-
[show abstract]
[hide abstract]
ABSTRACT: Cystic fibrosis liver disease (CFLD) is a rapidly progressive biliary fibrosis, resembling primary sclerosing cholangitis that develops in 5-10% of patients with cystic fibrosis. Further research and evaluation of therapies are hampered by the lack of a mouse model for CFLD. Although primary sclerosing cholangitis is linked to both ulcerative colitis and loss of cystic fibrosis transmembrane conductance regulator (CFTR) ion channel function, induction of colitis with dextran sodium sulfate (DSS) in cftr(-/-) mice causes bile duct injury but no fibrosis. Since profibrogenic modifier genes are linked to CFLD, we examined whether subthreshhold doses of the profibrogenic xenobiotic 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), along with DSS-induced colitis, lead to bile duct injury and liver fibrosis in mice that harbor loss of CFTR function. Exon 10 heterozygous (cftr(+/-)) and homozygous (cftr(-/-)) mice treated with DDC demonstrated extensive mononuclear cell inflammation, bile duct proliferation, and periductular fibrosis. In contrast, wild-type (cftr(+/+)) littermates did not develop bile duct injury or fibrosis. Histological changes corresponded to increased levels of alkaline phosphatase, hydroxyproline, and expression of profibrogenic transcripts for transforming growth factor-β(1), transforming growth factor-β(2), procollagen α(1)(I), and tissue inhibitor of matrix metaloproteinase-1. Immunohistochemistry demonstrated fibrosis and activation of periductal fibrogenic cells based on positive staining for lysyl oxidase-like-2, α-smooth muscle actin, and collagen I. These data demonstrate that subthreshold doses of DDC, in conjunction with DSS-induced colitis, results in bile duct injury and periductal fibrosis in mice with partial or complete loss of CFTR function and may represent a useful model to study the pathogenic mechanisms by which CFTR dysfunction predisposes to fibrotic liver disease and potential therapies.
AJP Gastrointestinal and Liver Physiology 06/2012; 303(4):G474-81. · 3.43 Impact Factor
-
Camilia R Martin,
Deborah A Dasilva,
Joanne E Cluette-Brown,
Clementina Dimonda,
Ashley Hamill, Abdul Q Bhutta,
Emmanuel Coronel,
Michael Wilschanski,
Alisa J Stephens,
David F Driscoll,
Bruce R Bistrian,
James H Ware,
Munir M Zaman,
Steven D Freedman
[show abstract]
[hide abstract]
ABSTRACT: To measure the changes in whole blood fatty acid levels in premature infants and evaluate associations between these changes and neonatal morbidities.
This was a retrospective cohort study of 88 infants born at <30 weeks' gestation. Serial fatty acid profiles during the first postnatal month and infant outcomes, including chronic lung disease (CLD), retinopathy of prematurity, and late-onset sepsis, were analyzed. Regression modeling was applied to determine the association between fatty acid levels and neonatal morbidities.
Docosahexaenoic acid (DHA) and arachidonic acid levels declined rapidly in the first postnatal week, with a concomitant increase in linoleic acid levels. Decreased DHA level was associated with an increased risk of CLD (OR, 2.5; 95% CI, 1.3-5.0). Decreased arachidonic acid level was associated with an increased risk of late-onset sepsis (hazard ratio, 1.4; 95% CI, 1.1-1.7). The balance of fatty acids was also a predictor of CLD and late-onset sepsis. An increased linoleic acid:DHA ratio was associated with an increased risk of CLD (OR, 8.6; 95% CI, 1.4-53.1) and late-onset sepsis (hazard ratio, 4.6; 95% CI, 1.5-14.1).
Altered postnatal fatty acid levels in premature infants are associated with an increased risk of CLD and late-onset sepsis.
The Journal of pediatrics 06/2011; 159(5):743-749.e1-2. · 4.02 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Cystic fibrosis (CF) patients display a fatty acid imbalance characterized by low linoleic acid levels and variable changes in arachidonic acid. This led to the recommendation that CF patients consume a high-fat diet containing >6% linoleic acid. We hypothesized that increased conversion of linoleic acid to arachidonic acid in CF leads to increased levels of arachidonate-derived proinflammatory metabolites and that this process is exacerbated by increasing linoleic acid levels in the diet. To test this hypothesis, we determined the effect of linoleic acid supplementation on downstream proinflammatory biomarkers in two CF models: 1) in vitro cell culture model using 16HBE14o(-) sense [wild-type (WT)] and antisense (CF) human airway epithelial cells; and 2) in an in vivo model using cftr(-/-) transgenic mice. Fatty acids were analyzed by gas chromatography-mass spectrometry (GC/MS), and IL-8 and eicosanoids were measured by ELISA. Neutrophils were quantified in bronchoalveolar lavage fluid from knockout mice following linoleic acid supplementation and exposure to aerosolized Pseudomonas LPS. Linoleic acid supplementation increased arachidonic acid levels in CF but not WT cells. IL-8, PGE(2), and PGF(2α) secretion were increased in CF compared with WT cells, with a further increase following linoleic acid supplementation. cftr(-/-) Mice supplemented with 100 mg of linoleic acid had increased arachidonic acid levels in lung tissue associated with increased neutrophil infiltration into the airway compared with control mice. These findings support the hypothesis that increasing linoleic acid levels in the setting of loss of cystic fibrosis transmembrane conductance regulator (CFTR) function leads to increased arachidonic acid levels and proinflammatory mediators.
AJP Lung Cellular and Molecular Physiology 11/2010; 299(5):L599-606. · 3.66 Impact Factor
