Background & Aims: Lubiprostone alleviates constipation by stimulating intestinal fluid secretion, purportedly through activation of ClC-2-type Cl(-) channels. Intestinal obstruction is also a recurrent cause of distress in cystic fibrosis (CF) patients, caused by loss of CF transmembrane conductance regulator (CFTR) Cl(-) channel activity. Because ClC-2 recruitment might be beneficial to CF patients, we investigated lubiprostone's mode of action.
Methods: Cl(-) transport was measured in an Ussing chamber, in 3 model systems: (1) T84 colonocytes, (2) intestinal epithelium of wild-type and CF mice, and (3) intestinal epithelium of CF patients and controls.
Results: In T84 monolayers, lubiprostone induced a robust secretory response. Selective permeabilization of the basolateral plasma membrane revealed that lubiprostone activated an apical Cl(-) conductance. The lubiprostone response was attenuated by H89, an inhibitor of the cAMP-dependent protein kinase, and lubiprostone precluded responsiveness to the cAMP agonist forskolin. CFTR blockage by CFTRinh172, but not ClC-2 blockage by CdCl(2), inhibited the lubiprostone response. Lubiprostone induced a CdCl(2)-insensitive secretory response in mouse intestine, but failed to induce intestinal Cl(-) secretion in Cftr-null mice. Correspondingly, lubiprostone induced a secretory response in human intestinal epithelium, but not in tissue of CF patients. The EP(4)-type prostanoid receptor antagonist L-161,982 blocked the lubiprostone response in all 3 models studied. In T84 cells, lubiprostone induced a rise in cAMP levels that was sensitive to EP(4)-receptor blockage.
Conclusions: Lubiprostone enhances intestinal Cl(-) and fluid secretion via prostanoid receptor signaling, triggering activation of CFTR. Therefore, it is of limited use for treatment of CF-related intestinal disease.
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http://dx.doi.org/10.1053/j.gastro.2009.05.037 | DOI Listing |
Pharmaceuticals (Basel)
October 2024
Department of Physiology, Chosun University College of Medicine, Gwangju 61452, Republic of Korea.
Expert Opin Pharmacother
September 2024
Faculty of Pharmacy and Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences (TUMS), Tehran, Iran.
Introduction: The rise in opioid use for managing chronic and oncologic pain has led to a significant increase in opioid-induced constipation (OIC) that impacts patient quality of life and pain management.
Areas Covered: In this study, emerging therapies for OIC were criticized for refining advancements and novel treatment options. Key topics included the efficacy of peripherally acting mu-opioid receptor antagonists (PAMORAs) such as methylnaltrexone, naloxegol, and naldemedine, which specifically target opioid-induced gut dysfunction.
Sci Total Environ
June 2024
Shenzhen Key Laboratory of Environmental Chemistry and Ecological Remediation, College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen 518060, China. Electronic address:
Soils represent crucial sinks for pharmaceuticals and microplastics, making them hotspots for pharmaceuticals and plastic pollution. Despite extensive research on the toxicity of pharmaceuticals and microplastics individually, there is limited understanding of their combined effects on soil biota. This study focused on the earthworm Eisenia fetida as test organism to evaluate the biotoxicity and bioaccumulation of the typical pharmaceutical naproxen and microplastics in earthworms.
View Article and Find Full Text PDFSci Rep
March 2024
Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea.
Expert Rev Gastroenterol Hepatol
November 2023
Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark.
Introduction: Opioid-induced constipation remains undertreated despite effective and safe treatment options exists. Previous guidelines have only been partially effective in improving management, possibly due to their complexity, and studies suggest that a simple setup of concise and behaviorally-orientated steps improves usability.
Areas Covered: This article introduces the concept of opioid-induced constipation and provides an overview of existing guidelines in this field.
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