sodium-taurodeoxycholate and Gastroesophageal-Reflux

Gastroesophageal reflux disease is related to various laryngeal sequelae. However, there is a lack of established reflux animal models covering longer observation periods. We evaluated the effects of acid, pepsin, and bile acid on healing of the traumatized subglottis in a simulated reflux model.. In the first experiment, 48 rabbits were inflicted with a posterior subglottic injury using a diode laser, and there were 10 unwounded controls. After catheter insertion under transoral endoscopic guidance, animals were randomly assigned to one of the four groups: acid reflux (pepsin 0.3 mg/mL+taurodeoxycholic acid 0.155 mg/mL+acid pH 2); nonacid reflux (pepsin+taurodeoxycholic acid+pH 6); saline reflux; and unwounded control. Animals received catheter irrigation with 3 mL of a mixed solution or saline, twice daily for 6 wk. In the second experiment, 36 animals were inflicted with a subglottic injury followed by acid or saline reflux treatment and were sacrificed after 1, 2, and 4 wk for time-serial observations. Gross and histological findings were compared among the different groups.. Catheter-related problems were minor. Most animals received laryngopharyngeal irrigation with the solutions well, and 19 were excluded. Inflammation scores, fibrosis, thickening, and luminal stenosis were greatest in the acid reflux group (p<0.005). Values were not different between the nonacid reflux and saline reflux groups (p>0.1).. Our data suggest that subglottic wound healing is significantly affected by pepsin and bile acid only under acidic conditions. This implies that acid-suppressive therapy can prevent further subglottic inflammation and stenosis by laryngeal reflux.

Topics: Analysis of Variance; Animals; Bile Acids and Salts; Chi-Square Distribution; Disease Models, Animal; Disease Progression; Gastroesophageal Reflux; Laryngitis; Laryngoscopy; Larynx; Pepsin A; Rabbits; Random Allocation; Statistics, Nonparametric; Taurodeoxycholic Acid; Vocal Cords; Wound Healing

Long-term bile duct obstruction causes sinusoidal regurgitation of bile acids, a shift in bile acid metabolism, and alterations of liver histology. In this study we investigated the regurgitation of bile acids during short-term bile duct obstruction and its reversibility and reproducibility. In addition, the biotransformation of taurodeoxycholate and its appearance in bile and perfusate effluent were studied as well as liver histology.. Rat livers (n = 5) were perfused in vitro with 32 nmol/min/g liver taurodeoxycholate over 85 min with the bile duct being intermittently closed for 30 and 20 min, respectively.. Within the first 5 min after bile duct obstruction bile acids started to regurgitate to the perfusate effluent amounting to approximately 15% of hepatic uptake until the end of the perfusion period. After relief of obstruction, bile flow and biliary bile acid excretion showed an overshoot phenomenon and were almost doubled compared to preobstruction. In contrast, sinusoidal bile acid regurgitation declined. The same phenomenon was observed during the second closure/opening cycle of the bile duct. Regurgitated bile acids consisted of significantly more taurodeoxycholate metabolites (approximately 70%) than did biliary bile acids (approximately 30%). Histology of liver parenchyma was preserved.. During repetitive short-term bile duct obstruction bile acid regurgitation is reversible and reproducible. The absence of altered mechanical barriers suggests that specific pathways are involved in the regurgitation process of bile acids.

Topics: Acute Disease; Animals; Bile; Bile Acids and Salts; Biotransformation; Cholagogues and Choleretics; Cholestasis; Gastroesophageal Reflux; In Vitro Techniques; Male; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Taurodeoxycholic Acid

Esophagitis occurs in patients with excessive acid and/or alkaline gastroesophageal reflux. This observation prompted us to develop a continuously perfused in vivo rabbit esophageal model to examine the potential for different endogenous injurious agents to cause H+ back diffusion and morphologic evidence of esophagitis. We found that HCl at physiologic pH values did not break the mucosal barrier to H+ back diffusion or cause esophagitis. Bile salts at physiologic concentrations in both an acid or alkaline perfusate broke the mucosal barrier and caused H+ back diffusion, but failed to cause a morphologic injury consistent with clinical reflux esophagitis. Instead, proteolytic enzymes, such as pepsin in an acid environment and trypsin in an alkaline environment, caused a severe hemorrhagic erosive esophagitis consistent with that seen clinically. We feel new therapeutic strategies for the treatment of reflux esophagitis should be directed at proteolytic enzymes rather than only HCl or bile salts. Finally, we showed sucralfate to be a mucosal protectant against the acid-pepsin injury.

Topics: Animals; Esophageal Stenosis; Esophagitis, Peptic; Esophagus; Gastric Juice; Gastroesophageal Reflux; Hydrogen-Ion Concentration; Mucous Membrane; Pepsin A; Rabbits; Taurodeoxycholic Acid; Trypsin

The pathogenesis of alkaline reflux esophagitis was investigated in an experimental model by assessing individually the influence of different bile salt moieties and trypsin on esophageal mucosa. An isolated segment of rabbit esophagus was perfused at pH 7 with a solution containing the test agent under study, and the severity of mucosal damage was assessed by using as indicators of mucosal integrity transmucosal potential difference, net flux of Na+, and mucosal permeability to two neutral molecules of different sizes, 3H-H2O and 14C-erythritol. The data indicate that the secondary dihydroxy bile salt, deoxycholate, in its deconjugated form was highly injurious to esophageal mucosa; it was the only test agent that caused gross mucosal lesions during the experiment. The respective conjugated bile salt moiety, taurodeoxycholate, had a weaker effect. Also the primary dihydroxy bile salt, chenodeoxycholate, in its deconjugated form caused moderate damage to the mucosa, whereas its conjugated form, taurochenodeoxycholate, had no effect. The effect of the other three bile salts tested--cholate, taurocholate, and taurolithocholate--was negligible. Trypsin also adversely affected the mucosa, but its effect was weaker than that of deoxycholate. The results suggest that the deconjugated bile salts deoxycholate and chenodeoxycholate (which are formed following bacterial colonization of the upper gastrointestinal tract in the absence of gastric acid), the conjugated bile salt taurodeoxycholate, and the proteolytic enzyme trypsin may have significant roles in the pathogenesis of alkaline reflux esophagitis.

Topics: Alkalies; Animals; Bile Acids and Salts; Chenodeoxycholic Acid; Cholic Acids; Deoxycholic Acid; Esophagus; Gastroesophageal Reflux; Rabbits; Taurochenodeoxycholic Acid; Taurocholic Acid; Taurodeoxycholic Acid; Taurolithocholic Acid; Trypsin