Endocrine cells and parietal cells in the stomach of the developing rat

Gastrin-immunoreactive cells were fairly numerous in the pancreas and upper duodenum of the rat at about the time of birth. A minor population of these cells stained with antibodies directed against the N-terminal region of gastrin-34 as well as with antibodies directed against the C-terminal region. The remainder of the cells stained with the C-terminally directed antibodies only. Within a fortnight after birth all gastrin-immunoreactive cells disappeared from the pancreas and were greatly reduced in number in the duodenum; those that remained were probably CCK cells. Gastrin cells were rare in the antrum at birth and remained rare during the first days after birth. They increased in number, slowly until after weaning (15-20 days of age) and then more rapidly, until 25-30 days of age when the gastrin cell density reached that in adult rats. At the time of birth the gastrin concentration in serum was low; the subsequent increase during the first 2 weeks paralleled the development of the antral gastrin cell system. Adult postprandial serum gastrin concentrations were reached 12 days after birth. Somatostatin cells were rare in both the antral and oxyntic mucosa at birth. They increased gradually in number until about a month after birth when the cell density reached that seen in adult rats. In the oxyntic mucosa the ECL and A-like cells are the predominant endocrine (argyrophil) cell types. They were not detected until about 4 days after birth. Their number increased slowly until about 30 days of age. They did not stain argyrophil until about 2-4 weeks after birth. Parietal cells were few at birth; ultrastructurally they appeared to be in an active state and histochemically they were shown to contain carbonic anhydrase. The pH of the gastric content of newborn rats was close to 5; 15-17 days after birth the pH was about 4 in freely fed rats. In fasted rats shortly after birth the pH was about 4. Two weeks later it was around 2, which is the pH measured in older rats. Hence, the full capacity for acid secretion is probably not established until weaning. Fasting greatly lowers the serum gastrin concentration and the histidine decarboxylase activity of the ECL cells in adult rats. Before weaning, fasting produced these effects only to a minor degree.(ABSTRACT TRUNCATED AT 400 WORDS)     

Ultrastructural investigations of the enterochromaffin-like (ECL) cells in three different rat strains (Sprague-Dawley, Fischer 344, Wistar) after treatment with the H+,K(+)-ATPase inhibitor pantoprazole.

The purpose of the present study was the evaluation of ultrastructural characteristics of the enterochromaffin-like (ECL) cells in the fundic mucosa of three different rat strains without treatment and after treatment with the H+, K(+)-ATPase inhibitor pantoprazole. In the study, 20 one year old female Sprague Dawley (SD), Fischer 344 (F) and Wistar (W) rats each were treated orally for three months with 4 mg pantoprazole/kg/d or with the vehicle only. The control animals showed close conformity of ECL cell density and morphology in all three strains. Treatment with pantoprazole led to a significant increase in serum gastrin concentration and GPC density in all strains. However, the electron microscopically determined ECL cell density was markedly increased in the SD strain only. Ultrastructurally all treated rats showed activation of the ECL cells, and enhanced histamine release. The SD and F strains had an enhanced proportion of large ECL cell granules, with the F rats also showing an increased granule density. In contrast, the treated W rats were found to have a lower granule density and a higher proportion of small and medium sized granules compared to their controls.     

The effect of the duodenal ulcerogen cysteamine on somatostatin and gastrin cells in the rat

Previous studies showed a rapid decrease of somatostatin concentration in the gut and an increase in serum gastrin levels after a single dose of the duodenal ulcerogen cysteamine. An attempt was made to identify morphologic changes that would correlate with these functional changes. Rats were killed 1, 4, 8 or 24 hr after a single dose of cysteamine and sections of gastric mucosa and pancreas were processed for electron and light microscopy. Subtle ultrastructural alterations were seen in D cells of the stomach (e.g., dilation of mitochondrial cristae and endoplasmic reticulum, and apparent increase in electron density of secretory granules) after cysteamine administration. The number of somatostatin-positive cells visualized by the immunoperoxidase technique using light microscopy was decreased in 1–4 hr but returned to normal by 24 hr. The alterations observed in the G cells after cysteamine administration are consistent with release of gastrin from mature granules and increased synthesis of the hormone. The lack of major morphologic changes in the D cells suggests that cysteamine affects somatostatin without causing cell necrosis or alteration in lysosome formation. The effect of the drug may thus be mediated at the biochemical level without marked morphologic alterations.     

The vagus regulates histamine mobilization from rat stomach ECL cells by controlling their sensitivity to gastrin

The ECL cells in the oxyntic mucosa secrete histamine in response to gastrin, stimulating parietal cells to produce acid. Do they also operate under nervous control? The present study examines histamine mobilization from rat stomach ECL cells in situ in response to acute vagal excitation and to food or gastrin following vagal or sympathetic denervation. Applying the technique of microdialysis, we monitored the release of histamine by radioimmunoassay. Microdialysis probes were placed in the submucosa on either side of the stomach, 3 days before experiments. The rats were awake during microdialysis except when subjected to electrical vagal stimulation. One-sided electrical vagal stimulation raised serum gastrin and mobilized gastric histamine. However, gastrin receptor blockade prevented the histamine mobilization, indicating that circulating gastrin accounts for the response. Vagal excitation by hypoglycaemia (insulin) or pylorus ligation did not mobilize either gastrin or histamine. The histamine response to food was almost abolished by gastrin receptor blockade, and it was halved on the denervated side after unilateral subdiaphragmatic vagotomy. While the histamine response to a near-maximally effective dose of gastrin was unaffected by vagotomy, the response to low gastrin doses was reduced significantly. Abdominal ganglionic sympathectomy failed to affect the histamine response to either food or gastrin. In conclusion, gastrin is responsible for most of the food-evoked mobilization of ECL-cell histamine. The histamine response to electrical vagal stimulation reflects the effect of circulating gastrin rather than a direct action of the vagus on the ECL cells. Vagal denervation was accompanied by an impaired histamine response to food intake, probably reflecting the right-ward shift of the serum gastrin concentration–histamine response curve. The results suggest that the vagus controls the sensitivity of the ECL cells to gastrin.     

Gastric enterochromaffin-like cell hyperplasia and neoplasia in the rat: an indirect effect of the histamine H2-receptor antagonist, BL-6341

Oral administration of BL-6341 hydrochloride, a long-acting histamine H2-receptor antagonist, to rats for 2 years at doses of 10, 55 or 300 mg/kg/day resulted in several changes in the fundic (oxyntic) mucosa of the glandular stomach. The most significant alteration was a proliferation of argyrophil endocrine cells that was demonstrated to be enterochromaffin-like (ECL) cells. The ECL cell proliferation consisted of a continuum of changes involving diffuse hyperplasia, focal adenomatous hyperplasia, and carcinoid tumor formation at the highest dose level of 300 mg/kg. At 55 mg/kg only ECL cell hyperplasia occurred, and at the low dose of 10 mg/kg there were no remarkable proliferative changes. The reference compound, cimetidine (950 mg/kg), produced a degree of ECL cell proliferation that was slightly less, but not significantly different than, that observed with 55 mg/kg of BL-6341. Dose-related elevations of serum gastrin were observed with BL-6341, while cimetidine produced hypergastrinemia that was generally intermediate between that produced by the middle and low doses of BL-6341. The hypergastrinemia resulted from the pharmacologic inhibition of acid secretion, which is the negative feedback mechanism controlling the production of gastrin. Only the 300 mg/kg dose of BL-6341 produced a significant, sustained (24 hours) hypergastrinemia and carcinoid tumors. The chronic, sustained hypergastrinemia was considered to be the primary cause of the ECL cell carcinoid neoplasia. All genetic toxicology tests performed with BL-6341 were negative. It was concluded that the demonstrated hypergastrinemia represents an indirect, hormonal, epigenetic mechanism of tumorigenesis.     

Effects of portacaval shunt on the rat stomach

In portacaval-shunted rats, basal but not pentagastrin-stimulated acid secretion was higher than in sham-operated controls. The basal serum gastrin concentration was unchanged and the postprandial serum gastrin concentration lowered following portacaval shunt. Thus, gastrin is not responsible for the elevated basal acid secretion. The present study provides evidence that there is no trophic effect on the oxyntic mucosa as a whole and that there is no change in parietal cell-associated gastrin receptors after portacaval shunting. Interestingly, however, endocrine cells in the oxyntic mucosa (the histamine-containing ECL cells) proliferated greatly and the pentagastrin- and cholecystokinin octapeptide-induced activation of the histamine-forming enzyme, histidine decarboxylase, in these cells was much greater than in control rats. Analysis of the dose-response curves for the enzyme-activating effect of pentagastrin and cholecystokinin-octapeptide indicated that the D50 values for these two stimulants were not altered by shunting but that the maximal enzyme activation was greatly elevated. The enhanced enzyme activation can be partly, but not fully, explained by the fact that the ECL cells were increased in number. The enhanced response following portacaval shunt probably reflects also an increased number of gastrin receptors per ECL cell. The effect of portacaval shunting on gastric ECL cells can perhaps be explained by impaired degradation in the liver of intestinal substance(s) exerting a highly specific trophic effect on the ECL cells or, alternatively, causing an enrichment of gastrin receptors on these cells, thereby making them more sensitive to the trophic effect of gastrin. The ECL cell hyperplasia is manifest about 4 weeks after the shunting. A modified procedure for portacaval shunting which left the gastroduodenal vein (otherwise ligated) drained to the liver produced the same trophic effect as conventional portacaval shunt, suggesting an intestinal rather than gastroduodenal origin of the agent(s) responsible for the trophic action.     

Phosphatidylserine increases acetylcholine release from cortical slices in aged rats

Acetylcholine release was investigated in cortical slices superfused with choline-enriched Krebs solution containing physostigmine. Slices were prepared from 3 and 24 month old rats treated with either Tris buffer or sonicated suspensions of phosphatidylserine and phosphatidylcholine in Tris buffer. Slices were electrically stimulated at frequencies of 1, 2 and 5 Hz for 5 min periods preceded and followed by rest periods. ACh content of the superfusate was quantified by bioassay. In the 24 month old rats treated with Tris buffer, acetylcholine release, at all frequencies tested, was approximately 50% lower than that in the 3 month old rats. On the contrary, no significant decrease in ACh release was found in the 24 month old rats treated for 30 days with phosphatidylserine (15 mg/kg IP). The same treatment did not increase acetylcholine release in 3 month old rats. Acetylcholine release in 24 month old rats receiving a single administration of phosphatidylserine (15mg/kg IP) or phosphatidylcholine (15 mg/kg IP) for 30 days was as low as in the 24 month old rats receiving the Tris buffer only. It is proposed that the chronic phosphatidylserine treatment may reduce the age-induced decrease in acetylcholine release by acting on the stimulus-secretion coupling mechanism.     

Phosphatidylserine increases acetylcholine release from cortical slices in aged rats

Acetylcholine release was investigated in cortical slices superfused with choline-enriched Krebs solution containing physostigmine. Slices were prepared from 3 and 24 month old rats treated with either Tris buffer or sonicated suspensions of phosphatidylserine and phosphatidylcholine in Tris buffer. Slices were electrically stimulated at frequencies of 1, 2 and 5 Hz for 5 min periods preceded and followed by rest periods. ACh content of the superfusate was quantified by bioassay. In the 24 month old rats treated with Tris buffer, acetylcholine release, at all frequencies tested, was approximately 50% lower than that in the 3 month old rats. On the contrary, no significant decrease in ACh release was found in the 24 month old rats treated for 30 days with phosphatidylserine (15 mg/kg IP). The same treatment did not increase acetylcholine release in 3 month old rats. Acetylcholine release in 24 month old rats receiving a single administration of phosphatidylserine (15mg/kg IP) or phosphatidylcholine (15 mg/kg IP) for 30 days was as low as in the 24 month old rats receiving the Tris buffer only. It is proposed that the chronic phosphatidylserine treatment may reduce the age-induced decrease in acetylcholine release by acting on the stimulus-secretion coupling mechanism.     

Gastrin stimulation of isolated gastric glands

The ability of gastrin to stimulate acid formation was studied in gastric glands and isolated parietal cells obtained from rabbit gastric mucosa. Accumulation of the weak base aminopyrine and increases in oxygen consumption were used as measures of acid secretory activity. The responses to gastrin were found to be very small (10-15% increase). However, inclusion of dithiothreitol (0.5 mM) in the incubation medium enhanced the responses in both glands and isolated cells to easily detectable levels. For the gastric gland preparation, gastrin stimulation was maximal at 1 X 10(-7) M, with an apparent ED50 of 5 nM. The response reached a maximum at about 30 min and was stable for at least an hour. The gastrin response was enhanced by the phosphodiesterase inhibitor isobutylmethylxanthine and partially inhibited by cimetidine, a histamine H2-receptor antagonist. Combinations of gastrin and histamine showed an additive response over a wide range of histamine concentrations. However, time-course studies revealed a transient potentiation of gastrin response by histamine, which reached a peak at 15 min and was reduced to an additive response by 30 min. Studies using isolated cell populations enriched in parietal cells (approximately 70%) revealed a gastrin stimulation that was not inhibited by cimetidine. The transient potentiation of the gastrin response by histamine was also found in the isolated cell preparation. Gastrin had no effect on cellular cAMP levels or adenylyl cyclase activity. The results are interpreted to indicate that gastrin stimulates acid secretion through three separate actions: 1) a direct stimulation of parietal cell activity, 2) a potentiating interaction with histamine, and 3) for more intact preparations, a release of histamine, which in turn acts as a paracrine stimulus. Quantitatively, the most important action appears to be the release of histamine. None of the actions of gastrin appear to involve a change in cAMP metabolism.     

The effect of lowering the 5-hydroxytryptamine content of the rat spinal cord on analgesia produced by morphine

After prolonged fasting the activity of histidine decarboxylase in the oxyntic mucosa of the rat stomach is low. Feeding or injection of gastrin or insulin rapidly raises the enzyme activity. It was earlier suggested that all enzyme-activating agents act through release of gastrin. This view has found experimental support in studies which show that in antrectomized rats the enzyme is activated by gastrin but not by gastrin-releasing stimuli like feeding or vagal excitation (insulin hypoglycemia). In the present investigation rats were subjected to a variety of treatments and serum gastrin concentrations and gastric histidine decarboxylase activities were measured. The main findings were as follows.1. Feeding raised the serum gastrin level and the enzyme activity in unoperated rats. In fasted antrectomized rats the serum gastrin concentration was low; in freely fed antrectomized rats it was at the same level as in fasted unoperated rats. In antrectomized rats the enzyme activity was low and not raised by feeding.2. Acid in the antrum inhibits the release of gastrin whereas an alkaline pH may facilitate such release. All treatments that blocked acid secretion, thereby raising the antral pH, also raised the serum gastrin concentration and concomitantly the histidine decarboxylase activity. Thus, vagotomy increased the serum gastrin level and the histidine decarboxylase activity in fasted rats. Treatment of fasted unoperated rats with atropine or hexamethonium had similar effects. Antral exclusion, which prevents HCl from reaching the pyloric glands, resulted in marked increase in the serum gastrin concentration and in the enzyme activity of fasted rats.3. Injection of insulin resulted in a rather slow, progressive increase in the serum gastrin concentration. The peak was reached after about 4 hr. The enzyme activity was also raised markedly and the peak response occurred about 1 hr later.4. An increase in the histidine decarboxylase activity was invariably preceded or accompanied by a raised serum gastrin level. With fasted or fed unoperated, vagotomized, antrectomized or antrally excluded rats, the correlation coefficient for the relation between enzyme activity and serum gastrin concentration was 0.69 (P < 0.05).5. Porta-caval-shunted fasted rats responded to feeding or injection of insulin with marked activation of gastric histidine decarboxylase. The response after feeding was at least 5 times higher in shunted than in nonshunted rats but serum gastrin was only slightly higher. Following antrectomy of porta-caval-shunted rats feeding no longer raised the enzyme activity. Thus, the enzyme-activating agent was of antral origin. In the shunted rats injection of pentagastrin induced an enzyme activation about 5 times that seen in intact rats. This response was not significantly reduced by antrectomy.In conclusion, we have observed a correlation between serum gastrin concentration and histidine decarboxylase activity. We have failed to obtain evidence for the existence of any physiological intermediate other than gastrin in the activation of histidine decarboxylase induced by feeding, vagal stimulation or inhibition of acid secretion.     

The origin of subdural neomembranes. I. Fine structure of the dura-arachnoid interface in man.

A patient with atrophic gastritis and excessively raised serum gastrin concentrations (4000 to 5000 pg/ml) was found to have multiple polypous tumors of the gastric corpus mucosa. Following gastrectomy, serum gastrin concentrations decreased to undetectable levels. The tumors consisted of a mixed population of endocrine cells. The majority of tumor cells were of the ECL type, but, in addition, enterochromaffin cells of various subtypes as well as agranular cells were found. The tumors were locally invasive and invaded the walls of submucosal blood vessels. The surrounding mucosa showed a severe atrophic gastritis with intestinalization and contained numerous goblet cells, enterochromaffin cells, and cholecystokinin cells. Cholecystokinin cells do not occur in the normal oxyntic mucosa. Hence, the observation of this cell type in intestinalized gastric epithelium suggests that "intestinalization also is associated with changes in endocrine cell populations. Gastrin has been shown to affect the function of the ECL cells. Indications for a trophic action of gastrin on these cells have been obtained. It is discussed whether greatly raised serum gastrin levels in patients with atrophic gastritis may be associated with increased risks for the development of certain types of gastric tumors.     

Comparison of the ECL-cell frequency in the stomachs of 3 different rat strains.

Three different rat strains, Sprague-Dawley, Wistar and Fischer 344, were treated for 3 months with 2 doses (0.8; 4 mg/kg) of the gastric acid suppressing ATPase inhibitor pantoprazole. The gastrin levels were determined, the height of the mucosa measured and the number of enterochromaffin-like (ECL) cells counted. Because these cells were stained according to the method of Grimelius they were designated as GPC (Grimelius positive cells). Under 4 mg/kg, the gastrin levels were increased 8 hours after administration, but fell again after 24 h. The Fischer rats showed the highest value. Also the height of the mucosa was increased under 4 mg/kg. A trend towards an increased mucosal height was noticeable even at 0.8 mg/kg. The number of GPC was determined in 2 ways: 1) without taking the mucosal height into account, 2) taking the height into account. An increase in GPC was observed at 4 mg/kg with both methods.     

On the interaction between intragastric pH and electrical vagal stimulation in causing gastric acid secretion and intraluminal release of gastrin and somatostatin in anesthetized rats

The effect of electrical vagal stimulation (5 V, 2 ms, 2, 5 and 10 Hz) on gastric acid secretion and on the intragastric release of gastrin and somatostatin was studied in anesthetized rats. The gastric lumen was perfused with Dextrane T 70 (21 g/1) at 3 different rates (2.0, 0.15 and 0.035 ml/min). pH as well as gastrin and somatostatin levels were measured in the perfusate. At a perfusion rate of 2 ml/min electrical vagal stimulation (10 Hz) reduced pH of the perfusate from 3.8 to 2.6. Neither gastrin nor somatostatin levels were influenced. At a perfusion rate of 0.15 ml/min pH fell to 1.87 during vagal stimulation at 10 Hz. During this period the somatostatin levels in the perfusate increased approximately 7-fold. No effect on gastrin release was observed. When the stomach was perfused with Dextrane at a rate of 0.035 ml/min. pH was lowered to 1.20 during vagal stimulation at 5 Hz. The somatostatin level increased approximately 14-fold and the gastrin levels 6-fold. In order to study the effect of low pH per se the stomach was perfused with 0.1 M HCl. Perfusion of the stomach with 0.1 M HCI (pH1.2) at a rate of 0.035 ml/min caused a small (3-fold) increase in somatostatin levels. In conclusion, electrical vagal stimulation or low antral pH alone had minor effects on somatostatin or gastrin release. However, when intragastric pH was <2, electrical vagal stimulation increased the intraluminal release of somatostatin and to a lesser extent that of gastrin. We suggest that both somatostatin and gastrin cells are activated by vagal stimulation at low antral pH. Less gastrin was found to be released in comparison to somatostatin, which may be due to inhibition of the gastrin cells by the somatostatin simultaneously released.     

Isopropanol and chlordecone potentiation of carbon tetrachloride liver injury: retention of potentiating action in hepatocyte suspensions prepared from rats given isopropanol or chlordecone

Administration of isopropanol (2.5 ml/kg, po) or chlordecone (15.2 mg/kg, po) potentiated the release of glutamic oxaloacetic transaminase (GOT) into serum 17- or 7-fold, respectively, in rats exposed subsequently to 30 microliter CCl4/kg, po. Hepatocytes isolated from isopropanol-treated rats, incubated with low concentrations of CCl4 (0.3 or 0.9 mM), did not have significant increase in the amount of GOT released after 30 min compared to control cells exposed to CCl4. However, at 3 hr cells from isopropanol-treated rats released 10- or 3-fold more GOT when exposed to 0.3 or 0.9 mM CCl4, respectively, than control cells exposed to CCl4. By hour 5 of incubation this differential of GOT release was not observed. The same dose and time-dependent pattern of potentiated GOT release upon exposure of CCl4 was seen in hepatocytes obtained from chlordecone-treated rats. These results indicate that the potentiation by isopropanol or chlordecone of CCl4-induced release of GOT from liver is retained through the procedures of cell isolation.     

The half-life of exogenous gastrin in the circulation

1. A method of gastrin bio-assay is described which can be used on as little as 30 ng synthetic human gastrin I at a minimum concentration of 2.5 ng/ml.2. Pentagastrin or synthetic human gastrin I added to cat plasma can be stored on ice or at 4 degrees C, for periods up to 27 hr without apparent loss of gastrin activity.3. Between 1(1/2) and 13 min after the rapid I.V. injection of pentagastrin in the anaesthetized cat and between 1(1/2) and 15 min after the injection of synthetic human gastrin I, there is a rapid reduction of the gastrin concentration in the arterial plasma. The data relating log(10) gastrin concentration in arterial plasma with time can be fitted by a single term.4. Studies in vitro show that over the periods of time involved in the in vivo studies, both pentagastrin and synthetic human gastrin I are stable in cat plasma at 37 degrees C in concentrations which occurred in the circulating plasma.5. The half-life of pentagastrin in the circulating arterial plasma of the anaesthetized cat is 1.50 min (S.E. +/- 0.08) and the half-life of synthetic human gastrin I is 2.65 min (S.E. +/- 0.09).     

Influence of hypergastrinemia secondary to long-term proton pump inhibitor treatment on ECL cell tumorigenesis in human gastric mucosa

Proton pump inhibitor (PPI) therapy causes hypergastrinemia, which could promote the development and progression of neuroendocrine tumors (NETs). Concerns have been raised about the safety of long-term PPI use due to a possible increased risk of NETs. This study aimed to investigate the association between hypergastrinemia and the risk of NETs. Twenty outpatients presenting with serum gastrin levels greater than 400 pg/mL after long-term PPI treatment were registered in this study. Immunohistochemical analyses for chromogranin A (CgA), Ki67, gastrin and CCK/B gastrin receptor (CCKBR) were performed, and positive cell numbers were counted. There were no NET or gastric epithelial neoplasia cases observed among any of the 20 patients examined throughout the PPI treatment period. Histologically, ECL cell hyperplasia were shown in all patients. However, no relationship was found between serum gastrin levels and the number of CgA positive ECL cells. There was also no relationship between serum gastrin levels and the proportion of Ki67 positive cells or the density of CCKBR positive cells. The data indicate no relationship may exist between NETs and hypergastrinemia secondary to PPI treatment in patients having no, or mild, atrophic gastritis.     

Kinetics of interaction of immune complexes with complement receptors on human blood cells: modification of complexes during interaction with red cells.

Antigen-antibody complexes, composed of 125I-BSA and guinea-pig or rabbit antibody, were incubated at 37 degrees C with human blood cells suspended in autologous serum and kinetics of binding analysed. When purified polymorphonuclear (PMN) or mononuclear cells (MNC) were studied, maximum binding was observed within 8 min, and immune complexes (IC) remained associated with cells even after 1 hr. When cells were studied unseparated (in the same amount of serum), maximum binding was observed slightly earlier (within 4 min), but within 15 min most of the IC were found in the serum. Separation of cell types at the time of maximal binding and studies with cell preparations depleted of different elements revealed that binding was principally to red blood cells (RBC). IC recovered in the serum 16 min after addition to unseparated cells bound very slowly to purified PMN or MNC; binding after 30 min was 10-15% of that observed with fresh IC at 8 min. Ultracentrifugal analysis revealed that reduction in binding efficiency correlated with decrease in the size of IC. RBC isolated after binding and release of IC bound newly-formed IC was identical rapidity and capacity as fresh RBC, indicating that receptors were not altered by IC. Kinetics studies with serum in the absence of cells suggested that interaction with RBC accelerated the rate of change in binding properties of IC. Rates of binding and release were independent of antigen/antibody ratio but were slowed and binding to RBC sustained when diluted or hypocomplementaemic (SLE) serum was substituted for neat serum. Our results suggest that competition for IC by RBC is associated with loss of ability of IC to bind to other blood cell types and reduction in size of IC, and that abnormalities of complement can lead to prolonged association of IC with RBC.     

Regulation of antral gastrin content

Five groups of rats were fasted for 3 days and injected with either NaCl or 5, 10, 20, or 40 micrograms/kg bombesin every 8 h. The animals were killed, and their serum and antral gastrin levels were compared with those of normally fed rats. Fasting reduced serum gastrin to 14% of control; antral gastrin was reduced to 21% of control. All doses of bombesin significantly increased serum gastrin in fasted rats, and 20 and 40 micrograms/kg significantly increased antral gastrin. A group of normally fed rats was also compared with one fed a liquid diet for 7 days. Half of each of these was injected with 20 micrograms/kg bombesin (3 times/day) and the other half with NaCl. Bombesin significantly increased serum and antral gastrin in the rats fed solid food. The liquid diet lowered serum and antral gastrin to 17 and 59% of control values, respectively. Bombesin injection totally prevented these decreases. These data indicate that food in the gastrointestinal tract is not required for either gastrin release or synthesis. Furthermore, the data suggest that gastrin synthesis is regulated primarily by gastrin release or by direct stimulation by bombesin rather than by specific food products.     

Enterochromaffin-like cell populations in human fundic mucosa: quantitative studies of their variations with age, sex, and plasma gastrin levels

The human gastric fundal mucosa contains a variety of endocrine cells, the most numerous of which are the so-called enterochromaffin-like (ECL) cells. We have studied the variations with age and sex of the ECL cell populations, utilizing an assessment based on multiple endoscopic biopsies from four groups of subjects. Plasma gastrin levels were also determined in these subjects. In males, endocrine cell densities declined with age but the ECL cell numbers in females opposed this trend. ECL cell counts showed no appreciable differences between young and old females. In older females, there was a high rate of gastritis and increased levels of circulating gastrin. Concentrations in older females (29.6 +/- 8.7 pmol/l) were higher than in both younger (less than 45 years) males (5.3 +/- 1.1 pmol/l) and older (greater than 55 years) males (6.3 +/- 0.6 pmol/l) (P less than 0.05). The plasma gastrin level was also higher in older females than in young females (13.1 +/- 4.5 pmol/l), although this difference failed to reach statistical significance. In conclusion, clinically silent gastritis, raised gastrin levels, and maintenance or rise of ECL cells numbers, in opposition to a general decrease in endocrine cells with age, appear to be features of women of more than 55 years of age. The variations in ECL cell populations reported here should be taken into account when evaluating possible pathological alterations of the stomach.     

Interleukin-1 potentiates antigen-mediated arachidonic acid metabolite formation in mast cells

Mast cells were isolated from human lung tissues using density gradient centrifugation and a fluorescence-activated cell sorter. Purified cells were sensitized passively with serum from allergic patients sensitive to grass pollen and then challenged with antigen (grass pollen). When these cells were challenged with antigen, LTC4, and PGD2 (19 +/- 6, and 42 +/- 9 pmol/10(6) cells, respectively) were released during 2 hr of incubation. When mast cells were incubated with interleukin-1 (IL-1) no detectable amount of LTC4 or PGD2 was generated. However, when mast cells were challenged with antigen and IL-1, LTC4 and PGD2 were released (60 +/- 15 and 97 +/- 21 pmol/10(6), respectively) after a 2 hr incubation period. The stimulatory action of IL-1 was both time- and dose-dependent (over a 10-1000 units/ml range). In addition, greater activity was observed if IL-1 was added 5-30 min prior to the antigen. Inhibitors of arachidonic acid metabolic pathways prevented the release of LTC4 and PGD2 from mast cells activated with antigen and IL-1. This study shows that IL-1 does not stimulate arachidonic acid metabolite release by mast cells but potentiates the release induced by antigen.