Barrier Breaker Research Articles

Hapten-Induced Model of Chronic Inflammation and Ulceration in the Rat Colon

We have developed a simple and reproducible rat model of chronic colonic inflammation by the intraluminal instillation of a solution containing a "barrier breaker" and a hapten. Administration of the hapten 2,4,6-trinitrobenzenesulfonic acid (5-30 mg) in 0.25 ml of 50% ethanol as the "barrier breaker" produced dose-dependent colonic ulceration and inflammation. At a dose of 30 mg, trinitrobenzenesulfonic acid/ethanol-induced ulceration and marked thickening of the bowel wall persisted for at least 8 wk. Histologically, the inflammatory response included mucosal and submucosal infiltration by polymorphonuclear leukocytes, macrophages, lymphocytes, connective tissue mast cells, and fibroblasts. Granulomas were observed in 57% of the rats killed 3 wk after induction of inflammation. Langhan's-type giant cells were also observed. Segmental ulceration and inflammation were common. The characteristics and relatively long duration of inflammation and ulceration induced in this model afford an opportunity to study the pathophysiology of colonic inflammatory disease in a specifically controlled fashion, and to evaluate new treatments potentially applicable to inflammatory bowel disease in humans.

Rapid induction of gastric ulceration in guinea pigs by sequential exposure to a barrier breaker and indomethacin

In short term experiments under halothane anesthesia, guinea pig total gastric pouches were initially and terminally exposed to 0.1 M HCl for 30 min. During an intervening 50-min test period, the gastric mucosa was exposed at pH 7.3, either to a barrier breaker (lysolecithin or diluted bile or sodium taurocholate) or to phosphate buffered saline (PBS) for half of the period, followed by exposure to indomethacin or further PBS for the second half of the test period. Scoring of mucosal damage was assessed from coded photographs and histological slides and by measurement of the transmucosal potential difference. In comparison with controls exposed only to PBS in the test period, indomethacin did produce minor but significant mucosal damage, whereas over this short time interval, the barrier breaking agents did not. Sequential exposure of pouches to lysolecithin and indomethacin caused a highly significant increase in ulceration, compared to controls or to indomethacin or lysolecithin exposure separately.

Electrophysiological approach to the action of taurine on rat gastric mucosa.

The effect of taurine on isolated rat gastric mucosa was examined electrophysiologically in order to clarify the mechanism of taurine-induced effect on drug absorption. Although taurine itself had little effect on the electrical parameters, potential difference (PD), short-circuit current (Isc), and tissue electrical resistance (R), of the gastric mucosa, sodium lauryl sulfate, an anionic surfactant, was shown to reduce these parameters remarkably. On the other hand, when aspirin was present, taurine showed different effects on the gastric mucosa depending on the concentrations of aspirin. Taurine decreased Isc significantly in the presence of aspirin at low concentration (1 mM), which has in itself no influence on the electric parameters. In contrast, aspirin at higher concentration (10 mM) was shown to act as barrier breaker of the gastric mucosa resulting in a marked decline of PD and Isc. When taurine was added, however, these parameters were reasonably recovered. It seems to be likely that taurine acts as a protector against the aspirin-induced damage in the gastric mucosa.

Hyperosmotic xylitol, prostaglandins and gastric mucosal barrier

We have previously reported that hyperosmotic solutions of sodium chloride or of xylitol possess potent anti-ulcer activity and reduce gastric acidity in the rat. They also stimulate gastric prostaglandin (PG) biosynthesis, which may bear a causal relationship to the above effects. In the present investigation we studied the effect of intragastric hyperosmolarity on the transmucosal potential difference (PD) and on the permeability to H + ions in the rat stomach. We also studied the effect of the prostaglandin synthetase inhibitors, indomethacin and flufenamic acid, on these parameters. Rat stomach was perfused in vivo, under urethane anesthesia, by xylitol solutions made up in 0.01 N HC1. While moderately hyperosmotic (13%) xylitol was without effect, the perfusion of intensely hyperosmotic xylitol (34.5%) resulted in a long lasting reduction of the transmucosal PD from a mean (±SEM) of −63±4 mV to a trough value of −40±3 mV. This depression of transmucosal PD was inhibited in a dose-related fashion by prior treatment with the PG-synthetase inhibitors. Acid recovery in the effluent was significantly reduced by the 34.5% xylitol solution, and indomethacin pretreatment did not modify the effect of hyperosmotic xylitol. It is concluded that, although intensely hyperosmotic xylitol produces some of the characteristic effects of a barrier breaker, i.e. depression of transmucosal PD and acid back diffusion, these two phenomena probably involve different mechanisms, as indicated by their differential response to indomethacin.

Aspirin- and taurocholate-induced metabolic damage in mammalian gastric mucosa in vitro.

To clarify the mechanism of initiation of the hydrogen ion backdiffusion, the effects of aspirin and taurocholate, two representative gastric mucosal barrier breakers, on the potential difference, secretory activity, energy metabolism, and the hydrogen ion permeability of guinea pig gastric mucosa was studied in vitro. 1) The ATP content and energy charge of the gastric mucosa showed a statistically significant reduction when the potential difference decreased to one-half of that before addition. 2) The mucosal acid secretion was reduced by addition of the barrier breaker. 3) However, the hydrogen ion backdiffusion, as measured by titrating the acid appearing in the serosal solution, became detectable when the potential difference decreased to one-fourth of that before addition. It has been concluded, therefore, that the primary action of gastric mucosal barrier breakers is to damage the energy metabolism of the mucosal cells, and that the hydrogen ion backdiffusion takes place as the result of cellular death caused by the impairment of energy metabolism.

Effect of 16,16-dimethyl prostaglandin E2 on the gastric mucosal barrier.

16,16-dimethyl prostaglandin E2 (16DM) can protect the gastric mucosa from injury and yet apparently damages the gastric mucosal barrier. The effect on the gastric mucosal barrier of 16DM (26.2 micromol/l), a dose 50 times the ED50 for inhibition of acid secretion, was investigated in Heidenhain pouches in four dogs by measuring plasma shedding from the pouches after the topical application of histamine (2.7 mmol/l) and ionic fluxes. The results were compared with those using 30% ethanol, a known barrier breaker. The topical application of histamine after three hours' perfusion with 30% ethanol led to plasma shedding at a rate of 7.5 (+/-2.6) ml/h, which was significantly greater than the rate of 1.2 (+/-1.4) ml/h after three hours' perfusion with 16DM and of 1.5 (+/-1.7) ml/h in the control group. Ethanol also caused an increase in the flux of H+, Na+, and Cl-, indicating an increase in mucosal permeability, whereas 16DM increased the flux of Na+ and Cl- but not of H+. It is concluded that 16DM does not damage the gastric mucosal barrier but stimulates the secretion of fluid containing Na+ and Cl-.

Absence of Na+--H+ barrier function in mucosa of canine small bowel.

The study was designed to determine whether the special Na+--H+ barrier function of the gastric mucosa is present in the mucosa of the small bowel and whether a gastric mucosal barrier breaker (hexanoic acid) would accelerate the fluxes of sodium in duodenum-jejunum and ileum as in the stomach. The observations were made in healthy conscious dogs with Thiry-Vella fistulae of the small bowel or Heidenhain pouches of the gastric corpus. These barrier characteristics of the stomach were completely absent in the small intestine where bidirectional Na fluxes were 5--10 times greater than in the stomach and were not accelerated by hexanoic acid as they were in the stomach. A comparison was made between the rates of absorption of hexanoic acid, sodium hexanoate, and HCl from the pouches and fistulae. The lipid-soluble fatty acid was transported at all sites more rapidly than its water-soluble sodium salt. In the stomach and ileum the H+ of HCl and sodium hexanoate were absorbed at similar slow rates. The duodenal-jejunal mucosa, however, transported H+ at rates nearly identical to those of hexanoic acid. In our tests HCl was not neutralized in duodenal contents while large quantities were neutralized in the contents of ileum.

Effects of E prostaglandins on canine gastric potential difference.

Measurement of the gastric transmucosal potential difference (PD) was used to study the effect of gastric antisecretory prostaglandins on the integrity of the gastric mucosa of the Heidenhain pouch dog. Intragastric administration of SC-29333 [(+/-)-15-deoxy-16-alpha,beta-hydroxy-16-methyl PGE1 methyl ester] slightly but significantly increased the transmucosal PD when compared to vehicle control. In addition, SC-29333 administered either intravenously or intragastrically, significantly inhibited the PD fall induced by aspirin, a well-established barrier breaker. In contrast, the intragastric administration of 16,16-dimethyl PGE2 methyl ester (Me-PGE2) significantly lowered the transmucosal PD and failed to modify the actions of aspirin on the integrity of the gastric mucosa. However, the intravenous administration of either prostaglandin did not affect the basal transmucosal PD values. These studies suggest that SC-29333 may strengthen the integrity of the gastric mucosal barrier against aspirin, and this could have important therapeutic potential.

Interactions of gastric blood flow, barrier breaker, and hydrogen ion back diffusion during ulcer formation in the rat

A rat gastric chamber preparation was used to determine the interrelations between H+ back diffusion, mucosal blood flow, the area of mucosa treated with bile salts and ulcer formation. The rate of H+ back diffusion was found to be dependent on both mucosal blood flow and the area of mucosa exposed to bile salts. It is concluded that, although H+ back diffusion is a convenient measure of barrier permeability under conditions of normal mucosal blood flow, during mucosal ischemia this parameter fails to reflect permeability because of decreased mucosal clearance of H+. These findings would explain apparent controversy whereby ulceration occurs under shock conditions in the absence of apparent H+ back diffusion.