Talniflumate increases survival in a cystic fibrosis mouse model of distal intestinal obstructive syndrome

Nancy M. Walker, Janet E. Simpson, Roy C Levitt, Kathryn T. Boyle, Lane L. Clarke

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Intestinal disease in cystic fibrosis (CF) mice closely mirrors aspects of obstructive syndromes in CF patients. The pathogenesis involves accumulation of mucoid debris in the crypts that fuse with intestinal content to form obstructing mucofeculant impactions. Treatment involves modalities that increase the fluidity of the luminal content, such as osmotic laxatives and liquid diets. We investigated the effects of talniflumate (Lomucin, Genaera Corporation, Plymouth Meeting, PA), a compound that may be beneficial to treatment of CF intestinal disease based on three mechanisms of action: mucus synthesis inhibition by blockade of the murine calcium-activated chloride channel 3 (mCLCA3), nonsteroidal anti-inflammatory effects, and inhibition of Cl-/HCO3- exchanger(s) involved in intestinal NaCl absorption. Cohorts of CF mice were fed control diet or diets containing either talniflumate (0.4 mg/g chow) or ibuprofen (0.4 mg/g chow) for 21 days to assess survival. Talniflumate significantly increased CF mouse survival from 26 to 77%, whereas ibuprofen had no effect (22% survival). Oral talniflumate did not alter crypt goblet cell numbers or change intestinal expression of mCLCA3 but tended to decrease crypt mucoid impaction. Ussing chamber studies indicated that talniflumate slightly increased the basal short-circuit current of CF intestine, but the change was not sensitive to secretagogue stimulation or bumetanide inhibition. In contrast, intracellular pH measurements of intact intestinal villous epithelium indicated that talniflumate significantly inhibited apical membrane Cl-/HCO3- exchange by >50%. We conclude that oral talniflumate increases the survival of CF mice, possibly by the beneficial effects of decreasing small intestinal NaCl absorption through the inhibition of apical membrane Cl-/HCO 3- exchanger(s).

Original languageEnglish
Pages (from-to)275-283
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume317
Issue number1
DOIs
StatePublished - Apr 1 2006
Externally publishedYes

Fingerprint

Cystic Fibrosis
Survival
Intestinal Diseases
Chloride Channels
Ibuprofen
Intestinal Absorption
Diet
Chloride-Bicarbonate Antiporters
Bumetanide
Laxatives
Gastrointestinal Contents
Goblet Cells
Membranes
Mucus
Intestinal Mucosa
talniflumate
Intestines
Anti-Inflammatory Agents
Cell Count
Therapeutics

ASJC Scopus subject areas

  • Pharmacology

Cite this

Talniflumate increases survival in a cystic fibrosis mouse model of distal intestinal obstructive syndrome. / Walker, Nancy M.; Simpson, Janet E.; Levitt, Roy C; Boyle, Kathryn T.; Clarke, Lane L.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 317, No. 1, 01.04.2006, p. 275-283.

Research output: Contribution to journalArticle

Walker, Nancy M. ; Simpson, Janet E. ; Levitt, Roy C ; Boyle, Kathryn T. ; Clarke, Lane L. / Talniflumate increases survival in a cystic fibrosis mouse model of distal intestinal obstructive syndrome. In: Journal of Pharmacology and Experimental Therapeutics. 2006 ; Vol. 317, No. 1. pp. 275-283.
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abstract = "Intestinal disease in cystic fibrosis (CF) mice closely mirrors aspects of obstructive syndromes in CF patients. The pathogenesis involves accumulation of mucoid debris in the crypts that fuse with intestinal content to form obstructing mucofeculant impactions. Treatment involves modalities that increase the fluidity of the luminal content, such as osmotic laxatives and liquid diets. We investigated the effects of talniflumate (Lomucin, Genaera Corporation, Plymouth Meeting, PA), a compound that may be beneficial to treatment of CF intestinal disease based on three mechanisms of action: mucus synthesis inhibition by blockade of the murine calcium-activated chloride channel 3 (mCLCA3), nonsteroidal anti-inflammatory effects, and inhibition of Cl-/HCO3- exchanger(s) involved in intestinal NaCl absorption. Cohorts of CF mice were fed control diet or diets containing either talniflumate (0.4 mg/g chow) or ibuprofen (0.4 mg/g chow) for 21 days to assess survival. Talniflumate significantly increased CF mouse survival from 26 to 77{\%}, whereas ibuprofen had no effect (22{\%} survival). Oral talniflumate did not alter crypt goblet cell numbers or change intestinal expression of mCLCA3 but tended to decrease crypt mucoid impaction. Ussing chamber studies indicated that talniflumate slightly increased the basal short-circuit current of CF intestine, but the change was not sensitive to secretagogue stimulation or bumetanide inhibition. In contrast, intracellular pH measurements of intact intestinal villous epithelium indicated that talniflumate significantly inhibited apical membrane Cl-/HCO3- exchange by >50{\%}. We conclude that oral talniflumate increases the survival of CF mice, possibly by the beneficial effects of decreasing small intestinal NaCl absorption through the inhibition of apical membrane Cl-/HCO 3- exchanger(s).",
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