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Am J Physiol Gastrointest Liver Physiol 292: G839-G848, 2007. First published November 9, 2006; doi:10.1152/ajpgi.00582.2005
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LIVER AND BILIARY TRACT

Long-term docosahexaenoic acid therapy in a congenic murine model of cystic fibrosis

Programs in ¹Integrative Biology, ²Population Health Sciences, and ³Laboratory Animal Services, The Research Institute, and Departments of ⁴Pediatrics and ⁵Pathology, Hospital for Sick Children, and Departments of ⁶Pediatrics and ⁷Public Health Sciences, University of Toronto, Toronto, Ontario, Canada; ⁸Department of Pathology, Weill Medical College of Cornell University, New York, New York; Departments of ⁹Medicine and ¹⁰Pathology, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Massachusetts; and ¹¹Department of Animal Care and Veterinary Services, University of Western Ontario, London, Ontario, Canada

Submitted 27 December 2005 ; accepted in final form 8 November 2006

We used a congenic C57Bl/6J cystic fibrosis transmembrane conductance regulator (Cftr)^–/– mouse model, which develops cystic fibrosis (CF)-like pathology in all organs, to evaluate the short- and long-term therapeutic effects of dietary docosahexaenoic acid (DHA). Thirty-day-old Cftr^–/– mice and wild-type littermates were randomized to receive a liquid diet with or without DHA (40 mg/day). Animals were killed for histological and lipid analysis after 7, 30, and 60 days of therapy. DHA had no significant therapeutic or harmful effect on the lung, pancreas, or ileum of the Cftr^–/– mice or their wild-type littermates. In contrast, dietary DHA resulted in highly significant amelioration of the severity of liver disease in the Cftr^–/– mice, primarily a reduction in the degree of peri-portal inflammation. Additionally, these detailed measurements confirm our previous findings that Cftr^–/– mice have significant alterations in the pancreas (except external acinar diameter), ileum, liver, lung, and salivary (except sublingual) glands at all ages compared with their age-matched wild-type littermates. In conclusion, inhibition of cytokines and/or eicosanoid metabolism and release of endogenous inhibitors of inflammation by DHA may account for the anti-inflammatory effects in the liver of this congenic murine model of CF. The potential therapeutic benefits of DHA in severe CF-associated liver disease remain to be explored.

cystic fibrosis transmembrane conductance regulator; postnatal organ development; anti-inflammatory effect; cystic fibrosis-associated liver disease