The prostone lubiprostone has been shown to stimulate chloride secretion via one of the minor intestinal epithelial channels, ClC-2. This results in sustained low-level secretion of water into the lumen. Previous studies by the same research group have identified ClC-2 as a key protein involved in re-assembly of interepithelial tight junctions. Activation of ClC-2 by lubiprostone hastens recovery of barrier function, apparently by recruiting tight junction proteins to the apical-lateral membrane. Alternate treatments for constipation, such as PEG 3350, generate an osmotic gradient within the lumen that drags electrolytes and fluid into the lumen. Osmotic agents have also been shown to enhance barrier function by alteration of tight junction structure. However, the ability of PEG 3350 to enhance recovery of acutely injured mucosa as compared to lubiprostone has not been previously assessed.
A research article to be published on October 21, 2008 in the World Journal of Gastroenterology addresses this question. The research team led by Dr. Moeser and Blikslager at North Carolina State University in collaboration with investigators at Sucampo Inc. used electrophysiological techniques to study ischemic-injured mucosa ex vivo. Electrical responses were further assessed using mucosal-to-serosal fluxes of radiolabeled paracellular probes and tissues were examined histologically.
Ischemic-injured mucosa treated with either lubiprostone or PEG 3350 showed sharp elevations in short-circuit current, most likely associated with movement of chloride toward the luminal side of the tissue. Chloride secretion has previously been shown to be an important signal for subsequent re-assembly of tight junctions and closure of paracellular spaces within the epithelium. However, only lubiprostone stimulated rapid recovery of barrier function as detected by marked elevations in transepithelial electrical resistance and confirmed by measurement of macromolecular fluxes. Injured tissues had all restituted to the same degree, indicating that changes in barrier function were likely attributable to conformational change of the tight junction and paracellular spaces.
These results demonstrate potential therapeutic properties of the prostones beyond the current indications. Rapid recovery of barrier function has previously been shown to be linked to selective activation of ClC-2, and may lead to novel treatments of intestinal conditions characterized by periodic reductions in barrier function. A greater understanding of the signaling pathways used by prostones to initiate intestinal barrier repair may refine authors' ability to develop targeted treatments for intestinal disease.