP, Carey MC, LaMont J. Aspirin prevention of cholesterol gallstone formation in prairie dogs. Science 1981; 211:1429-31. LaMont J, Turner BS, Dibenedetto D, Handin R, Schafer AL. Arachidonic acid stimulates mucin secretion in prairie dog gallbladder. Am J Physiol 1983;245(Gastrointest Liver Physiol 8):G92-8. LaMorte WW, Lamont JT, Hale W, Booker ML, Scott TE, Turner B. Gallbladder prostaglandins and lysophospholipids as mediators of mucin secretion during cholelithiasis. Am J Physiol 1986;251(Gastrointest Liver Physiol 13):G7019. Broomfield PH, Chopra R, Scheinbaum RC, et al. Effects of ursodeoxycholic acid and aspirin on the formation of lithogenie bile and gallstones during loss of weight. N Engl J Med 1988;319:1567-72, Ravdin IS, Johnston CB, Austin JH, Riegel C. Studies of gallbladder function. IV. The absorption of chloride from the bile-free gallbladder. Am J Physiol 1932;99:638-47. Svanvik J, Allen B, Way L. An experimental method to study the inflammatory secretion in the gallbladder (abstr). Gastroenterology 1979;76:1257. Neiderhiser DH. Acute acalculous cholecystitis induced by lysophosphatidycholine. Am J Path01 1986;124:559-63. Weltzien HU. Cytolytic and membrane-perturbing properties of lysophosphatidylcholine. Biochem Biophys Acta 1979;559:259-87. Gottfries A, Nilsson S, Samuelsson B, Schersten T. Phospholipids in human hepatic bile, gallbladder bile and plasma in cases with acute cholecystitis. Stand J Clin Lab Invest 1968;21:168-76. Sjodahl R, Wetterfors J. Lysolecithin and lecithin in the gallbladder wall and bile: their possible roles in the pathogenesis of acute cholecystitis. Stand J Gastroenterol 1974; 9:519-25. Thornell E, Jivegard L, Bukhave K, Rash-Madsen J, Svanvik J. Release of prostaglandin E, into the gallbladder lumen in lysolecithin-induced cholecystitis (abstr). Gastroenterology 1983;84:1335. Vinegar R, Truax JF, Sellph JL, Johnston PR, Venable AL, McKenzie KK. Pathway to carrageenan-induced inflammation in the hind limb of the rat. Fed Proc 1987;46:118-26. Ferreira SH. Prostaglandins. In: Houck JC, ed. Chemical messengers of the inflammatory process. Amsterdam: Elsevier, 1979;113+0. Booker ML, LaMorte WW. Prostaglandin release from in vitro guinea-pig gallbladders. Prostaglandins 1983:25:14353. Kaminski DL, Desphande YG. Thomas L, Blank W. Evaluation of the role of prostaglandins E and F in human cholecystitis. Prostaglandins Leukotrienes Med 1984;16:109-20. Kaminski DL, Deshpande YG, Thomas L. Qualy J, Blank W. The effect of oral ibuprofen on formation of prostaglandins E and F by human gallbladder muscle and mucosa. Dig Dis Sci 1985;30:70-4.

PROSTAGLANDINS IN THE BILIARY TRACT

791

93. Glenn F, Becker CG. Acute acalculous cholecystitis. An increasing entity. Ann Surg 1982;195:131-6. 94. Nora PF, David RP, Fernandez MJ. Chronic acalculous gallbladder disease: a clinical enigma. World J Surg 1984; 8:106-12. 95. Kaminski DL, Deshpande YG, Thomas LA. The role of prostaglandins E and F in acalculous gallbladder disease. 1987;34:70-4. Hepatogastroenterology 96. Soloway RR. Comment. Gastroenterology 1980;79:1341-2. 97. Meyers SI, Thomasson D, Davis BB, Rettke C, Parks L. Role of inflammatory cells in enhanced gallbladder prostaglandin biosynthesis. Surg Forum 1987;38:180-2. 98. Goetzl EJ, Woods JM, Gorman RR. Stimulation of human eosinophil and neutrophil polymorphonuclear leukocyte chemotaxis and random migration by 12-L-hydroxy5,8,10,14 eicosatetraenoic acid. J Clin Invest 1977;59:17983. 99. Thornell E, Kral JG, Jansson R, Svanvik J. Inhibition of prostaglandin synthesis as a treatment for biliary pain. Lancet 1979;i:584. 100. Thornell E, Jansson R, Svanvik K. Indomethacin intravenously-a new way for effective relief of biliary pain: a double blind study in man. Surgery 1981;90:468-72. 101. Abramson S, Korchak H, Ludewig R, et al. Modes of action of aspirin-like drugs. Proc Nat1 Acad Sci USA 1985;82:722731. 102. Sheard P, Holroyde MC, Ghelani AM, Bantick J, Lee TB. Antagonists of SRS-A and leukotrienes. In: Samuelsson B, Paoletti R, eds. Leukotrienes and other lipoxygenase products. New York: Raven, 1982:229. 103. Higgs GA, Mudridge KG, Moncada SP. Inhibition of tissue damage by the arachidonate lipoxygenase inhibitor BW755C. Proc Nat1 Acad Sci USA 1984;81:2890-2. 104. Krell RD, Brown FJ, Willard AK, Giles RE. Pharmacologic antagonism of the leukotrienes. In: Chakrin LW, Bail DM, eds. The leukotrienes: chemistry and biology. Orlando, Fla.: Academic, 1984. 105. Keppler D, Forsthove C, Hagmann W, Rapp S, Denzlinger C, Hock HK. Leukotrienes and liver injury. In: Bianchi L, Gerok W, Popper H, eds. Trends in hepatology. Lancaster: MTP Press, 1985:137-45. 106. Ahlberg JT, Curstedt K, Einarsson K, Sjovall J. Molecular species of biliary phosphatidylcholines in gallstone patients: the influence of treatment with cholic acid and chenodeoxycholic acid. J Lipid Res 1981;22:404-9. 107. Applegren LE, Hammarstrom S. Distribution and metabolism of 3H-labeled leukotriene C, in the mouse. J Biol Chem 1982;257:531-5.

108. Ormstad K. Uehara N, Orrenius S, Orning L, Hammarstrom S. Uptake and metabolism of leukotriene C, by isolated rat organs and cells. Biochem Biophys Res Commun 1982; 103:1434-40. 109. Dawson W. Ramwell PW. Shaw JE. Metabolism of prostaglandins by the rat isolated liver. Br J Pharmacol 1968; 34:668-9P. 110. Dawson W, Jessup SJ. McDonald-Gibson W, Ramwell PW, Shaw JE. Prostaglandin uptake and metabolism by the perfused rat liver. Br J Pharmacol 1970;39:585-98. 111. Taylor BM, Sun FF. Tissue distribution and biliary excretion of prostacyclin metabolites in the rat. J Pharmacol Exp Ther 1980;214:24-30. 112. Bedrick AD, Wells MA, Ford DL, Koldovsky 0. Intact biliary excretion of gastrically administered prostaglandin F,, in rats: developmental differences. Am J Physiol 1987;253: G787-92. 113. Decker K. Eicosanoids. signal molecules of liver cells. Semin Liver Dis 1985:5:175-90.

792

KAMINSKI

114.

Hirata K, Kaneko A, Ogawa K. Effect of endotoxin on rat liver-analysis of acid phosphatase isoenzymes in the liver of normal and endotoxin treated rats. Lab Invest 1980;

115.

116.

117.

118.

119.

120.

121.

122.

123.

124.

125.

126.

43:165-71. Utili R, Abernathy CO, Zimmerman HJ. Cholestatic effects of Escherichia coli endotoxin on the isolated perfused rat liver. Gastroenterology 1976;70:248-53. Hagmann W, Denzlinger L, Keppler D. Production of peptide leukotrienes in endotoxin shock. FEBS Lett 1985;180:30913. Keppler D, Hagmann W, Rupp S. Denzlinger C, Koch HK. The relation of leukotrienes to liver injury. Hepatology 1985:5:883-91. Trudell JR, Bendix M, Bosterling B. Hypoxia potentiates killing of hepatocyte monolayers by leukotrienes. hydroperoxyeicosateraenoic acids, or calcium ionophore A23187. Biochem Biophys Acta 1984;830:338-41. Perez D, Roll FJ, Bissel DM. Production of chemotactic activity for polymorphonuclear leukocytes in cultured rat hepatocytes exposed to ethanol. J Clin Invest 1984;74:13507. Back MK. Inhibitors of leukotrienes synthesis and action. In: Chakrin LW, Bailey DM, eds. The leukotrienes: chemistry and biology. Orlando, Fla.: Academic, 1984;163-94. Hagmann W, Steffan AM, Kirn A, Keppler D. Leukotrienes as mediators in frog virus 3-induced hepatitis in rats. Hepatology 1987;7:732-6. Ruwart MJ, Rush BD, Friedle NM, et al. 16,16-Dimethyl-PGE protection against alpha-Naphthylisothiocyanate-induced experimental cholangitis in the rat. Hepatology 1984;4: 658-60. Lancaster C, Robert A. Intestinal lesion produced by prednisolone: prevention (cytoprotection) by 16. 16 dimethyl prostaglandin E,. Am J Physiol 1978:235:E703-8. Stachura J. Tarnamski A, Ivey KJ. et al. Prostaglandin protection of carbon tetrachloride-induced liver cell necrosis in the rat. Gastroenterology 1981;81:211-7. Rush B, Merritt MV, Kaluzny M. Van Schorick T. Bruden MN, Ruwart M. Studies on the mechanism of the protective PGE, in carbon tetrachlorideaction of 16, 16-dimethyl induced acute hepatic injury in the rat. Prostaglandins 1986;32:439-55. Noda Y, Hughes RD, Williams R. Effect of prostacyclin PGI,

GASTROENTEROLOGY

127.

128.

129.

130.

131.

132.

133.

134.

135.

Vol. 97, No. 3

and a prostaglandin analogue BN 245-C on galactosamineinduced hepatic necrosis. J Hepatol 1986;2:53-64. Mizoguchi Y, Tsutsui H. Miyajima K, et al. The protective effects of prostaglandin E, in an experimental massive hepatic cell necrosis model. Hepatology 1987;7:1184-7. Ruwart MJ, Rush BD, Snyder KF, Peters KM, Appelman HD, Henley KS. 16. 16-Dimethyl prostaglandin E, delays collagen formation in nutritional injury in rat liver. Hepatology 1988;8:61-4. Abecassis M, Falk JA, Makowka L, Dinzans VJ, Falk RE, Levy E, prevents the developGA. 16. 16 Dimethyl prostaglandin ment of fulminant hepatitis and blocks the induction of monocyteimacrophage procoagulant activity after murine hepatitis virus strain 3 injection. J Clin Invest 1987;80: 881-9. Araki H. Lefer A. Cytoprotective actions of prostacyclin during hypoxia in the isolated perfused cat liver. Am J Physiol 1980;238:H176-81. Monden M, Fortner JG. Twenty-four and 48-hour canine liver preservation by simple hypothermia with prostacyclin. Ann Surg 1982;196:38-42. Sikujara 0, Monden M, Toyoshima K, Okamura J, Kosaki G. Cytoprotective effect of prostaglandin I, on ischemia-induced hepatic cell injury. Transplantation 1983;36:238-43. Abeceassis M, Falk R. Blendis L, et al. Treatment of fulminant hepatic failure with a continuous infusion of prostin VR (PGE) (abstr]. Hepatology 1987;7:1104. Graf J, Gautam A, Boyer JL. Isolated rat hepatocyte couplets: a primary secondary unit for electrophysiologic studies of bile secretory function. Proc Nat1 Acad Sci USA 1984; 81:6516-20. Sirica AE. Sattler CA, Cinla HP. Characterization of a primary bile ductular cell culture from the livers of rats during extrahepatic cholestasis. Am J Path01 1985;120:67-78.

Received February 19. 1988. Accepted February 10, 1989. Address requests for reprints to: Donald L. Kaminski, M.D., Department of Surgery, The University Hospital, St. Louis University Medical Center, 3635 Vista Avenue at Grand Boulevard, P.O. Box 15250, St. Louis, Missouri 63110-0250. This work was supported by United States Public Health Service grants DK 27695-06 and AM28178.