Gastric mucosal integrity: gastric mucosal blood flow and microcirculation. An overview.

The stomach is in a state of continuous exposure to potentially hazardous agents. Hydrochloric acid together with pepsin constitutes a major and serious threat to the gastric mucosa. Reflux of alkaline duodenal contents containing bile and pancreatic enzymes are additional important injurious factors of endogenous origin. Alcohol, cigarette smoking, drugs and particularly aspirin and aspirin-like drugs, and steroids are among exogenous mucosal irritants that can inflict mucosal injury. The ability of the stomach to defend itself against these noxious agents has been ascribed to a number of factors constituting the gastric mucosal defense. These include mucus and bicarbonate secreted by surface epithelial cells, prostaglandins, sulfhydryl compounds and gastric mucosal blood flow. The latter is considered by several researchers to be of paramount importance in maintaining gastric mucosal integrity. The aim of this paper is to review the experimental and clinical data dealing with the role of mucosal blood flow and in particular the microcirculation in both damage and protection of the gastric mucosa.

The key-role of vagal nerve and adrenals in the cytoprotection and general gastric mucosal integrity.

BACKGROUND: Our laboratory group observed earlier that the gastric mucosal cytoprotective effect of prostacyclin (PGI(2)) disappeared after surgical vagotomy in rats. Similarly to this, the beta-carotene induced gastric cytoprotection disappeared in adrenalectomized rats too. AIMS: In these studies we aimed to investigate the possible role of vagal nerve and adrenals in the development of gastric mucosal lesions induced by exogenously administered chemicals (ethanol, HCl, NaOH, NaCl and indomethacin), and on the effects of cytoprotective and antisecretory drugs (atropine, cimetidine), and scavengers (vitamin A and beta-carotene). METHODS: The observations were carried out in fasted CFY strain rats. The gastric mucosal lesions were produced by intragastric (i.g.) administration of narcotising agents (96% ethanol; 0.6 M HCl; 0.2 M NaOH; 25% NaCl) or subcutaneously (s.c.) administered indomethacin (20 mg/kg) in intact, surgically bilaterally vagatomized, and adrenalectomized rats without or with glucocorticoid supplementation (Oradexon, 0.6 mg/kg given i.m. for 1 week). The gastric mucosal protective effect of antisecretory doses of atropine (0.1-0.5-1.0 mg/kg i.g.) and cimetidine (10-25-50 mg/kg i.g.), and vitamin A and beta-carotene (0.01-0.1-1.0-10 mg/kg i.g.) was studied. The number and severity of mucosal gastric lesions was numerically or semiquantitatively measured. In other series of observations the gastric acid secretion and mucosal damage were studied in 24 h pylorus-ligated rats without and with acute bilateral surgical vagotomy. RESULTS: It was found that: (1) the chemical-induced gastric mucosal damage was enhanced in vagotomized and adrenalectomized rats, meanwhile the endogenous secretion of gastric acid, and the development of mucosal damage can be prevented by surgical vagotomy; (2) the gastric cyto- and general protection produced by the drugs and scavengers disappeared in vagotomized and adrenalectomized rats; (3) the gastric mucosal protective effects of drugs and of scavengers returned after sufficient glucocorticoid supplementation of the rats. CONCLUSION: It has been concluded that the intact vagal nerve and adrenals have a key role in the gastric mucosal integrity, and in drugs- and scavengers-induced gastric cyto- and general mucosal protection.

mRNA expression of cytokines and chemokines in the normal gastric surface mucous epithelial cell line GSM06 during bacterial infection with Helicobacter felis.

BACKGROUND AND AIM: A group of the proinflammatory and chemotactic cytokines (chemokines) has been considered as an important factor in the pathomechanism of different bacterial diseases, among them the common Helicobacter pylori infection. Experimental results obtained with gastric biopsy samples of H. pylori positive patients, and with H. pylori infected tumor originated gastric cell lines indicated that these cytokines have essential roles in the development and maintenance of the immune response and inflammation of the gastric mucosa during H. pylori infection. Although the mRNA expression was shown in these biopsy samples and cell lines, it is not yet proved that the normal gastric mucosal epithelial cells themselves express these cytokines. The establishment of a gastric surface mucous cell line with non-tumor origin (GSM06), and the usage of Helicobacter felis as a model of the classic H. pylori infection gave us the possibility to check this question. MATERIALS AND METHODS: in this study GSM06 cells were infected with different numbers (10(5), 10(6), 10(7), 10(8), 10(9) bacterium/ml medium) of H. felis for two different time periods (2, 4 h). Cells treated with medium only were used as control. Then the mRNA expression of the following cytokines was measured by RT-PCR method in the GSM06 cells: proinflammatory cytokine IL1-beta, and chemokine RANTES, eotaxin, MCP-1, MIP1-alpha and MIP1-beta. RESULTS: we found that neither mRNA of the investigated cytokines was expressed constitutively, however the GSM06 cells expressed the mRNA of each cytokine during H. felis infection. CONCLUSION: our results prove that normal gastric surface mucous epithelial cells express immunologically active peptides during H. felis infection. We may suppose that the epithelial cells of the gastric mucosa contribute to the immune response and inflammation by expressing proinflammatory (IL1-beta) and chemotactic (RANTES, eotaxin, MCP-1, MIP1-alpha and beta) cytokines during H. pylori infection in human.

An oral drug delivery system targeting immune-regulating cells ameliorates mucosal injury in trinitrobenzene sulfonic acid-induced colitis.

Control of immune-regulating cells in the colonic mucosa is important in the treatment of patients with inflammatory bowel disease (IBD). The aim of study was to examine the therapeutic effect of dexamethasone (DX) microspheres on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats, a model for human Crohn's disease. DX microspheres and DX alone were administered orally to rats with TNBS-induced colitis. The macroscopic score, histological score, myeloperoxidase (MPO) activity, nitric oxide (NO) production, and gene expressions of proinflammatory cytokines, cyclooxygenase (COX)-1, and COX-2 in the colonic tissue were determined. Proliferating cell nuclear antigen (PCNA) staining and expression of nuclear transcription factor (NF)-kappaB in colonic tissues were also investigated. Macroscopic score, histological score, MPO activity, and NO production in rats treated with DX microspheres were significantly lower than in those treated with DX alone. The gene expression of proinflammatory cytokines and COX-2 in rats treated with DX microspheres was down-regulated, compared with that in rats treated with DX alone. The number of PCNA-positive cells in the DX microsphere group was larger than in the group treated with DX alone. DX microspheres suppressed NF-kappaB activation in TNBS-induced colitis more strongly than DX alone. Oral administration of DX microspheres appears to ameliorate mucosal injury in TNBS-induced colitis. This drug delivery system could be an ideal therapy for human IBD.

Helicobacter pylori. One bacterium and a broad spectrum of human disease! An overview.

Since the historical rediscovery of gastric spiral Helicobacter pylori in the gastric mucosa of patients with chronic gastritis by Warren and Marshall in 1983, peptic ulcer disease has been largely viewed as being of infectious aetiology. Indeed, there is a strong association between the presence of H. pylori and chronic active gastritis in histology. The bacterium can be isolated in not less than 70% of gastric and in over 90% of duodenal ulcer patients. Eradication of the organism has been associated with histologic improvement of gastritis, lower relapse rate and less risk of bleeding from duodenal ulcer. The bacterium possesses several virulence factors enabling it to survive the strong acid milieu inside the stomach and possibly damaging host tissues. The sequence of events by which the bacterium might cause gastric or duodenal ulcer is still not fully elucidated and Koch's postulates have never been fulfilled. In the majority of individuals, H. pylori infection is largely or entirely asymptomatic and there is no convincing data to suggest an increase in the prevalence of peptic ulcer disease among these subjects. An increasingly growing body of literature suggests an association between colonization by H. pylori in the stomach and a risk for developing gastric mucosa-associated lymphoid tissue (MALT), MALT lymphoma, gastric adenocarcinoma and even pancreatic adenocarcinoma. The bacterium has been implicated also in a number of extra-gastrointestinal disorders such as ischaemic heart disease, ischaemic cerebrovascular disease, atherosclerosis, and skin diseases such as rosacea, but a causal role for the bacterium is missing. Eradication of H. pylori thus seems to be a beneficial impact on human health. Various drug regimens are in use to eradicate H. pylori involving the administration of three or four drugs including bismuth compounds, metronidazole, clarithromycin, tetracyclines, amoxycillin, ranitidine, omeprazole for 1-2 weeks. The financial burden, side effects and emergence of drug resistant strains due to an increase in the use in antibiotics for H. pylori eradication therapy need further reconsideration.

Small doses of capsaicin given intragastrically inhibit gastric basal acid secretion in healthy human subjects.

Although the direct inhibitory effect of small dose of capsaicin on gastric secretory responses was proved in animal observations, the role of capsaicin-sensitive afferent nerves (CSAN) and the effect of capsaicin applied in small and high doses on gastric secretion in human has not been clarified yet. In this study we investigated the influence of different small doses (100-800 microg) of capsaicin given intragastrically through an orogastric tube on gastric basal secretory responses in 10 healthy human subjects. Gastric basal secretory responses (volume, H+-concentration, H+-output) were measured from the suctions of gastric juice for a 1-h period. It has been found that: a) capsaicin dose-dependently inhibited the volume and H+-output of gastric juice; b) ID50 was found to be about 400 microg for capsaicin on gastric acid secretion; c) the time interval for capsaicin-induced gastric inhibition existed for about 1 h indifferently from the higher dose (800 microg) of capsaicin given after. It has been concluded that the capsaicin (given in small doses) inhibits the gastric basal acid output via stimulation of the inhibition of capsaicin sensitive afferent nerves.

Capsaicin-sensitive afferent sensory nerves in modulating gastric mucosal defense against noxious agents.

In the rat stomach, evidence has been provided that capsaicin-sensitive sensory nerves (CSSN) are involved in a local defense mechanism against gastric ulcer. In the present study capsaicin or resiniferatoxin (RTX), a more potent capsaicin analogue, was used to elucidate the role of these sensory nerves in gastric mucosal protection, mucosal permeability, gastric acid secretion and gastrointestinal blood flow in the rat. In the rat stomach and jejunum, intravenous RTX or topical capsaicin or RTX effected a pronounced and long-lasting enhancement of the microcirculation at these sites, measured by laser Doppler flowmetry technique. Introduction of capsaicin into the rat stomach in very low concentrations of ng-microg x mL(-1) range protected the gastric mucosa against damage produced by topical acidified aspirin, indomethacin, ethanol or 0.6 N HCl. Resiniferatoxin exhibited acute gastroprotective effect similar to that of capsaicin and exerted marked protective action on the exogenous HCl, or the secretagogue-induced enhancement of the indomethacin injury. The ulcer preventive effect of both agents was not prevented by atropine or cimetidine treatment. Capsaicin given into the stomach in higher desensitizing concentrations of 6.5 mM markedly enhanced the susceptibility of the gastric mucosa and invariably aggravated gastric mucosal damage evoked by later noxious challenge. Such high desensitizing concentrations of capsaicin, however, did not reduce the cytoprotective effect of prostacyclin (PGI2) or beta-carotene. Capsaicin or RTX had an additive protective effect to that of atropine or cimetidine. In rats pretreated with cysteamine to deplete tissue somatostatin, capsaicin protected against the indomethacin-induced mucosal injury. Gastric acid secretion of the pylorus-ligated rats was inhibited with capsaicin or RTX given in low non-desensitizing concentrations, with the inhibition being most marked in the first hour following pylorus-ligation. Low intragastric concentrations of RTX reduced gastric hydrogen ion back-diffusion evoked by topical acidified salicylates. It is concluded that the gastropotective effect of capsaicin-type agents involves primarily an enhancement of the microcirculation effected through local release of mediator peptides from the sensory nerve terminals. A reduction in gastric acidity may contribute to some degree in the gastric protective action of capsaicin-type agents. The vasodilator and gastroprotective effects of capsaicin-type agents do not depend on vagal efferents or sympathetic neurons, involve prostanoids, histaminergic or cholinergic pathways.

Capsaicin increases gastric emptying rate in healthy human subjects measured by 13C-labeled octanoic acid breath test.

The role of capsaicin-sensitive primary afferent sensory nerves in the regulation of gastrointestinal motility in human is not clarified yet. In this study, we investigated the effect of 400 microg capsaicin given intragastrically on gastric emptying measured by 13C-octanoic acid breath test in ten healthy human subjects. Four parameters of gastric emptying curves were taken into consideration: 1) maximum value of the curve, 2) time belonging to this maximum, 3) slope of the rising part of the curve and 4) time belonging to the 50% of the area under the curve. Administration of 400 microg capsaicin significantly increased the slope of gastric emptying curve (from 0.1 +/- 0.01 to 0.139 +/- 0.014 U x min(-1), P < 0.05) and significantly decreased the time belonging to the maximum value of emptying curve (from 150 +/- 18 to 75 +/- 12 min, P < 0.05) and the time belonging to the 50% of the area under the curve (from 112 +/- 15 to 99 +/- 14 min, P < 0.05). According to our results 400 microg capsaicin enhances gastric emptying rate in healthy human subjects.

Capsaicin inhibits the pentagastrin-stimulated gastric acid secretion in anaesthetized rats with acute gastric fistula.

The effect of capsaicin on basal and pentagastrin-stimulated gastric acid secretion was investigated in the urethane anaesthetized acute gastric fistula rat. Gastric acid secretion was measured by flushing of the gastric lumen with saline every 15 min or by continuous gastric perfusion. Capsaicin given into the rat stomach at 120 ng x mL(-1) prior to pentagastrin (25 microg x kg(-1), iv) reduced gastric acid secretory response to pentagastrin by 24%. Intravenous (iv) capsaicin (0.5 microg x kg(-1)) did not reduce the pentagastrin-stimulated gastric acid secretion. After topical capsaicin desensitization (3 mg x mL(-1)), basal gastric acid secretion and that in response to pentagastrin (25 microg x kg(-1), intraperitonaeally) was unaltered compared with the control group. Data indicate that topical capsaicin inhibits gastric acid secretion stimulated with pentagastrin in anaesthetized rats.

A study of the actions of naloxone and morphine on gastric acid secretion and gastric mucosal damage in the rat.

There exists a considerable controversy in the literature with regard to the effect of either opiate receptor blockade or that of morphine in different gastric and intestinal ulcer models in the rat. We performed experiments to evaluate the effects of naloxone and morphine on gastric acid secretion and gastric mucosal damage in different experimental models of gastric mucosal injury, namely in indomethacin-, HCl (0.6N)- and ethanol (96%)-models. We found that: 1) 10 mg/kg naloxone i.p. given twice, effectively protected gastric mucosa against indomethacin (30 mg/kg i.p.) and against the acid-dependent injury caused by 0.6 N HCl (1 mL i.g.), but not against the non acid-dependent injury caused by 96% ethanol (1 mL i.g.); 2) morphine (10 + 10 mg/kg i.p.) increased ulcers in the HCl-model, but had no effect in the two other models; 3) this ulcer-aggravating effect of morphine in the HCl-model was blocked by pretreatment of 2 mg/kg i.p. naloxone; and 4) both naloxone (5 + 5 and 10 + 10 mg/kg i.p.) and morphine (10 + 10 mg/kg i.p.) significantly decreased gastric acid secretion in 1-h pylorus ligated rats. We conclude that: 1) naloxone dose-dependently protects against the indomethacin- and HCl-, but not against the ethanol-induced gastric mucosal damage; 2) morphine aggravates the HCl-induced ulcerogenesis; and 3) both opioid receptor agonist and antagonist decrease gastric acid secretion.

Results of transcutaneous electrical stimulation (TES) in cure of lower extremity arterial disease.

The results of the treatment of 24 subjects--10 of them diabetic--with peripheral obstructive arterial disease of the lower limbs by transcutaneous electrical stimulation (TES) have been studied. The chronic ischemia of the lower extremities was complicated with ulceration in 12 and initial or advanced gangrene in 6 patients. All patients had been treated with antiplatelet drugs, pentoxifylline, and vasodilating drugs for many years. The drug therapy was continued, and TES was given daily for twenty minutes. The results were estimated after four to eight weeks of hospitalization and during a one-year follow-up in numerous cases. Except for 4 patients the improvement was very significant in all cases: the pain disappeared, the gangrenous process of the toes stopped, regression or complete healing of the ulceration could be observed, and the painfree walking distance increased. The oxygen saturation measured on the toes increased significantly during electrical stimulation. The blood pressure measured in the tibial artery showed very different changes. According to these observations TES appears to be a useful method superior to drug therapy in curing arterial circulatory disturbances of the lower extremities.

An implantable electromagnetic sound source for speech production.

Our goal is to provide laryngectomized cancer patients with a method of speech rehabilitation as an alternative to esophageal speech when required. With the cooperation of otolaryngologists, biomedical engineers, and speech therapists, an implantable electromagnetic sound source for voice production has been produced. It is biocompatible, durable, and functional in animal experimentation. A small, carefully selected clinical trial will soon begin.