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In examination of 51 patient with acute gastrointestinal bleeding of ulcer etiology, the activity of lysosomal enzymes, peroxide oxidation of lipids were increased, the activity of antioxidant system was decreased. This can lead to inhibition of proliferative processes, stipulating the severity of blood loss, course of the postoperative period, the incidence of postoperative complications, and lethality.

Free glutamine content and phosphate-dependent glutaminase activity were studied in the biopsy specimens from the tissue of ulcer, polyps, carcinoma and the surrounding gastric mucosa of patients with precancerous diseases and carcinoma of the stomach. The glutamine content in carcinoma was not significantly different from that in the normal gastric mucosa. The glutamine level in the gastric mucosa remote from the tumour was considerably higher than normal. In case of polyposis of the stomach glutamine was present in the polyps and absent in the remote gastric mucosa. A marked glutaminase activity was revealed in the carcinoma of the stomach, but its level did not differ from the normal or in the case of precancerous diseases.

Gastric mucosal damage was produced by intragastric administration of 96% ethanol, 0.6 M HCl, 0.2 M NaOH or 25% NaCl. The animals were killed 1 hr later, when the number and severity of gastric lesions (ulcers) was recorded. At the time of the sacrifice of the animals gastric mucosal superoxide dismutase (SOD) activity was measured. It was found that (1) the gastric mucosal damage could be induced by the administration of any of the necrotizing agents in all animals, (2) superoxide dismutase (SOD) activity increased significantly in the damaged gastric mucosa following 96% ethanol, while its activity decreased significantly during the development of gastric mucosal damage produced by the intragastric administration of 0.6 M HCl, 0.2 M NaOH or 25% NaCl. It has been concluded that: (1) the enzyme systems necessary to generate the superoxide free radical anions can be stimulated by ethanol, and they can be inhibited by the application of 0.6 M HCl, 0.2 M NaOH and 25% NaCl: (2) the observed stimulation or inhibition of the enzyme systems to generate the superoxide free radical anions may be of pathological significance in the development of gastric mucosal damage produced by the intragastric administration of 96% ethanol, 0.6 M HCl, 0.2 M. NaOH or 25% NaCl.

The LDH isoenzyme pattern of the uninvolved mucosa of gastric cancer patients differs as regards the LDH isoenzyme pattern from that of similar tissue of patients with benign gastric disease; the former tissue is characterised by a high M/H ratio of the LDH isoenzymes (M and H sub-units). A high M/H ratio characterises antral mucosa when the latter is compared with fundic mucosa. Mucosa showing superficial and atrophic gastritis also has a higher M/H ratio, whereas the presence of intestinal metaplasia does not appear to influence the M/H ratio. These observations are consistent with the concept that the tissue from which the cancer arose may possess a pre-malignant biochemical lesion.

The mucosal superoxide dismutase (SOD) activities were serially examined on the acute gastric mucosal lesion (AGML) induced by water-immersion restraint stress to rats for six hours. The mucosal SOD activities gradually increased in proportion to the time up to 3 hours after the restraint stress. But it decreased 6 hours after when severe damage had been established in the mucosa. On the other hand, the mucosal SOD activities of the margins of human gastric ulcer showed to be higher on the healing stage than on the active stage. And the SOD activities of the intractable ulcer were lower than those of the curable ulcer. These results indicate that the mucosal SOD may play some important roles both on the protecting process information of AGML and on the healing process in gastric ulcer.

Gastric mucosal damage was produced in rats by the intragastric administration of 96% ethanol or 0.6 M HCl, according to the method of Robert et al. Vitamin A or beta-carotene, in doses of 10 mg/kg, given intragastrically 30 min before the administration of the necrotizing agents. The animals were killed 1 hr after the administration of the necrotizing agents. The following experimental parameters were studied, without and with application of vitamin A and beta-carotene; number of gastric lesions (ulcers); severity of gastric mucosal lesions (ulcers); gastric mucosal superoxide dismutase (SOD) activity. It was found that; vitamin A and beta-carotene, in doses of 10 mg/kg, are able to prevent significantly both the number and severity of gastric mucosal lesions (ulcers) produced by the application of 96% ethanol or 0.6 M HCl; the significant increase of ethanol-induced gastric mucosal SOD activity can be inhibited by the application of vitamin A and beta-carotene; vitamin A and beta-carotene are capable of preventing the development of gastric mucosal lesions (ulcers) produced by the intragastric administration of 0.6 M HCl, while these agents fail to compensate for the HCl-induced decrease of gastric mucosal SOD activity. It has been suggested that; vitamin A and beta-carotene are gastric cytoprotective agents; the ulcer preventive effects of vitamin A and beta-carotene are partly dependent on their scavanger behaviour.

The activities of HMGCoA reductase and cholesterol 7 alpha-hydroxylase were assayed in liver biopsies of patients with or without cholestyramine treatment. The active dephosphorylated form of HMGCoA reductase and the activity of cholesterol 7 alpha-hydroxylase were under the detection limits in untreated subjects. After cholestyramine treatment activities of both enzymes were stimulated and the active form of HMGCoA reductase became detectable in four out of the five tested patients. In two subjects who received cholestyramine, the effect of exogenously added [4-14C] cholesterol on cholesterol 7 alpha-hydroxylase was tested. In the presence of Tween 80, the detergent by which [14C]cholesterol was suspended, the enzyme activity was profoundly inhibited and synthesis of 7 alpha-hydroxycholesterol was extremely low.

In combination with routine gastric secretion test and endoscopic congo red test, alkali labile pepsin (ALP) and alkali stable pepsin (ASP) were separately determined in total of 41 patients with peptic ulcer including 20 gastric (GU), 12 duodenal (DU) and 9 gastroduodenal ulcers (GDU), and in 10 normal controls. In both of basal and tetragastrin stimulated states, percent of ASP in total acid protease (%ASP) was increased in order of GU, GDU, normal control and DU with a close relation to the dimension of acid secreting area determined by endoscopic congo red test. Percent ASP was decreased after tetragastrin provocation in all disease groups. GU had high % ASP and low maximal acid output (MAO), GDU had high %ASP and high MAO, and DU showed low %ASP and high MAO.

Gastric mucosal damage was produced by the intragastric administration of 96% ethanol or 0.6 M HCl. The cytoprotective doses of prostacyclin (PGI2) (5 micrograms/kg), atropine (0.025 mg/kg) or cimetidine (2.5 mg/kg) were given intraperitoneally 30 min before the administration of the necrotizing agents. The animals were killed 1 hr later. The number and severity of gastric mucosal lesions (ulcer) were recorded. At the time of the sacrifice of the animals, superoxide dismutase (SOD) was prepared from the gastric fundic mucosa and its activity was measured. It was found that PGI2 (5 micrograms/kg), atropine (0.025 mg/kg) and cimetidine (2.5 mg/kg) significantly decreased the number and severity of gastric mucosal lesions (ulcers) produced by the intragastric administration of 96% ethanol a 0.6 M HCl, PGI2, atropine, cimetidine, given in cytoprotective doses, significantly mounted the ethanol-induced increase of gastric mucosal SOD activity; PGI2, atropine, cimetidine, given them in cytoprotective doses significantly shunted the HCl-induced decrease of gastric mucosal SOD activity. It has been concluded that; chemically different cytoprotective agents (PGI2, atropine, cimetidine) give rise to similar tendencies in the changes of gastric mucosal SOD activity; both the significant decrease (in the ethanol-model) and the significant increase (in the HCl-model) of this enzyme seem to be involved in the development of gastric mucosal protection by PGI2, atropine and cimetidine.

A metalloproteinase was extracted from a medium of cultured gastric tissues following acetic acid-induced ulcer or taurocholic acid-induced gastritis, and the enzyme was partially purified by Sephadex G-200 column chromatography. This proteinase was released in active and latent forms with apparent molecular weights of 170,000 and 210,000, respectively. Its activity was abolished by treatment with ethylenediaminetetraacetic acid or 1,10-phenanthroline, but not with phenylmethylsulfonyl fluoride or soybean trypsin inhibitor. This enzyme degraded type I gelatin and type IV collagen but did not attack type I collagen. In contrast, very little of this enzyme was released from gastric tissue following erosion caused by water-immersion stress or from normal gastric tissue. These results suggest that this metalloproteinase plays an important role in gastric lesions by breaking down the basement membrane.

Using a simple hemoglobin method on the basis of Anson-Mirsky's method, acid protease levels in serum were measured at pH 1.8 (pepsin) and pH 3.5 (gastricsin) in 18 healthy controls and 14 patients with duodenal ulcer, 19 patients with gastric ulcer and 18 patients with gastric cancer. Though acid protease activity in pH 1.8 in duodenal ulcer has a tendency to show a little higher level than healthy controls, there is no significant difference in acid protease levels between controls and each of three diseases.

Fundic mucosal pepsinogens reveal six major bands of protease activity on gel electrophoresis and four minor bands. Antral mucosa shows two major bands of activity; the four rapidly moving bands found in fundic mucosa are found in lesser activity in the antral mucosa. Duodenal mucosa shows only one slowly moving band of protease activity. There is a significant difference in the pepsinogen pattern when the uninvolved fundic mucosa of gastric ulcer patients is compared with that of cancer patients.A satisfactory method is described for separating the pepsinogens on column chromatography.

This study was designed to establish the role of tissue phospholipase (PLase) and prostaglandins (PGs) in the genesis of gastric ulcers. The activity of PLase and levels of PGs in rat gastric mucosa were measured by high-performance liquid chromatography, using water immersion stress ulcer. Four kinds of PGs in gastric mucosa were determined: 6-keto-PGF1 alpha, PGF2 alpha, PGE2, and PGD2. Decreases in PG levels and in PLase activity were observed, depending on the duration of water immersion stress. Either administration of pirenzepine or vagotomy maintained both the PG levels and PLase activity. The longer duration of stress induced a more severe ulcer index. Premedication with pirenzepine or vagotomy prevented ulceration. Furthermore, there was a clear reciprocal correlation between the PLase activity and the ulcer index. The decrease in PG levels observed could be linked with the decrease in the activity of PLase, the initiating enzyme of the arachidonate cascade reaction. Thus, PLase might be a responsible factor in the genesis of stress ulcers. Pirenzepine or vagotomy protected gastric mucosa from ulceration by maintaining the PLase activity and PG levels.

Experiments were performed on white rats with experimental acetate ulcer of the stomach and intestine. At the height of destruction of gastric mucosa tissue (60 minutes from the onset of ulcer formation) a consistent increase in acid phosphatase secretion was recorded. This process was accompanied, as a rule, by significant elevation of proteolytic activity (pH 6.5-7.0) in tissue extract obtained from the affected area. It is suggested that the increased proteolytic activity observed at pH 6.5-7.0 in the tissue extract from the ulcerous area is most likely related to the release of lysosomal proteases at the height of tissue destruction. It thus appears that ulcer of the gastric mucosa induced by acetic acid application is determined by interstitial proteolytic activity of cathepsins that are released during the destruction of lysosomal membranes.

Peptic activity has long been recognized as an essential factor in the pathogenesis of peptic ulcer and related diseases, but only recently has it become clear that this activity is derived from a remarkable diversity of enzymes, all of which belong to the aspartic proteinase family of enzymes. These include two types of pepsinogens and two types of cathepsins. In recent years, considerable progress has been made in characterizing these proteinases and in applying this information to the study of a number of gastrointestinal disorders. The intent of this article is to update recent basic and clinical information on these topics and to suggest several areas that merit further investigation.

Lipid peroxidation, a state of the antioxidative system and activity of acid phosphatase were studied in mucosal membrane of 53 patients with ulcerous disease of stomach. Increase of the acid phosphatase activity in cytoplasm, activation of lipid peroxidation and inhibition of the antioxidative system were detected in ulcer border and periulcerous region. These alterations in lipid peroxidation and the state of the antioxidative system were considered as distinct pathogenetic factors responsible for deterioration of lysosomal membranes and contributing to chronic and relapsing development of ulcerous disease.

1. Electrophoretic separation of proteases from human gastric mucosal extracts of five patients with gastric ulcer, one with duodenal ulcer and three with gastric cancer were investigated by agar-gel electrophoresis at pH 8.3 and pH 5.0. 2. In the fundic mucosal study, there were seven faster moving proteases in all nine cases, but the slowest moving protease showed a slightly different picture in each case. In the antral mucosal study, two of eight cases showed mainly group II pepsinogens, seven of nine cases, however, showed the same results as in the fundic mucosal study. 3. In the cases of the nine mucosal extracts activated at pH 1.5 or pH 4.0, they all showed the same electrophoretic separation at each pH level. At these two pH levels, however, quite different electrophoretic patterns were observed. The presence of pepsin 3 appeared to diminish at the higher levels of pH, although that of pepsin 5 and pepsin 7 appeared to increase at pH 4.0 and above. Pepsin 6 appeared for the first time at pH 4.0 and existed at higher pH levels. 4. We thus conclude that electrophoretic patterns of pepsins in the gastric mucosal extracts are changeable depending on the pH level of the incubating medium, and further that diversity of pepsins in gastric juices may also depend on the pH level of gastric juices.

Lysozyme concentration in the gastric juice of 34 patients with peptic ulcer and 10 practically healthy persons was studied. In the patients with peptic ulcer the lysozyme levels in the gastric juice were found to be lower. A significant decrease in the lysozyme concentration was observed in the patients suffering from peptic ulcer for more than 2 years. During the first months of the disease increased levels of lysozyme were recorded. Relationship between the lysozyme concentration in the gastric juice and the acidity of the gastric contents was shown. Decreased concentrations of lysozyme were more pronounced in the patients with increased levels of hydrochloric acid.

Cathepsin B and L activities were determined with 7-amino-4-methyl-coumarin conjugates as substrates using small tissue specimens of gastric cancer and benign gastric ulcer. Both cathepsin B and L activities were higher in homogenates of gastric cancer tissue than in regenerative mucosa of benign gastric ulcer. Cathepsin B activity was much higher in cancer tissue than in tissue surrounding the tumor. In contrast, the activity in regenerative mucosa of benign gastric ulcer was not elevated as compared with the tissue surrounding the ulcer. Similar results were obtained with cathepsin L activity. These results indicate that cathepsin B and L are related to proliferation and evolvement of gastric cancer.

In order to determine if lysosomes are causally involved in gastric ulcerogenesis, we (a) systematically characterized homogenization techniques and assay conditions for measurement of lysosomal enzymes in guinea pig gastric mucosa, and (b) assessed the relationship among histamine-induced gastric erosions, lysosomal enzyme activities, and the integrity of lysosomal membranes. We developed procedures that yielded tissue homogenates of gastric mucosa in which a majority of cells had been disrupted, but at least two-thirds of the lysosomes were preserved. We also demonstrated that two lysosomal enzymes from gastric mucosa, N-acetyl-beta-glucosaminidase and beta-glucuronidase, had acid pH optima and activities that were linear with time, mucosal protein, and substrate concentration, and exhibited Michaelis-Menten kinetics. Moreover, using isopycnic centrifugation of light mitochondrial fractions on continuous and discontinuous sucrose gradients, we showed that Triton WR-1339, a non-ionic detergent known to accumulate in hepatic cells, also accumulates in gastric mucosal cell lysosomes, causing a decrease in their density and an increase in their fragility. Finally, we found no correlation between histamine-induced gastric erosions and the integrity of gastric mucosal cell lysosomes; pretreatment of guinea pigs with Triton WR-1339 increased the fragility of gastric cell lysosomes, but did not enhance the ulcerogenic effect of histamine. Our findings do not support a role for gastric cell lysosomes in histamine-induced gastric mucosal injury.

The method of Okabe was used to induce experimental gastric ulcer in rats. The content of serotonin and histamine was determined in gastric mucosa extracts. The spectrum of proteolytic enzymes and proteolytic activity in gastric mucosa extracts were determined by polyacrylamide gel disc electrophoresis at varying pH. It was found that in "acetate" gastric ulcer the rats had the increased content of serotonin in the gastric mucosa followed by the elevated histamine content. In the early stages of "acetate" ulcer the proteolytic activity was detectable at pH 6.5-7. At the same time there took place a reconstruction of the spectrum of proteolytic enzymes. Analogous changes in the spectrum of proteolytic enzymes of gastric mucosa extracts and occurrence of the proteolytic activity at pH 6.5-7 were also recorded after serotonin administration (30 mg/kg) to intact rats. Thus it has been demonstrated that the increased serotonin output is implicated in the changes seen in the enzymatic spectrum and in the occurrence of proteolytic activity at high pH (6.5-7). The latter might be related to the release of lysosomal proteases responsible for intratissular proteolysis in the gastric mucosa and for ulcer formation.

An antitryptic activity and effect of trypsin and chymotrypsin, administered parenterally, on the activity were studied in blood serum of patients, subjected to surgical operations. The antitryptic activity and content of alpha1- and alpha2-globulins were shown to increase in blood serum of patients within 5 days of the postoperative period. Intramuscular administration of the proteolytic enzymes within 5 days decreased the anti-tryptic activity and content of alpha1- and alpha2-globulins in blood serum.

Gastric mucosal damage was provoked by the topical application of 96% ethanol (1 ml) or 0.6 M HCl, (1 ml) by the method of Robert et al. [11]. Different doses of PGF2 alpha 100, 200 and 400 micrograms/kg) were given ip 30 min before the administration of the necrotizing agents. The animals were killed 1 hr after the application of the necrotizing agents. The number and severity of gastric lesions (ulcers) were recorded. Gastric mucosal superoxide dismutase (SOD) activity was measured by the method of Misra and Fridovich [8]. It was found that: PGF2 alpha dose-dependently decreased the number and severity of gastric lesions produced by 96% ethanol or 0.6 M HCl: gastric mucosal superoxide dismutase activity could be increased significantly by PGF2 alpha in the HCl-model: gastric mucosal superoxide dismutase activity could be significantly decreased by PGF2 alpha administration in the ethanol-model: no significant difference was obtained between the ulcer preventive effect of PGF2 alpha and the changes in the gastric mucosal SOD activity. It was concluded that: the ulcer preventive effect of PGF2 alpha partly depends on the scavanger mechanism (in the ethanol-model): the cytoprotective (100 micrograms/kg) and by antisecretory (400 micrograms/kg) doses of PGF2 alpha; exert similar effects on the changes of gastric mucosal SOD activity.

Bilirubin UDP-glucuronyl transferase (BGT), bilirubin UDP-glucosyl transferase (BGLT) and bilirubin UDP-xylosyl transferase (BXT) activities were measured in wedge-biopsied liver specimens obtained from patients with various liver diseases, and compared with those in controls with normal liver histology. BGT was measured alone using needle biopsy liver specimens from the patients with Gilbert's syndrome (15 patients). Rotor's syndrome (one) and posthepatitic hyperbilirubinemia (3). BGT was decreased to about 30% of controls in Gilbert's syndrome, but showed no change in posthepatitic hyperbilirubinemia and Rotor's syndrome. About 90% decrease in BGT, and BGLT and BXT were observed in Crigler-Najjar syndrome type II (3 patients). In patients with cholelithiasis and chronic hepatitis, statistically significant changes of these three enzymes were not observed, except the statistically significant increase in BGT activity in chronic hepatitis. Slight increases in BGT and BXT activities were observed in anicteric cases with cholelithiasis. The ratio of BGT, BGLT and BXT activities in controls was 1:0.50:0.98 (expressed as "per mg protein"). Slight differences existed between the ratios of BGT, BGLT and BXT in various liver diseases, and this may suggest the separate identities of BGLT and BXT from BGT. Determination of bilirubin-conjugation is essential in the diagnosis of Gilbert's syndrome and Crigler-Najjar syndrome type II, but shows no specific change in the other chronic liver diseases.

Anti-ulcer effects of cetraxate, a new compound possessing anti-plasmin, anti-casein and anti-trypsin actions were investigated by using experimental gastric ulcer models in rats. Cetraxate, 300 mg/kg p.o. showed significant inhibitory effects of 65.3%, 70.0%, 30.2%, and 67.1% against aucte types of ulcers producing by aspirin, phenylbutazone, indomethacin, and pyloric ligature (Shay's ulcer), respectively. These effects were greater than those obtained by gefarnate and aluminum sucrose sulfate may be mainly attributed to the protecting action of this drug on gastric mucosa. Ctraxate further revealed remarkable inhibitory effects on chronic types of ulcers produced by acetic acid, clamping, and clamping-cortisone. In acetic acid ulcer in particular, cetraxate was found to have a dose-dependent inhibitory effect at doses over 50 mg/kg. Of test drugs including L-glutamine and methylmethionine sulfonium chloride, cetraxate showed the most remarkable inhibitory effect on beta-glucuronidase activity in ulcer tissue of these three types of ulcers. These findings suggest that cetraxate may prevent the connective tissue in the ulcer location from decomposition due to lysosomal enzymes such as beta-glucuronidase, thereby accelerating the recovery from ulcer.