16,16-Dimethyl prostaglandin E2 suppresses the increases in the proliferative activity of rat colonic epithelium induced by indomethacin and aspirin

Treatment of rats with indomethacin rapidly increased ornithine decarboxylase (4 h) of colonic mucosa and [3H]thymidine incorporation into colonic mucosal deoxyribonucleic acid (DNA) (1 or 5 days) when this parameter was examined in vivo and ex vivo. The changes in colonic mucosal ornithine decarboxylase and DNA synthesis induced by indomethacin were correlated temporally with suppression of colonic prostaglandin synthesis, as assessed from ex vivo colonic production of prostaglandin E, the dominant prostaglandin product of colon. Autoradiographic studies indicated that the enhancement of proliferative activity of colonic epithelium after treatment with indomethacin for 1 day was confined to the lower third of the colonic crypt (normal proliferative zone). After 5 days of indomethacin treatment, however, there was an extension of the proliferative zone to the upper third of the colonic crypts. Concurrent treatment of rats with the stable prostaglandin E2 analogue, 16,16-dimethyl prostaglandin E2, suppressed indomethacin-induced increases in colonic mucosal ornithine decarboxylase and DNA synthesis. Concurrent administration of 16,16-dimethyl prostaglandin E2 also prevented the extension of the proliferative zone of colonic epithelium induced by 5 days of indomethacin administration. 16,16-Dimethyl prostaglandin E2 alone for 1-5 days had no detectable effects on colonic mucosal ornithine decarboxylase and DNA synthesis compared with corresponding control values. Increases in colonic mucosal DNA synthesis were also induced by treatment of rats for 5 days with aspirin (ASA). The stimulation of colonic mucosal DNA synthesis induced by ASA was significantly suppressed by concurrent administration of 16,16-dimethyl prostaglandin E2 and was also correlated with the inhibition of colonic prostaglandin synthesis by ASA. The colons of rats treated with indomethacin for 1 day or ASA for 5 days appeared normal by light microscopy. However, treatment of rats for 5 days with indomethacin resulted in mild to moderate inflammation of the lamina propria and some goblet cell depletion at the mucosal surface, but no loss of surface epithelium. The ultrastructure of the surface epithelium of the colons of rats treated with indomethacin or ASA was normal as assessed by electron microscopy. The results thus demonstrate that inhibition of local colonic prostaglandin synthesis is associated with increases in the proliferative activity of colonic epithelium, and that these increases are suppressed by administration of 16,16-dimethyl prostaglandin E2.(ABSTRACT TRUNCATED AT 400 WORDS)     

Parenteral aspirin and sodium salicylate are equally injurious to the rat gastric mucosa

The effects of parenteral aspirin (ASA) or sodium salicylate (SA) on the gastric mucosa were investigated in anesthetized pylorus-ligated rats 3 h after a bolus intravenous injection of ASA or SA, 150 mg/kg, or NaCl (control). Aspirin or SA produced similar extensive gross mucosal hemorrhagic lesions and similar microscopic damage in the presence of luminal acid (luminal pH 1.3 +/- 0.05). Neither ASA nor SA produced gastric mucosal injury with intragastric instillation of saline (luminal pH 3.7 +/- 0.5). Pretreatment for 1 h with luminal or subcutaneous 16,16-dimethyl prostaglandin E2 completely prevented the formation of red streaks in ASA-treated rats but not in SA-treated rats, although prostaglandin E2 pretreatment significantly reduced the gross lesion area in SA-treated rats (p less than 0.05). We conclude the following: (a) Intravenous SA is as damaging as intravenous ASA as long as luminal acid is present. (b) 16,16-Dimethyl prostaglandin E2 completely protected the gastric mucosa from injury by intravenous ASA, and to a lesser extent by intravenous SA. (c) In view of the damaging effects of SA on the gastric mucosa and the rapid conversion of ASA to SA, the mechanism of the gastric mucosal injury by intravenous ASA is much more complex than simple inhibition of endogenous prostaglandin synthesis.     

Cimetidine reduces bile acid-mediated small intestinal mucosal injury in ratsin vivo

Whether cimetidine has protective effects on the gastrointestinal mucosa independent of its ability to reduce gastric acid secretion is still controversial. To study this, rats had small intestinal mucosal injury induced in vivo by perfusion with 5 mM chenodeoxycholic acid. Control rats were compared to rats receiving either intraperitoneal or intravenous pretreatment with 50 mg/kg cimetidine or intraluminal pretreatment with 0.5 mM cimetidine. Mucosal injury was assessed by measuring villus tip epithelial cell denudation by computerized quantitative morphology. Intraperitoneal cimetidine reduced the average denudation/villus (micrometers) caused by 45-min perfusion with chenodeoxycholic acid: control = 39.1 +/- 7.7 (SEM), intraperitoneal cimetidine = 20.8 +/- 3.5 (P less than 0.05). Additionally, both intraluminal and intravenous cimetidine reduced villus denudation caused from 30 min perfusion with chenodeoxycholic acid: control = 62.5 +/- 5.8, intravenous cimetidine = 42.6 +/- 4.7 (P less than 0.05), intraluminal cimetidine = 44.6 +/- 7.2 (P less than 0.05). The observation that reduced mucosal injury is observed in an in vivo model that is independent of gastric acid supports the conclusion that cimetidine indeed has acid-independent protective properties.     

Prostaglandin prevents aspirin injury in the canine stomach under in vivo but not in vitro conditions

This study compared the ability of topical 16,16-dimethyl prostaglandin E2 in a dose range of 0.3-3.0 micrograms/ml to prevent aspirin-induced injury in the canine stomach under both in vivo and in vitro conditions. For in vitro studies, isolated strips of oxyntic mucosa were exposed to 10 or 20 mM aspirin (ASA) at pH 1-4, with and without treatment with 16,16-dimethyl prostaglandin E2. For in vivo experiments, a portion of the oxyntic stomach was mounted between the rings of a Lucite chamber, with splenic vessels intact, such that the mucosa was divided into halves. Both sides were exposed to 20 mM ASA at pH 1 or 2, and one side also received concomitant treatment with 16,16-dimethyl prostaglandin E2. After ASA exposure, tissue samples were prepared for quantitative microscopic analysis of the degree of injury. Under both experimental conditions, the magnitude of gastric injury by ASA was pH-related, being most pronounced at pH 1; this damage was worse under in vitro conditions, and both concentrations of ASA were equally damaging in this setting. 16,16-Dimethyl prostaglandin E2 failed to prevent ASA injury in vitro at any pH and ASA concentration tested, but markedly reduced the magnitude of injury in vivo. The most effective protective dose of 16,16-dimethyl prostaglandin E2 under in vivo conditions was 1.0 micrograms/ml. The diminished tolerance to ASA damage in vitro when compared with in vivo, and the inability of 16,16-dimethyl prostaglandin E2 to prevent these damaging effects in vitro, underscores the probable crucial role for blood flow, and possibly neural innervation, in mediating the protective effects of prostaglandins.     

Isoproterenol-induced gastric mucosal protection from bile acid

Topical isoproterenol is a potent protective agent against bile acid-induced gastric mucosal injury in hypotensive and normotensive rats. This study was undertaken to ascertain what role endogenous prostaglandins and gastric mucosal blood flow play in isoproterenol-induced protection. Accordingly, anesthetized, fasted rats were given the cyclooxygenase inhibitor, indomethacin (5 mg/kg subcutaneously), 30 min prior to topical pretreatment with 3 ml of intragastric saline, isoproterenol (3 M), or 16,16-dimethyl prostaglandin E₂ (3 M) for 15 min. Gastric injury was induced with topical 5 mM acidified taurocholate and damage assessed by measuring net transmucosal ion fluxes, the appearance of DNA into the gastric lumen, and histology of the gastric epithelium. In a separate set of experiments, the effects of topical isoproterenol on gastric mucosal blood flow (laser Doppler flowmetry) and luminal PGE₂ concentrations (¹²⁵I radioimmunoassay) were examined. Pretreatment with topical isoproterenol or 16,16-dimethyl prostaglandin E₂ significantly decreased bile acid-induced net luminal ion fluxes and DNA accumulation, suggesting mucosal protection. The protective effect of isoproterenol, but not 16,16-dimethyl prostaglandin E₂, was negated by indomethacin (corroborated by histology). Further, isoproterenol did not significantly alter gastric mucosal blood flow, but did augment luminal PGE₂ concentrations, an effect also abolished by indomethacin. Thus, isoproterenol appears to protect the gastric mucosa from the damaging effects of bile acid through a mechanism that requires the synthesis and release of cytoprotective endogenous prostaglandins.     

Histologic and microcirculatory changes in alcohol-induced gastric lesions in the rat: effect of prostaglandin cytoprotection

The effect of 16,16-dimethyl prostaglandin E2 (dmPGE2) on histologic and microcirculatory changes in alcohol-induced gastric mucosal injury was studied. A histologic study confirmed that dmPGE2 does not protect the surface mucous cells against ethanol injury but does protect against the deeper necrotic lesion. Both the gross injury and the necrotic lesion were as severe after 1 min of ethanol exposure as after 60 min. A study of benzidine-stained sections and hematoxylin and eosin-stained sections revealed marked engorgement of microvessels and hemorrhage in the superficial mucosa after ethanol injury. Pretreatment with dmPGE2 prevented these. An in vivo fluorescent microscopy study revealed that there was total stasis of blood flow in the injured area. After the intravascular injection of a fluorescein-albumin conjugate, the conjugate filled microvessels in grossly normal areas of mucosa but not in grossly injured areas. Pretreatment with dmPGE2 prevented this microcirculatory change. This alcohol-induced stasis of flow in injured areas may be of pathogenetic significance and prostaglandin protection might involve prevention of this microcirculatory change.     

16,16-Dimethyl prostaglandin E2 delays collagen formation in nutritional injury in rat liver

Chronic nutritional injury was induced in rats by a high-fat, lipotrope-deficient diet. The hepatoprotective effect of 16,16-dimethyl prostaglandin E2 on the deposition of collagen and fat was assessed by histological evaluation and measurement of hydroxyproline. Dose-response studies established that optimal protection was achieved by the twice daily administration of 16,16-dimethyl prostaglandin E2 at 100 micrograms per kg (subcutaneous) or 250 micrograms per kg (oral). 16,16-Dimethyl prostaglandin E2 and a crystalline analog [(p-acetamidobenzamido)phenyl ester of 16,16-dimethyl prostaglandin E2 significantly delayed both the deposition of collagen and the increase in hepatic hydroxyproline content. There was an excellent correlation between the histological assessment of collagen and the biochemical measurement of hydroxyproline. These data provide a rationale for the evaluation of prostaglandins in the treatment of human liver disease.     

Effect of 16,16-dimethyl prostaglandin E2 on oxygen uptake and microcirculation in the perfused rat liver

Previous work demonstrated that collagen deposition in the liver of rats fed a nutritionally deficient diet for 3 to 4 months was diminished markedly by 16,16-dimethyl prostaglandin E2 treatment. In this study, rats were fed a high-fat diet or a high-fat diet deficient in lipotropes for 2 to 4 weeks prior to liver perfusion. Rates of O2 uptake by the liver were not changed by dietary manipulation. Infusion of 16,16-dimethyl prostaglandin E2 (10 microM), however, decreased O2 uptake by the whole organ by 20 to 40% in both groups. O2 tension was measured at the liver surface with a miniature O2 electrode placed alternatively on periportal and pericentral regions of the liver lobule. Mean O2 tensions in both periportal and pericentral regions were reduced 2- to 3-fold during the infusion of 16,16-dimethyl prostaglandin E2 suggesting an action on the microcirculation. This hypothesis was supported by the observation that fluorescein isothiocyanate-dextran fluorescence detected from the liver surface as well as hepatic vascular volume determined by dye dilution techniques were decreased 30 to 50% by 16,16-dimethyl prostaglandin E2. In addition, 16,16-dimethyl prostaglandin E2 increased portal pressure by about 10 mm Hg in a reversible manner. Thus, it is concluded that pharmacological levels of 16,16-dimethyl prostaglandin E2 affects the microcirculation dramatically in the isolated perfused liver.     

Surface hydrophobicity of the gastric mucosa in the developing rat. Effects of corticosteroids, thyroxine, and prostaglandin E2

Surface hydrophobicity of the gastric mucosa and its variation in response to treatments with corticosteroids, thyroxine, and 16,16-dimethyl prostaglandin E2 were measured in developing rats. A developmental increase in the hydrophobicity of the luminal surface of the gastric mucosa was recorded between the first and third weeks of life. The hydrophobicity of the stomach was not consistently influenced by an acute administration of 16,16-dimethyl prostaglandin E2 (5 micrograms/kg, 30 min before examination) until the end of the third week of life, at which time a significant 40% increase was recorded. Similarly, the decrease in surface hydrophobicity that resulted from luminal administration of an ulcerogenic dose of HCl (0.6 N, 6 ml/kg) was blocked by 16,16-dimethyl prostaglandin E2 only in 3-wk-old rats and not in rats 1 and 2 wk of age. Neither the normal developmental increase nor the 16,16-dimethyl prostaglandin E2-induced enhancement in gastric surface hydrophobicity was induced precociously by corticosterone or thyroxine. The possible importance of these findings on the development of gastric surface hydrophobicity to the ontogeny of both gastric barrier function and prostaglandin-induced gastric protection is discussed.     

Prostaglandin protects against taurocholate-induced damage to rat gastric mucosal cell culture

Prostaglandins protect gastric mucosa against noxious agents, but it is unknown whether this protection includes a direct action on the cells themselves, this action is limited to damaging agents that inhibit prostaglandin synthesis, or cellular cyclic adenosine monophosphate is the mediator. The present study tested these questions in cultured gastric mucous epithelial cells. The effect of 16,16-dimethyl prostaglandin E2 on cellular cyclic adenosine monophosphate level and the effect of 16,16-dimethyl prostaglandin E2, dibutyryl cyclic adenosine monophosphate, and isobutyl methyl xanthine on taurocholate-induced damage to cultured rat gastric mucosal cells was determined. As parameters of cell damage, the trypan blue dye exclusion test and 51Cr-release were employed. Taurocholate significantly increased 51Cr-release in a dose-dependent manner and decreased the number of viable cells. 16,16-Dimethyl prostaglandin E2 (1.0 microM) diminished the cell damage caused by 10 mM taurocholate (p less than 0.01) and increased cyclic adenosine monophosphate levels. Prostaglandin F2 alpha but not prostaglandin I2 was also cytoprotective. Addition of dibutyryl cyclic adenosine monophosphate (1.0 mM) and isobutyl methyl xanthine while significantly increasing cyclic adenosine monophosphate levels did not significantly reduce taurocholate-induced cell damage. Thus, in vitro 16,16-dimethyl prostaglandin E2 directly protects gastric mucous cells against taurocholate-induced injury, direct prostaglandin cytoprotection is not limited to damaging agents that inhibit prostaglandin synthesis, and cyclic adenosine monophosphate levels do not correlate with gastric mucosal cell damage and may not be involved in the direct protective effect of prostaglandins.     

Effect of portal hypertension onIn Vivo bile acid-mediated small intestinal mucosal injury in the rat

This study's purpose was to determine whether portal hypertension adversely affects small intestinal mucosal injury. Portal hypertension was produced in male Sprague-Dawley rats by two-stage ligation of the portal vein. Sham-operated rats were used as controls. Two weeks later, intestinal injury was produced byin vivo perfusion with 5 mM chenodeoxycholic acid for 30 min. Intestinal injury was assessed by quantitative morphometry and by measuring intestinal water and mannitol absorption. Portal hypertension resulted in more injury in the distal perfused intestine as manifested by increased villus tip denudation [portal hypertensive 52.5±9.6sem) vs controls 28.1±5.7m, P=0.05). Additionally there was a significant decrease in the unperfused duodenal villus height in portal hypertensive rats (portal hypertensive 755±22 vs controls 848±28m, P<0.02). Portal hypertension had no significant effect on the increase in mannitol absorption or water secretion caused by chenodeoxycholic acid perfusion. This study suggests that portal hypertension alters small intestinal mucosa and increases susceptibility to injury.This work was supported in part by a grant from the Research Service of the Veterans Administration.     

Prostaglandin cytoprotection against ethanol-induced gastric injury in the rat. A histologic and cytologic study

Using macroscopic criteria for injury, prostaglandins have been alleged to possess potent antiulcer properties despite meager histologic evidence for this cytoprotective action. This time-sequence study used light, scanning, and transmission electron microscopy to evaluate the effects of 16,16-dimethyl prostaglandin E2 on gastric mucosal integrity after exposure to 100% ethanol. Macroscopically, virtually complete protection against injury to the glandular mucosa of the in vivo rat stomach was noted in animals receiving 10 micrograms/kg body wt of prostaglandin subcutaneously before oral ethanol administration when killed at 5, 20, and 60 min after ethanol exposure compared with oral ethanol after saline injection. On light microscopy the length of injured epithelium in prostaglandin/ethanol- and saline/ethanol-treated tissues was not significantly different at all time periods studied. Although the depth of injury extended into gastric glands in both groups killed at 5 min, the deep pit surface mucus cells in prostaglandin/ethanol mucosa were less damaged and necrotic lesions were virtually absent when compared with saline/ethanol mucosa. At 20 and 60 min, cellular injury could still be identified in prostaglandin/ethanol-treated mucosa but the depth of injury became even less pronounced over time in contrast to mucosa exposed to ethanol without prostaglandin. Scanning electron microscopy and transmission electron microscopy confirmed these differences. Despite the macroscopic findings, these results indicate that prostaglandin does not prevent superficial surface mucus cell necrosis in ethanol-exposed mucosa even though it does spare cells in the pit base. The reduction in damaged cells over time in prostaglandin/ethanol-treated mucosa, in contrast to saline/ethanol-treated mucosa, supports the hypothesis that the reepithelialization of the lamina propria is initiated by spared deep-lying pit cells.     

Effects of zincl-carnosine on gastric mucosal and cell damage caused by ethanol in rats

The effects of zinc L-carnosine on ethanol-induced damage and the correlation of these effects with endogenous prostaglandin E2 were evaluated in rat gastric mucosa in vivo and in vitro. When given either intragastrically or intraperitoneally, zinc L-carnosine (10 or 30 mg/kg) prevented gross visible damage to gastric mucosa caused by ethanol without affecting the mucosal prostaglandin E2 level. This protective effect of zinc L-carnosine was not inhibited by indomethacin. Histological assessment showed that zinc L-carnosine inhibited deep mucosal necrosis, as did 16,16-dimethyl prostaglandin E2. Zinc L-carnosine (10(-6) or 10(-5) M) inhibited the damage caused by ethanol to gastric cells isolated from rat gastric mucosa in vitro; this effect was not inhibited by indomethacin. The results suggested that zinc L-carnosine protects the gastric mucosa and enhances cellular resistance to ethanol without the mediation of endogenous prostaglandins.     

Early microcirculatory stasis in acute gastric mucosal injury in the rat and prevention by 16,16-dimethyl prostaglandin E2 or sodium thiosulfate

We used in vivo microscopy and laser-Doppler velocimetry to examine the effects on the gastric mucosal microcirculation and in gastric mucosal blood flow of agents that induce acute gastric mucosal damage. In vivo microscopic observation of superficial mucosal capillaries revealed vascular stasis within a mean of 54, 81, or 61 s after 100% ethanol, 0.6 N HCl, or 0.2 N NaOH, with the subsequent development of hemorrhagic mucosal lesions. Mucosal blood flow estimated by laser-Doppler velocimetry decreased by 30% at 5 min after luminal application of 100% ethanol, and decreased further to about 40% of basal levels by 15 min. The decreased mucosal blood flow 15 min after application of 50% ethanol correlated with the extent of hemorrhagic mucosal lesions. Examination of the submucosal vessels that supply and drain the mucosa showed moderate dilation of small arterioles 1, 3, and 6 min after exposure to 100% ethanol but there were no consistent changes in venules. Mild vasoconstriction of small- and medium-sized venules could be detected 6, 10, and 15 min after NaOH but not after exposure to HCl. Pretreatment with 16,16-dimethyl prostaglandin E2 or sodium thiosulfate before exposure of the mucosa to ethanol prevented capillary stasis, maintained mucosal blood flow, and prevented the development of hemorrhagic gastric mucosal lesions. Topical mucosal application of 16,16-dimethyl prostaglandin E2 decreased, whereas topical exposure to sodium thiosulfate increased gastric mucosal blood flow, indicating that change in blood flow per se is an unlikely mediator of protection.     

Effect of cholecystokinin and 16,16-dimethyl prostaglandin E2 on RNA and DNA of gastric and duodenal mucosa.

Fasted rats were injected with either cholecystokinin-octopeptide (CCK-OP), 20 mug per kg; 16,16-dimethyl prostaglandin E2 (16,16-dimethyl PGE2), 0.2 mg per kg; pentagastrin, 250 mug per kg, or saline every 8 hr for 48 hr. The rats were killed and the incorporation of [3H]thymidine into DNA as well as the total DNA and RNA content of the mucosa of the oxyntic gland area and the duodenum were determined. Pentagastrin increased DNA synthesis 60% (P less than 0.001) in gastric mucosa and 90% (P less than 0.001) in duodenal mucosa when compared with rates for saline controls. Neither CCK-OP nor 16,16-dimethyl PGE2 altered gastric mucosal DNA synthesis. Pentagastrin significantly increased the DNA and RNA content of both the gastric and duodenal mucosa. CCK-OP and 16,16-dimethyl PGE2 caused a slight but significant increase in duodenal DNA synthesis, CCK-OP did not significantly increase duodenal DNA content, and 16,16-dimethyl PGE 2 increased duodenal RNA but not DNA content. CCK-OP (20 mug per kg) in combination with pentagastrin did not alter the stimulation of gastric DNA synthesis but significantly decreased the effect of pentagastrin on duodenal DNA. A dose of CCK-OP (370 mug per kg) equimolar to 250 mug per kg of pentagastrin did not stimulate DNA synthesis in either tissue and significantly inhibited stimulation by pentagastrin in both tissues. Low doses of CCK-OP (2.5, 5.0, 10.0, 20.0 mug per kg) caused statistically significant increases in DNA synthesis and DNA content of the pancreas, but had no effect on either mucosa of the oxyntic gland area or duodenum. 16,16-Dimethyl PGE2 did not inhibit the stimulation of DNA synthesis or the increases in DNA and RNA content stimulated by pentagastrin. From these results it appears that: (1) moderate doses of CCK have a weak trophic effect in the duodenum but not in the stomach, (2) physiological doses of CCK-OP stimulated pancreatic DNA synthesis and increased pancreatic DNA content without affecting these parameters in the oxyntic gland area or duodenum in the same animals, (3) in the stomach and duodenum CCK is not as potent a trophic hormone as gastrin and inhibits, probably competitively, the trophic effects of gastrin, (4) 16,16-dimethyl PGE2 does not stimulate growth and does not interfere with the trophic response to gastrin even though it inhibits acid secretion, and (5) 16,16-dimethyl PGE2 increased the RNA content of duodenal mucosa indicating that it may stimulate activity resulting in hypertrophy.     

Chemotactic peptide-induced acute colitis in rabbits

Bacterial chemotactic peptides from the intestinal lumen could potentially induce inflammation if they reached the mucosa. We tested several peptides chemotactic for different inflammatory cells, as well as a nonchemotactic peptide, bradykinin, for their ability to induce colitis in vivo in rabbits. These peptides were also assessed for their ability to stimulate release of the eicosanoids leukotrienes B4 and C4 and prostaglandin E2 from normal rabbit colons perfused ex vivo. Intracolonic administration of n-formyl-methionyl-leucyl-phenylalanine (chemotactic for neutrophils); its methyl ester (chemotactic for monocytes), and alanyl-glycyl-seryl-glutamic acid (chemotactic for eosinophils) all produced colitis (assessed grossly and histologically) within 4 days. Bradykinin did not induce colitis although it did release prostaglandin E2. n-Formyl-methionyl-leucyl-phenylalanine methyl ester induced the greatest degree of colitis in vivo and released prostaglandin E2 and leukotrienes ex vivo. n-Formyl-methionyl-leucyl-phenylalanine and alanyl-glycyl-seryl-glutamic acid induced comparable degrees of inflammation, but alanyl-glycyl-seryl-glutamic acid produced no eicosanoid release while n-formyl-methionyl-leucyl-phenylalanine released both prostaglandin E2 and leukotriene B4 and leukotriene C4 products from normal ex vivo perfused colons. Thus alanyl-glycyl-seryl-glutamic acid produces colitis independent of proinflammatory eicosanoids while eicosanoid release could contribute to colitis produced by n-formyl-methionyl-leucyl-phenylalanine methyl ester. This experimental model of colitis may reflect one possible etiology of inflammatory bowel disease in humans, when bacterial chemotactic peptides breach mucosal defenses in susceptible individuals.     

Effects of dietary linoleic acid on mucosal adaptation after small bowel resection

We have shown that dietary long-chain triglycerides and 16,16-dimethyl prostaglandin E2 enhance and aspirin impairs postresection mucosal adaptation in rats. The present studies examined the hypothesis that supplemental linoleic acid (LA) above the minimum requirement may enhance postresection mucosal adaptation through altered prostaglandin (PG) synthesis. Forty male Sprague-Dawley rats (105 +/- 5 g) were fed purified diet containing either 5% LA or 4% palmitic acid and 1% LA. After 2 weeks, 12 rats from each dietary group underwent 70% proximal jejunoileal resection and the remainder were sham-operated. Dietary regimens were continued for an additional 13 days. Mucosal fatty acid analysis of 1% LA group revealed a ratio of 20:3 n-9/20:4 n-6 lower than 0.2, indicating normal essential fatty acid status. Mucosal protein per centimeter bowel was higher in the 5% LA group compared to the 1% group, but mucosal DNA, maltase, and ex vivo PG synthesis were not affected. These results indicate that LA stimulates postresection mucosal hypertrophy, which does not appear to be related to PG synthesis.     

Protection by 16,16-dimethyl prostaglandin E2 and dibutyryl cyclic AMP against complement-mediated hepatic necrosis in rats.

16,16-Dimethyl prostaglandin E2, a known cytoprotective agent, was examined for its ability to protect the liver against complement-mediated necrosis induced by an intravenous injection of a monoclonal antibody against a rat liver-specific antigen in rats. The hepatic injury induced by the antibody was characterized by (a) rapid development of numerous massive hemorrhagic foci of necrotic liver cells, (b) marked increases in serum liver enzyme activities and (c) pronounced reduction in the CH50 level, presumably as a result of complement consumption in the liver. Pretreatment with 16,16-dimethyl prostaglandin E2 at intraperitoneal doses of 20 and 100 micrograms/kg suppressed the hepatic injury, as evidenced by markedly mitigated liver-cell necrosis and much smaller increases in the serum-enzyme activities compared with the values in diseased control animals. The prostaglandin analogue failed to prevent serum complement consumption in response to the antibody injection or affect the CH50 level at the preinjury stage, indicating that neither complement inactivation nor interference with the antigen-antibody reaction was involved in the hepatic protection. The hepatoprotective doses of 16,16-dimethyl prostaglandin E2 produced a significant increase in liver cyclic AMP content in a dose-related manner. In addition, intravenous dibutyryl cyclic AMP at 3 and 10 mg/kg dose-dependently prevented histological and biochemical changes in the hepatic damage without altering the rate of reduction in serum complement activity. Like 16,16-dimethyl prostaglandin E2, dibutyryl cyclic AMP did not affect the preinjury CH50 level.(ABSTRACT TRUNCATED AT 250 WORDS)     

A fluorescent in vivo microscopic method to assess surface mucosal integrity in the rat stomach. Effects of ethanol and prostaglandin

A new sensitive in vivo fluorescent method to assess gastric mucosal integrity in the anesthetized rat is described. Topically applied fluorescein diacetate enters gastric mucosal cells. The diacetate is cleaved by intracellular esterases leaving fluorescein trapped within the cells. The pattern of fluorescence can be visualized, and the intensity of fluorescence measured, using a fluorescent in vivo microscopy system. Frozen section studies revealed that fluorescein was located in the surface mucous cells and the mucous neck cells. Topically applied ethanol caused a dose-dependent decline in intensity of fluorescence. Measurement of fluorescence in the supernatant bathing the mucosa revealed that leak of fluorescein out of cells or shedding of cells was, at least in part, responsible for the decline in fluorescence intensity. Pretreatment with a "cytoprotective" dose of 16,16-dimethyl prostaglandin E2 did not protect against the decline in fluorescence seen after 12.5% and 25% ethanol. This confirms findings of previous histologic studies that prostaglandin "cytoprotection" does not include surface cell protection. We conclude that this technique provides a sensitive, quantitative in vivo method to study gastric surface cell injury.     

Gastric mucosal blood flow in rats after administration of 16,16-dimethyl prostaglandin E2 at a cytoprotective dose

The purpose of the present study was to determine whether the gastric cytoprotective effect of a prostaglandin such as 16,16-dimethyl prostaglandin (dmPGE2) is mediated by an increase in mucosal blood flow. Gastric mucosal blood flow was measured in urethane-anesthetized rats by the hydrogen gas clearance technique. In control rats given no ethanol, intragastric administration of dmPGE2 (10 micrograms/kg body wt) produced a significant reduction (15.3%) in gastric mucosal blood flow 30 min after treatment. This dose of dmPGE2 significantly reduced the formation of the gross gastric lesions produced by absolute ethanol in anesthetized rats. In vehicle-pretreated animals, blood flow was invariably absent in the ethanol-induced mucosal lesion areas. In the nonlesion areas, gastric mucosal blood flow was the same in prostaglandin-pretreated and vehicle-pretreated animals as in control (no ethanol) rats. Thus, although dmPGE2 pretreatment protected against ethanol-induced gastric mucosal injury and prevented the accompanying blood flow stasis, it did not do this by an increase in gastric mucosal blood flow. The protection also is not due to a decrease in flow because, in separate groups of anesthetized rats, a 15% reduction in gastric mucosal blood flow induced by either hemorrhage or intravenous vasopressin did not protect the gastric mucosa against absolute ethanol-induced injury. Whether the maintenance of gastric mucosal blood flow is a primary or secondary effect of prostaglandin cytoprotection remains to be determined.