Gastroprotection with rebamipide
Reinforcing the integrity of the epithelial barrier during basal conditions
The digestive epithelial barrier forms an important mechanism against microorganisms, prevents antigen absorption, and presents antigens for control of the immune response. An abnormal response to this mechanism may be implicated in the development of inflammatory bowel disease, gastritis, celiac disease, food allergy, and indirectly, gastric cancer. Thus, protecting the digestive epithelial barrier is vital to general gastrointestinal health.
Tamara Matysiak-Budnik, associate professor at the Necker Faculty in Paris, spoke in a medical symposium organized by Otsuka Philippines about the role of rebamipide (Mucosta) as a mucosal protective agent.
Transepithelial transport pathways
To study the effects of rebamipide on the digestive barrier and its functions, Matysiak-Budnik used the Ussing chamber to measure epithelial integrity.
The Ussing chamber determines varying electrical resistance of the epithelium in two separate chambers using an electrode.
Epithelial integrity is damaged when electrical resistance drops while the markers' fluxes increase. Radio-labeled markers also measure the fraction of the protein that has remained intact or degraded after transport.
In the study, intestinal epithelial monolayer HT29-19A was incubated initially with rebamipide under noninflammatory conditions. Baseline results showed higher electrical resistance against control. Under inflammatory conditions using the cytokine IL-1 , there was disruption of epithelial integrity noted as a drop in resistance and a surge in HRP flux. When the monolayer was incubated with both IL-1 and rebamipide, the inflammatory effect was notably "compensated," recovering baseline electrical resistance and stabilizing fluxes.
Infecting the epithelium initially with H. pylori showed the same increases in HRP fluxes during antigen absorption across the monolayer. However, Matysiak-Budnik said, when the tissue was incubated at the same time with H. pylori and rebamipide, "you can see very clearly that this effect is reversed and there is clear protection by rebamipide against this increase in antigenic transport."
Apoptotic index
One of the hypothesized mechanisms for the protective action of rebamipide may involve the apoptotic index of the epithelial cells.
In rodents whose gastric mucosa had been infected with H. felis, successful eradication treatment did not significantly decrease macromolecular transport across the barrier. With rebamipide treatment for five weeks, however, there was a more pronounced and significant reduction in protein transport. Likewise, there was faster and greater reduction in degraded peroxidase fluxes with rebamipide that with eradication treatment alone.
"Rebamipide reinforces the integrity of the epithelial barrier during basal conditions and protects against the deleterious effects of IL-1 and H. pylori in vitro. It also leads to normalization of gastric permeability to macromolecules when increased by H. felis infection in mice," said Matysiak Budnik.
To determine whether rebamipide also interfered with the mucosal immune response to antigens, oral tolerance to food antigen (ovalbumin) with rebamipide was studied among mice infected with H. felis. Results showed rebamipide clearly prevented the inhibition of oral tolerance to ovalbumin by H. felis in mice. The mechanism for the immunologic action could involve interference with the antigen presentation itself. Incubating an antigen (human serum albumin) with antigen-presenting cells (human B cell MHCII) and effector cells (mouse T cell hybridoma) with or without rebamipide, there was a strong dose-dependent inhibition by rebamipide on actual T cell activation (Matysiak-Budnik et al., 2003).
Rebamipide and experimental colitis
Rectal rebamipide has also been shown to confer the greatest protection on barrier integrity with significant decreases in mannitol fluxes in IL-10-deficient mice infected with H. hepaticus. The same effects were noted with macromolecular transport using HRP protein fluxes. Rebamipide action on the inflammatory response of mesenteric lymph nodes were also noted after stimulation with concavalin A, showing the rectal group with the least interferon response to stimulation.
Concluded Matysiak-Budnik: "The protective effect of rebamipide on the epithelial barrier function, its capacity to diminish macromolecular absorption across the digestive mucosa, leading to a decrease in the antigenic load, as well as its capacity to downregulate mucosal immune response to antigens, may contribute to its gastroprotective and antiinflammatory properties and explain its beneficial effect in the treatment of certain gastric diseases and some intestinal diseases."
R. Badillo, MD
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