Linaclotide improves gastrointestinal transit in cystic fibrosis mice by inhibiting sodium/hydrogen exchanger 3
| Autor: | Dana M. Valerio, Walter F. Boron, Thomas J. Kelley, Craig A. Hodges, Daniel R. McHugh, Mitchell L. Drumm, Shuyu Hao, Robert C. Stern, Anjum Jafri, Kimberly McBennett, Calvin U. Cotton, Megan Vitko, Fraser J. Moss |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Cystic Fibrosis Physiology Gastroenterology Cystic fibrosis 03 medical and health sciences chemistry.chemical_compound Mice Physiology (medical) Internal medicine medicine Animals Humans In patient Intestinal Mucosa Gastrointestinal Transit Linaclotide Chronic constipation Hepatology biology business.industry Sodium-Hydrogen Exchanger 3 Gastrointestinal transit medicine.disease Cystic fibrosis transmembrane conductance regulator Intestines Mice Inbred C57BL Sodium–hydrogen antiporter 030104 developmental biology Mechanism of action chemistry Intestinal Absorption biology.protein medicine.symptom Caco-2 Cells business Peptides Research Article |
| Zdroj: | Am J Physiol Gastrointest Liver Physiol |
| ISSN: | 1522-1547 |
| Popis: | Gastrointestinal dysfunction in cystic fibrosis (CF) is a prominent source of pain among patients with CF. Linaclotide, a guanylate cyclase C (GCC) receptor agonist, is a US Food and Drug Administration-approved drug prescribed for chronic constipation but has not been widely used in CF, as the cystic fibrosis transmembrane conductance regulator (CFTR) is the main mechanism of action. However, anecdotal clinical evidence suggests that linaclotide may be effective for treating some gastrointestinal symptoms in CF. The goal of this study was to determine the effectiveness and mechanism of linaclotide in treating CF gastrointestinal disorders using CF mouse models. Intestinal transit, chloride secretion, and intestinal lumen fluidity were assessed in wild-type and CF mouse models in response to linaclotide. CFTR and sodium/hydrogen exchanger 3 (NHE3) response to linaclotide was also evaluated. Linaclotide treatment improved intestinal transit in mice carrying either F508del or null Cftr mutations but did not induce detectable Cl− secretion. Linaclotide increased fluid retention and fluidity of CF intestinal contents, suggesting inhibition of fluid absorption. Targeted inhibition of sodium absorption by the NHE3 inhibitor tenapanor produced improvements in gastrointestinal transit similar to those produced by linaclotide treatment, suggesting that inhibition of fluid absorption by linaclotide contributes to improved gastrointestinal transit in CF. Our results demonstrate that linaclotide improves gastrointestinal transit in CF mouse models by increasing luminal fluidity through inhibiting NHE3-mediated sodium absorption. Further studies are necessary to assess whether linaclotide could improve CF intestinal pathologies in patients. GCC signaling and NHE3 inhibition may be therapeutic targets for CF intestinal manifestations. NEW & NOTEWORTHY Linaclotide’s primary mechanism of action in alleviating chronic constipation is through cystic fibrosis transmembrane conductance regulator (CFTR), negating its use in patients with cystic fibrosis (CF). For the first time, our findings suggest that in the absence of CFTR, linaclotide can improve fluidity of the intestinal lumen through the inhibition of sodium/hydrogen exchanger 3. These findings suggest that linaclotide could improve CF intestinal pathologies in patients. |
| Databáze: | OpenAIRE |
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