Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 7-Day Trial for You or Your Team.

Learn More →

Epithelial dysfunction associated with the development of colitis in conventionally housed mdr1a–/– mice

Epithelial dysfunction associated with the development of colitis in conventionally housed... P-glycoprotein, the product of the multidrug resistance protein 1 (MDR1) gene, is a xenobiotic transporter that may contribute to the physiology of the intestinal barrier. Twenty-five percent of mdr1a -deficient (mdr1a –/– ) mice spontaneously develop colitis at variable ages when maintained under specific pathogen-free conditions. We hypothesized that this disease would result from epithelial dysfunction and that conventional housing would increase incidence and severity of the colitis phenotype. Wild-type congenic FVB (+/+) mice were maintained under the same conditions as controls. Knockout and wild-type mice were matched for age and gender and observed for signs of colitis. Colonic tissues from both groups of mice were examined for macroscopic and microscopic injury and for basal ion transport and transepithelial resistance (TER). Translocation of bacteria across the intestine was assessed by culturing the spleen and mesenteric lymph nodes. Protein analysis was performed by Western blot analysis. All mdr1a –/– mice developed weight loss and signs of colitis, whereas wild-type mice never showed such signs. Within the mdr1a –/– group, males consistently developed severe colitis earlier than females. Knockout mice showed increased basal colonic ion transport (females, 162.7 ± 4.6 vs. 49.7 ± 3.8 µA/cm 2 ; males, 172.6 ± 5.6 vs. 54.2 ± 3.1 µA/cm 2 ; P < 0.01) and decreased TER (females, 25.4 ± 0.3 vs. 36.4 ± 0.8 Ω·cm 2 ; males, 23.1 ± 1.0 vs . 38.3 ± 0.2 Ω·cm 2 ; P < 0.01) compared with wild-type mice. Barrier dysfunction was accompanied by decreased phosphorylation of tight junction proteins. Expression of cyclooxygenase-2 and inducible nitric oxide synthase in intestinal tissues was increased in the mdr1a –/– group ( P < 0.01) and correlated with disease severity. Bacterial translocation was greater both in incidence ( P < 0.01) and severity ( P < 0.001) for the knockout group. With respect to all indexes studied, mdr1a –/– males performed worse than females. Our data support the hypothesis that alterations in the intestinal barrier alone, in the absence of immune dysfunction, may rapidly lead to colitis in the setting of a normal colonic flora. animal models; gender differences; barrier function Address for reprint requests and other correspondence: S. Resta-Lenert, UCSD Medical Center 8414, 200 West Arbor Drive, San Diego, CA 92103 (E-mail: [email protected] ) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png AJP - Gastrointestinal and Liver Physiology The American Physiological Society

Epithelial dysfunction associated with the development of colitis in conventionally housed mdr1a–/– mice

Download PDF
12 pages

Loading next page...
 
/lp/the-american-physiological-society/epithelial-dysfunction-associated-with-the-development-of-colitis-in-w4I0w0JfvQ

References (30)

Publisher
The American Physiological Society
Copyright
Copyright © 2011 the American Physiological Society
ISSN
0193-1857
eISSN
1522-1547
DOI
10.1152/ajpgi.00395.2004
pmid
15774938
Publisher site
See Article on Publisher Site

Abstract

P-glycoprotein, the product of the multidrug resistance protein 1 (MDR1) gene, is a xenobiotic transporter that may contribute to the physiology of the intestinal barrier. Twenty-five percent of mdr1a -deficient (mdr1a –/– ) mice spontaneously develop colitis at variable ages when maintained under specific pathogen-free conditions. We hypothesized that this disease would result from epithelial dysfunction and that conventional housing would increase incidence and severity of the colitis phenotype. Wild-type congenic FVB (+/+) mice were maintained under the same conditions as controls. Knockout and wild-type mice were matched for age and gender and observed for signs of colitis. Colonic tissues from both groups of mice were examined for macroscopic and microscopic injury and for basal ion transport and transepithelial resistance (TER). Translocation of bacteria across the intestine was assessed by culturing the spleen and mesenteric lymph nodes. Protein analysis was performed by Western blot analysis. All mdr1a –/– mice developed weight loss and signs of colitis, whereas wild-type mice never showed such signs. Within the mdr1a –/– group, males consistently developed severe colitis earlier than females. Knockout mice showed increased basal colonic ion transport (females, 162.7 ± 4.6 vs. 49.7 ± 3.8 µA/cm 2 ; males, 172.6 ± 5.6 vs. 54.2 ± 3.1 µA/cm 2 ; P < 0.01) and decreased TER (females, 25.4 ± 0.3 vs. 36.4 ± 0.8 Ω·cm 2 ; males, 23.1 ± 1.0 vs . 38.3 ± 0.2 Ω·cm 2 ; P < 0.01) compared with wild-type mice. Barrier dysfunction was accompanied by decreased phosphorylation of tight junction proteins. Expression of cyclooxygenase-2 and inducible nitric oxide synthase in intestinal tissues was increased in the mdr1a –/– group ( P < 0.01) and correlated with disease severity. Bacterial translocation was greater both in incidence ( P < 0.01) and severity ( P < 0.001) for the knockout group. With respect to all indexes studied, mdr1a –/– males performed worse than females. Our data support the hypothesis that alterations in the intestinal barrier alone, in the absence of immune dysfunction, may rapidly lead to colitis in the setting of a normal colonic flora. animal models; gender differences; barrier function Address for reprint requests and other correspondence: S. Resta-Lenert, UCSD Medical Center 8414, 200 West Arbor Drive, San Diego, CA 92103 (E-mail: [email protected] )

Journal

AJP - Gastrointestinal and Liver Physiology – The American Physiological Society

Published: Jul 1, 2005

There are no references for this article.