title: Ileal smooth muscle dysfunction and remodeling in cystic fibrosis.
abstract: Patients with cystic fibrosis (CF) often suffer from gastrointestinal cramps and intestinal obstruction. The CF transmembrane conductance regulator (CFTR) channel has been shown to be expressed in vascular and airway smooth muscle (SM). We hypothesized that the absence of CFTR expression alters the gastrointestinal SM function and that these alterations may show strain-related differences in the mouse. The aim of this study was to measure the contractile properties of the ileal SM in two CF mouse models. CFTR(-/-) and CFTR(+/+) mice were studied on BALB/cJ and C57BL/6J backgrounds. Responsiveness of ileal strips to electrical field stimulation (EFS), methacholine (MCh), and isoproterenol was measured. The mass and the cell density of SM layers were measured morphometrically. Finally, the maximal velocity of shortening (Vmax) and the expression of the fast (+)insert myosin isoform were measured in the C57BL/6J ileum. Ileal hyperreactivity was observed in response to EFS and MCh in CFTR(-/-) compared with CFTR(+/+) mice in C57BL/6J background. This latter observation was not reproduced by acute inhibition of CFTR with CFTR(inh)172. BALB/cJ CFTR(-/-) mice exhibited a significant increase of SM mass with a lower density of cells compared with CFTR(+/+), whereas no difference was observed in the C57BL/6J background. In addition, in this latter strain, ileal strips from CFTR(-/-) exhibited a significant increase in Vmax compared with control and expressed a greater proportion of the fast (+)insert SM myosin isoform with respect to total myosin. BALB/cJ CFTR(-/-) ilium had a greater relaxation to isoproterenol than the CFTR(+/+) mice when precontracted with EFS, but no difference was observed in response to exogeneous MCh. In vivo, the lack of CFTR expression induces a different SM ileal phenotype in different mouse strains, supporting the importance of modifier genes in determining intestinal SM properties.
authors.affiliation: Meakins-Christie Laboratories, McGill University, 3626 St.-Urbain St., Montréal, Québec, Canada. anne-marie.lauzon@mcgill.ca
authors.forename: P-A
authors.initials: PA
authors.lastname: Risse
authors.forename: L
authors.initials: L
authors.lastname: Kachmar
authors.forename: O S
authors.initials: OS
authors.lastname: Matusovsky
authors.forename: M
authors.initials: M
authors.lastname: Novali
authors.forename: F R
authors.initials: FR
authors.lastname: Gil
authors.forename: S
authors.initials: S
authors.lastname: Javeshghani
authors.forename: R
authors.initials: R
authors.lastname: Keary
authors.forename: C K
authors.initials: CK
authors.lastname: Haston
authors.forename: M-C
authors.initials: MC
authors.lastname: Michoud
authors.forename: J G
authors.initials: JG
authors.lastname: Martin
authors.forename: A-M
authors.initials: AM
authors.lastname: Lauzon
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D003550:Cystic Fibrosis / Q000473:pathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000502:physiology; D004558:Electric Stimulation; D007082:Ileum / Q000473:pathology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018721:Muscarinic Agonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009129:Muscle Tonus / Q000187:drug effects; D009130:Muscle, Smooth / Q000473:pathology*; D018995:Myosin Heavy Chains / Q000378:metabolism
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D018721:Muscarinic Agonists; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D018995:Myosin Heavy Chains; D007545:Isoproterenol