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.     

Transforming growth factor alpha and epidermal growth factor in protection and healing of gastric mucosal injury.

Transforming growth factor alpha (TGF) and epidermal growth factor (EGF) present in the gastric mucosa are polypeptides with similar biologic activity. This study compares the activity of TGF and EGF in the protection against injury by 100% ethanol and stress and in healing of acute gastric ulcerations. TGF and EGF (12.5-100 micrograms/kg-h) infused subcutaneously 30 min before and during ethanol or stress decreased mucosal lesions dose-dependently. The ID50 for ethanol- and stress-induced lesions after TGF were 40 and 70 micrograms/kg-h and after EGF 60 and 100 micrograms/kg-h. TGF and EGF infused subcutaneously into intact rats inhibited gastric acid secretion but did not affect the gastric blood flow or mucosal generation of prostaglandin E2 (PGE2). Both TGF and EGF also significantly enhanced the healing of stress-induced lesions and the restoration of DNA synthesis. Ethanol and stress reduced blood flow in the oxyntic mucosa by 68% and 51%, respectively, and this effect was partially reversed by EGF and TGF. Pretreatment with indomethacin (5 mg/kg intraperitoneally), which reduced mucosal generation of PGE2 by 85%, decreased in part the protection by TGF and EGF against ethanol-induced damage and virtually abolished the protective action of these peptides against stress-induced injury.(ABSTRACT TRUNCATED AT 250 WORDS)     

丹参抗大鼠乙醇性胃粘膜损伤的作用及机制

目的 :探讨丹参抗大鼠乙醇性胃粘膜损伤的作用及机制。方法 :采用 10 0 %乙醇复制大鼠乙醇性胃粘膜损伤模型 ,用放射免疫法测定胃粘膜内前列腺素 E2 (PGE2 )、前列腺素 I2 (PGI2 )的含量 ,用浓盐法测定胃粘膜内DNA的含量。结果 :丹参组的胃粘膜损伤指数低于对照组 (P <0 .0 1) ;胃粘膜内 PGE2 、PGI2 含量高于对照组 (均 P<0 .0 1) ;DNA含量高于对照组 (P <0 .0 1)。结论 :丹参促进胃粘膜细胞 DNA的合成和胃粘膜细胞的增殖 ,使PGE2 、PGI2 含量增加 ,进而促进了胃粘液的分泌。     

Gastroprotective effect of histamine and acid secretion on ammonia-induced gastric lesions in rats

BACKGROUND: Previous studies have shown that ammonia produced by Helicobacter pylori urease or administrated intragastrically exhibits a toxic effect on the gastric mucosa. In the present study we investigated the influence of histamine and gastric acid secretion on ammonia (NH4OH)-induced gastric lesions. METHODS: The gastric mucosa in rats was exposed to NH4OH (1.5 ml of 250 mM solution) under basal conditions, after administration of histamine (1 mg/kg), urea with urease, and ranitidine (40 mg/kg subcutaneously) given alone or in combination. We measured the area of gastric lesions, gastric blood flow (GBF), plasma gastrin concentration, DNA synthesis, gastric acid secretion and gastric luminal concentration of PGE2. RESULTS: Application of NH4OH resulted in the formation of acute gastric lesions. This effect was accompanied by a fall in GBF, a rise in gastric pH, and a reduction in mucosal DNA synthesis. Administration of histamine 30 min prior to NH4OH reduced the area of gastric lesions. This was accompanied by an increase in GBF, DNA synthesis, and prostaglandin E2 (PGE2) production. Ranitidine given prior to NH4OH enhanced gastric mucosa damage, and reduced GBF and DNA synthesis. This effect was accompanied by a reduction in gastric acid secretion. Ranitidine given prior to histamine abolished gastric acid secretion and the protective effect of histamine against NH4OH-induced damage; these effects were accompanied by a decrease in GBF, DNA synthesis, and concentration of PGE2. Pretreatment with 2% urea with urease given prior to NH4OH reduced NH4OH lesions. This effect was associated with an increase in gastric acid secretion, gastric generation of PGE2, GBF, and DNA synthesis. Ranitidine given prior to urea with urease inhibited gastric acid secretion and the gastroprotective effect of urea-urease gastroprotection. CONCLUSIONS: Histamine and gastric secretion exhibit a protective effect against ammonia-induced gastric lesions. This effect appears to depend upon the stimulation of gastric acid secretion and PGE2 production, and the improvement of gastric microcirculation.     

Comparison of prostacyclin and prostaglandin E2 on gastric secretion,gastrin release,and mucosal blood flow in dogs

In dogs with gastric fistulae (GF) and Heidenhain pouches (HP), intravenous graded doses of prostacyclin (PGI2) (dose range: 2.5-20 micrograms/kg/hr), and prostaglandin E2 (PGE2) (dose range: 10-80 micrograms/kg/hr) produced a dose-dependent inhibition of acid and pepsin secretion stimulated by pentagastrin (3 micrograms/kg/hr). The ID50 (dose inhibiting acid output by 50% were 6 micrograms/kg/hr for PGI2 and 26 micrograms/kg/hr for PGE2 for the GF, and 7 micrograms/kg/hr for PGI2 and 22 micrograms/kg/hr for PGE2 for the HP. Acid secretion from the GF stimulated by histamine (20 micrograms/kg/hr) was also inhibited by both prostaglandins: the ID50 were 16 micrograms/kg/hr for PGI2 and 22 micrograms/kg/hr for PGE2. For the HP, the ID50 were about 20 and 40 micrograms/kg/hr for PGI2 and PGE2, respectively. Meal-induced acid secretion from the GF reached a level similar to that observed in tests with pentagastrin and was inhibited by both prostaglandins. The ID50 were 5 and 20 micrograms/kg/hr for PGI2 and PGE2, respectively. PGI2 significantly increased serum gastrin above that obtained with meal alone whereas PGE2 did not affect postprandial serum gastrin. The inhibition of pentagastrin and meal-induced acid secretion was accompanied by a marked reduction in gastric mucosal blood flow (MBF) measured by the [14C]aminopyrine method, without significant change in the ratio of gastric blood flow to gastric secretion. The MBF in the resting HP mucosa was significantly increased by PGI2 but reduced by PGE2. This study shows that PGI2 is about 3-4 times more potent than PGE2 in inhibiting pentagastrin and meal-induced gastric secretion and MBF; PGI2 unlike PGE2, increases the postprandial serum gastrin and raises the MBF of the resting mucosa. Therefore, both PGI2 and PGE2 are antisecretory, but their effects on gastrin release and resting MBF are qualitatively different.     

Role of epidermal growth factor, prostaglandin, and sulfhydryls in stress-induced gastric lesions

Epidermal growth factor promotes the growth of and protects gastric mucosa against various ulcerogens, including stress, but little is known about its role in the pathogenesis of stress ulcerations. In this study, Wistar rats with intact and resected salivary glands were exposed to water-immersion and restraint stress. During 2-14 hours of water-immersion restraint stress, the formation of gastric ulcerations increased progressively and the duration of stress was accompanied by a decrease in DNA synthesis in the gastric mucosa. Following sialoadenectomy, a significant increase in the number of stress ulcerations and further reduction in DNA synthesis were observed. Exogenous epidermal growth factor and dimethyl prostaglandin E2 significantly reduced the ulcerations in the stressed rats with intact salivary glands, but this reduction was significantly less pronounced after sialoadenectomy. Water-immersion restraint stress also resulted in about 50% reduction in mucosal prostaglandin E2 generation, and the pretreatment with indomethacin, which suppressed prostaglandin E2 by about 90%, almost doubled the number of stress ulcerations and abolished the gastro-protective effect of exogenous epidermal growth factor (but not dimethyl prostaglandin E2) against the stress lesions. An inhibition of ornithine decarboxylase activity by difluoromethyl ornithine also augmented stress-induced ulcerogenesis and abolished the protective action of epidermal growth factor while the administration of spermine almost completely prevented stress ulcerations in rats both without and with pretreatment with difluoromethylornithine. Water-immersion restraint stress also significantly reduced mucosal content of glutathione. Cysteamine increased tissue glutathione and reduced stress ulcerations but N-ethylmaleimide, an sulfhydryl blocker, decreased mucosal content of glutathione without affecting the stress ulcerations. This study indicates that the stress ulcers are accompanied by the reduction in mucosal synthesis of DNA, prostaglandin, and glutathione and that the presence of salivary glands attenuates the stress ulcerogenesis probably by releasing epidermal growth factor which acts, in part, by enhancing ornithine decarboxylase activity, mucosal growth, and prostaglandin and glutathione formation.     

Effect of salivarectomy on the growth of gastrointestinal mucosa and urinary secretion of epidermal growth factor in rats

The effect of salivary epidermal growth factor (EGF) on the growth and metabolism of gastrointestinal mucosa was examined by comparing DNA synthesis, DNA and RNA content, and weight of mucosa of salivarectomized and sham operated male rats. DNA synthesis of gastric mucosa was suppressed at 2 days after salivarectomy. Both weight and DNA content of oxyntic mucosa in the salivarectomized group were significantly lower than that of the sham operated group. Although salivarectomy suppressed DNA synthesis of jejunal mucosa, the difference was not significant statistically. The effect of salivarectomy on colonic mucosa was least in the gastrointestinal tract. Such a result suggested that the gradient-oriented antitrophic effect was brought about by salivarectomy. Urinary EGF excretion after salivarectomy was examined by radioreceptor assay. Although the antitrophic effect of salivarectomy on oxyntic mucosa was highest on day 2, no significant difference of urinary EGF concentration was detected on day 2. From these results it is suggested that the effect of salivarectomy on the gastrointestinal tract was not due to the change of EGF in systemic circulation but due to the change of luminal EGF.     

Effect of salivarectomy on the growth of gastrointestinal mucosa and urinary secretion of epidermal growth factor in rats

The effect of salivary epidermal growth factor (EGF) on the growth and metabolism of gastrointestinal mucosa was examined by comparing DNA synthesis, DNA and RNA content, and weight of mucosa of salivarectomized and sham operated male rats. DNA synthesis of gastric mucosa was suppressed at 2 days after salivarectomy. Both weight and DNA content of oxyntic mucosa in the salivarectomized group were significantly lower than that of the sham operated group. Although salivarectomy suppressed DNA synthesis of jejunal mucosa, the difference was not significant statistically. The effect of salivarectomy on colonic mucosa was least in the gastrointestinal tract. Such a result suggested that the gradient-oriented antitrophic effect was brought about by salivarectomy. Urinary EGF excretion after salivarectomy was examined by radioreceptor assay. Although the antitrophic effect of salivarectomy on oxyntic mucosa was highest on day 2, no significant difference of urinary EGF concentration was detected on day 2. From these results it is suggested that the effect of salivarectomy on the gastrointestinal tract was not due to the change of EGF in systemic circulation but due to the change of luminal EGF.     

Prostaglandins and renin release: the effect of PGI2, PGE2, and 13,14-dihydro PGE2 on the baroreceptor mechanism of renin release in the dog.

We compared the ability of the vasodilator prostaglandins PGI2, PGE2, and 13,14-dihydro PGE2 to release renin when infused into the denervated, nonfiltering canine kidney in vivo. Papaverine was used as a nonprostaglandin vasodilator. All the prostaglandins tested were capable of stimulating renin secretion, with the scale of potency being 13,14-dihydro PGE2 greater than PGI2 greater than PGE2; papaverine had no effect on renin secretion. These results indicate that both PGE2 and PGI2 can stimulate renin secretion but that vasodilation per se is not a stimulus. 13,14-Dihydro PGE2 was included because it is a poorer substrate than PGE2, both for transport into cells and catabolism to inactive products, but has comparable potency to PGE2 when tested in systems with limited ability to catabolize PGE2. The fact that 13,14-dihydro PGE2 was the most potent prostaglandin tested suggests that the effects of PGE2 in our system are reduced by the kidneys' recognized ability to extract and catabolize PGE2. Since PGI2 is less avidly metabolized than PGE2 by the kidney, the differences in observed potency between PGE2 and PGI2 could be largely the result of differences in renal catabolism of the two prostaglandins rather than differences in intrinsic potency. Therefore, both PGE2 and PGI2 are candidates for the endogenous prostaglandin responsible for stimulating renin secretion.     

Cell cycle-dependent inhibition of DNA synthesis by prostaglandin I2 in cultured rabbit aortic smooth muscle cells

The role of prostaglandin I2 (PGI2) in the control of DNA synthesis during the cell cycle was investigated in cultured rabbit aortic smooth muscle cells (SMC). SMC at confluency in the G0 state reached the S phase about 16 h after stimulation with serum, as judged by measurement of [3H]thymidine incorporation into DNA (DNA synthesis). Cyclooxygenase inhibitors such as indomethacin and aspirin enhanced DNA synthesis, suggesting that endogenously synthesized prostaglandins inhibit DNA synthesis. Added PGE1 or PGE2 had little effect on DNA synthesis. PGI2 inhibited DNA synthesis only when added from 10 to 16 h after stimulation of SMC in the G0 state with serum. Addition of CS-570, a stable PGI2 analogue, inhibited DNA synthesis at any time after serum stimulation. The endogenous syntheses of PGI2 and DNA were negatively correlated. These results suggest that PGI2 inhibits DNA synthesis by acting on the progression stage of the G1 state.     

Protective action of omeprazole, a benzimidazole derivative, on gastric mucosal damage by aspirin and ethanol in rats

This study was designed to compare the influence of omeprazole, a potent inhibitor of H+/K+-ATP-ase involved in the final step of H+ secretion and prostaglandin (PG) I2 on the formation of gastric mucosal lesions induced by absolute ethanol or acidified aspirin (ASA). Omeprazole given intragastrically in both inhibitory (20 or 200 mumol/kg) and noninhibitory doses (2 mumol/kg) prevented dose dependently ASA- and ethanol-induced gastric lesions. The protective effect of omeprazole against ASA-induced lesions occurred when mucosal generation of PGs was completely suppressed and that against ethanol lesions when PG generation was increased above normal values. Pretreatment with PGI2 given intragastrically or subcutaneously both in inhibitory and noninhibitory doses prevented almost completely the formation of gastric mucosal lesions caused by both absolute ethanol and acidified ASA. This study indicates that omeprazole is capable of protecting gastric mucosa against ASA- and ethanol-induced injury and that this protection is unrelated to gastric inhibition or the biosynthesis of mucosal PGs.     

Gastric cytoprotection by acetazolamide: role of endogenous prostaglandins

This study was designed to determine the influence of acetazolamide, a potent inhibitor of carbonic anhydrase, on the formation of gastric mucosal lesions induced by acidified aspirin (ASA) or absolute ethanol and on gastric cytoprotection induced by prostaglandin E2 (PGE2). Acetazolamide prevented dose-dependently ethanol-induced gastric lesions and this effect was accompanied by an increased biosynthesis of mucosal PGs, indicating that endogenous PGs may be involved in cytoprotection by acetazolamide. This is supported by the finding that acetazolamide failed to affect gastric ulcerations produced by acidified ASA when mucosal PG biosynthesis was almost completely suppressed. Pretreatment with acetazolamide did not influence the protective action of PGE2 on ethanol-induced mucosal lesions and only slightly inhibited the protective effect of PGE2 on ASA-induced gastric ulcerations. This study indicates that: (1) acetazolamide prevents ethanol- but not ASA-induced gastric mucosal lesions probably via stimulation of PG biosynthesis and (2) gastric alkaline secretion, mediated by carbonic anhydrase, is probably not an essential mechanism responsible for this cytoprotection induced by PGE2.     

Effect of epidermal growth factor on the development of rat gastric mucosa

Epidermal growth factor (EGF) has been shown to stimulate the growth of adult rat gastric mucosa and to increase DNA synthesis of mouse small and large intestinal mucosa. This study examines whether EGF affects the functional and structural development of the rat gastric mucosa. Rats were injected with 20 micrograms/kg EGF three times/day for 5 days beginning on the 10th day after birth. A control group of animals received saline injections of identical volume. All rats were killed on day 15. EGF significantly increased the weight of the whole stomach and the DNA, RNA, and protein content of the oxyntic gland mucosa, but had no effect on the RNA/DNA ratio, or antral and serum gastrin levels. Two groups of similarly treated rats, were anesthetized with ether, pylorus-ligated, and injected with either saline or pentagastrin (250 micrograms/kg) after they had recovered from anesthesia. EGF-treated rats had significantly higher rates of basal acid secretion and pentagastrin-stimulated acid secretion than the saline-treated controls. EGF, however, did not alter basal or pentagastrin-stimulated pepsin secretion nor did it change mucosal pepsinogen content. These results indicate that EGF stimulates oxyntic mucosal growth in unweaned rats but that it does not lead to precocious maturation or functional development.     

Transforming Growth Factor Alpha and Epidermal Growth Factor in Protection and Healing of Gastric Mucosal Injury

Transforming growth factor alpha (TGF) and epidermal growth factor (EGF) present in the gastric mucosa are polypeptides with similar biologic activity. This study compares the activity of TGF and EGF in the protection against injury by 100% ethanol and stress and in healing of acute gastric ulcerations. TGF and EGF (12.5-100 μg/kg-h) infused subcutaneously 30 min before and during ethanol or stress decreased mucosal lesions dose-dependently. The ID₅₀ for ethanol- and stress-induced lesions after TGF were 40 and 70 μg/kg-h and after EGF 60 and 100 ug/kg-h. TGF and EGF infused subcutaneously into intact rats inhibited gastric acid secretion but did not affect the gastric blood flow or mucosal generation of prostaglandin E₂ (PGE₂). Both TGF and EGF also significantly enhanced the healing of stress-induced lesions and the restoration of DNA synthesis. Ethanol and stress reduced blood flow in the oxyntic mucosa by 68% and 51%, respectively, and this effect was partially reversed by EGF and TGF. Pretreatment with indomethacin (5 mg/kg intraperitoneally), which reduced mucosal generation of PGE₂ by 85%, decreased in part the protection by TGF and EGF against ethanol-induced damage and virtually abolished the protective action of these peptides against stress-induced injury. We conclude therefore that 1) TGF and EGF show similar and comparable gastroprotective activity against ethanol- and stress-induced damage; 2) the protection by TGF and EGF is accompanied by an increase in gastric blood flow which appears to be an essential factor in gastroprotection; 3) mucosal PG is necessary for manifestation of the protective activity of TGF and EGF against acute gastric damage; and 4) TGF and EGF enhance the healing of gastric lesions, possibly via stimulation of DNA synthesis and cell proliferation.     

Stimulation of mucus and nonparietal cell secretion by the E2 prostaglandins

The effects of prostaglandin E₂ (PGE₂), 15-methyl prostaglandin E₂ (15M), and 16,16-dimethyl prostaglandin E₂ (16DM) on gastric mucus and nonparietal cell secretion in rats were measured. Alcian blue binding was used as a measure of gastric mucus. Applied topically, all three agents stimulated nonparietal cell secretion, and PGE₂ and 16 DM stimulated the secretion of mucus, increasing the fraction in the gastric contents but not that adherent to the mucosa. Topical 15M did not stimulate the production of mucus. Given intravenously, all three agents increased the amount of mucus in the gastric contents without altering the amount of mucus bound to the mucosa. The prostaglandins had no effect on nonparietal cell secretion when given intravenously. These effects could be relevant to the ability of the E₂ prostaglandins to protect the gastric mucosa from damage.Support by: grant MA-5316 from the Medical Research Council, and the Upjohn Company     

Potentiation of aspirin-induced gastric lesions by exposure to cold in rats. Role of acid secretion, mucosal blood flow, and gastric mucosal prostanoid content

We investigated the mechanism by which exposure to cold sensitizes rats to the formation of gastric lesions after a low dose of aspirin (50 mg/kg). Six times more lesions were produced by aspirin plus cold than by aspirin alone. Three hypotheses were studied to explain the synergism of aspirin plus cold on lesion formation: gastric acid hypersecretion, reduced gastric mucosal blood flow, and decreased prostanoid synthesis by the stomach. Cold, and cold plus aspirin, stimulated gastric acid secretion (to a similar extent), whereas aspirin had no effect. Gastric mucosal blood flow, measured by the hydrogen gas clearance method, was decreased by cold, aspirin, and aspirin plus cold, and the extent of decrease was similar. Prostanoid generation [prostaglandin E2 (PGE2), PGF2 alpha, 6-keto PGF1 alpha, and thromboxane B2] by the gastric corpus mucosa was not affected by cold, but was reduced equally (by at least 90%) in animals receiving aspirin alone or aspirin plus cold. After oral administration of aspirin, the plasma contained mostly salicylic acid (98%), whereas the gastric mucosa contained mostly aspirin (80%-85%). We conclude that the synergism of aspirin plus cold on the formation of gastric lesions probably results from the combined effects of three factors: increased secretion of acid (because of exposure to cold) that is in contact with a gastric mucosa in which blood flow is reduced (because of exposure to cold or to aspirin), and in which the synthesis of cytoprotective prostaglandins is inhibited (by aspirin). Such mucosa may be particularly vulnerable to the damaging effect of hyperacidity.     

Cytoprotection by prostaglandins in rats. Prevention of gastric necrosis produced by alcohol, HCl, NaOH, hypertonic NaCl, and thermal injury.

Oral administration to fasted rats of either absolute ethanol, 0.6 N hydrochloric acid, 0.2 N sodium hydroxide, 25% sodium chloride, or boiling water produced extensive necrosis of the gastric mucosa. Pretreatment with several prostaglandins of the A, E, or F type, either orally or subcutaneously, prevented such necrosis, and the effect was dose-dependent. This property of prostaglandins is called "cytoprotection." The protective effect against oral administration of absolute ethanol was already maximal 1 min after PGE2 given orally, and 15-30 min after PGE2 given subcutaneously. Cytoprotection by prostaglandins is unrelated to the inhibition of gastric acid secretion since, (a) it is maximal at doses that have no effect on gastric secretion, and (b) anti-secretory compounds (cimetidine, methscopolamine bromide) and antacids are not cytoprotective. Although the mechanism of gastric cytoprotection is unknown, prostaglandins appear to increase the resistance of gastric mucosal cells to the necrotizing effect of strong irritants. These results suggest that certain prostaglandins, by a mechanism other than the inhibition of gastric acid secretion, maintain the cellular integrity of the gastric mucosa, and might be beneficial in the treatment of a variety of diseases in which gastric mucosal injury is present.     

Protective action of endogenous prostacyclin (PGI2) and prostaglandin E2 (PGE2) in endoscopic polypectomy-induced human ulcers

To assess how endogenous prostaglandin (PG) in gastric mucosa acts against ulcer formation, we determined the mucosal prostacyclin (PGI2), PGE2, PGF2 alpha, and thromboxane A2(TXA2) concentrations before and after polypectomy in 6 patients in whom gastric ulcers were produced by electric burning resection of gastric polyps. These artificially induced ulcers all healed within short periods (25.7 +/- 7.4 days, mean +/- SE). Of the PGs assayed, the level of PGI2 was highest. The pG levels were increased at 4 and 7 days post-polypectomy; the most remarkable increase took place in the mucosa along the ulcer margin rather than the mucosa far from the ulcer site. We suggest that the observed increase in endogenous PGs represents a physiological response against polypectomy-induced ulcer formation.     

Use of minoxidil to demonstrate that prostacyclin is not the mediator of bone resorption stimulated by growth factors in mouse calvariae

Growth factors, such as human transforming growth factor-alpha (hTGF alpha) and epidermal growth factor, as well as human tumor necrosis factor (hTNF) stimulate the resorption of bone in neonatal mouse calvariae in organ culture via a prostaglandin (PG)-mediated pathway. In response to such factors mouse calvariae produce substantial quantities of prostaglandin E2 (PGE2) and prostacyclin (PGI2). We have selectively inhibited the production of PGI2, but not PGE2, using the drug minoxidil and have measured the effects on stimulated bone resportion and arachidonic acid metabolism. The increased production of 6-keto-PGF1 alpha (6k-PGF1 alpha), the hydrolytic product of PGI2, stimulated by recombinant hTGF alpha and hTNF as well as murine epidermal growth factor was inhibited by minoxidil. There was no inhibition by minoxidil of PGE2 production. Despite essentially complete inhibition of stimulated 6k-PGF1 alpha formation, there was no inhibition of bone resorption. The possibility was investigated that growth factors and TNF enhanced enzymatic conversion of PGI2 to 6k-PGE1, which stimulates bone resorption in mouse calvariae with a potency about one fourth that of PGE2. Enzymatic conversion of PGI2 to 6k-PGE1 is inhibited by rutin. Rutin did not inhibit bone resorption stimulated by hTGF alpha or hTNF. We conclude, on the basis of these new results and previously published data, that the cyclooxygenase product that acts as the mediator of bone resorption enhanced by growth factors and TNF in mouse calvariae is probably PGE2.     

Endothelial prostaglandin secretion: effects of typhus rickettsiae

Cultured human umbilical vein-derived endothelial cells were incubated with typhus rickettsiae, and supernatants were examined for the presence of prostaglandins I2 (PGI2) and E2 (PGE2). Cells incubated with metabolically active rickettsiae secreted significantly more PGI2 and PGE2 than did those incubated with buffer alone or with killed rickettsiae. The amount of PGI2 secreted was directly related to the number of hemolytically active rickettsiae present; abolishing rickettsial hemolytic activity abolished their effect on PGI2 secretion. Mice injected with a lethal dose of native typhus rickettsiae exhibited a rapid rise in circulating PGI2 levels; mice given hemolytically inactive rickettsiae survived and exhibited no rise in plasma PGI2 levels. Finally, endothelial cells were infected with rickettsiae, and secretion of prostaglandins was monitored during rickettsial multiplication; intracellular accumulation of rickettsiae resulted in endothelial destruction and a dramatic increase in endothelial secretion of PGI2 and PGE2. Therefore, typhus rickettsiae can increase endothelial secretion of arachidonate-derived autocoids.