Abstract
A healthy intestinal barrier prevents uptake of allergens and toxins, whereas intestinal permeability increases following chemotherapy and in many gastrointestinal and systemic diseases and disorders. Currently, there are no approved drugs that target and repair the intestinal epithelial barrier while there is a medical need for such treatment in gastrointestinal and related conditions. The objective of this single-pass intestinal perfusion study in rats was to investigate the preventive cytoprotective effect of three mucosal protective drugs—melatonin, misoprostol, and teduglutide—with different mechanisms of action on an acute jejunal injury induced by exposing the intestine for 15 min to the anionic surfactant, sodium dodecyl sulfate (SDS). The effect was evaluated by monitoring intestinal clearance of 51Cr-labeled ethylenediaminetetraacetate and intestinal histology before, during, and after luminal exposure to SDS. Our results showed that separate pharmacological pretreatments with luminal misoprostol and melatonin reduced acute SDS-induced intestinal injury by 47% and 58%, respectively, while their use in combination abolished this injury. This data supports further development of drug combinations for oral treatments of conditions and disorders related to a dysregulated or compromised mucosal epithelial barrier.
Highlights
The role of the intestinal mucosa is to form a selective and dynamic barrier between the external luminal contents and the underlying tissue and systemic circulation [1]
The mucosal barrier consists of a single layer of intestinal epithelial cells (IEC) covered with a mucus layer and the underlying immune system
A true association between increased intestinal permeability and different disease entities is difficult to define as it requires a cause and effect analysis through studies of temporal relationships
Summary
The role of the intestinal mucosa is to form a selective and dynamic barrier between the external luminal contents and the underlying tissue and systemic circulation [1]. A true association between increased intestinal permeability and different disease entities is difficult to define as it requires a cause and effect analysis through studies of temporal relationships It is yet unproven whether reinforcement of the intestinal barrier can prevent or cure GI or systemic clinical manifestations as there are no approved drugs that target the intestinal epithelial barrier. The main objective of our single-pass intestinal perfusion (SPIP) study in rats was to investigate the mucosal preventive cytoprotective effect of melatonin, misoprostol, and teduglutide, each with a different mechanism of action. Intestinal mucosal injury was induced by exposing the intestinal mucosa to the anionic surfactant, sodium dodecyl sulfate (SDS), for 15 min This surfactant causes an acute general mucosal injury manifested by an increase in paracellular and transcellular permeability, coupled with histological changes and leakage of intracellular components [19,20]. Mucosal preventive cytoprotective effects of the drugs were evaluated by monitoring intestinal passive transport of 51Cr-labeled ethylenediaminetetraacetate (51Cr-EDTA)—an inert market for mucosal barrier integrity—and evaluation of histological changes before, during, and after luminal exposure to SDS [21]
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