title: Increased susceptibility of Cftr-/- mice to LPS-induced lung remodeling.
abstract: Cystic fibrosis (CF) is caused by homozygous mutations of the CF transmembrane conductance regulator (CFTR) Cl(-) channel, which result in chronic pulmonary infection and inflammation, the major cause of morbidity and mortality. Although these processes are clearly related to each other, each is likely to contribute to the pathology differently. Understanding the contribution of each of these processes to the overall pathology has been difficult, because they are usually so intimately connected. Various CF mouse models have demonstrated abnormal immune responses compared with wild-type (WT) littermates when challenged with live bacteria or bacterial products acutely. However, these studies have not investigated the consequences of persistent inflammation on lung tissue in CF mice, which may better model the lung pathology in patients. We characterized the lung pathology and immune response of Cftr(-/-) (CF) and Cftr(+/+) (WT) mice to chronic administration of Pseudomonas aeruginosa lipopolysaccharide (LPS). We show that, after long-term repeated LPS exposure, CF mice develop an abnormal and persistent immune response, which is associated with more robust structural changes in the lung than those observed in WT mice. Although CF mice and their WT littermates develop lung pathology after chronic exposure to LPS, the inflammation and damage resolve in WT mice. However, CF mice do not recover efficiently, and, as a consequence of their chronic inflammation, CF mice are more susceptible to morphological changes and lung remodeling. This study shows that chronic inflammation alone contributes significantly to aspects of CF lung pathology.
authors: Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut;
authors: Emanuela M
authors: EM
authors: Bruscia
authors: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut;
authors: Ping-Xia
authors: PX
authors: Zhang
authors: Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut;
authors: Christina
authors: C
authors: Barone
authors: Department of Cell Biology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors: Bob J
authors: BJ
authors: Scholte
authors: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut;
authors: Robert
authors: R
authors: Homer
authors: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut; Department of Pathology, Yale University School of Medicine, New Haven, Connecticut;
authors: Diane S
authors: DS
authors: Krause
authors: Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut; and marie.egan@yale.edu.
authors: Marie E
authors: ME
authors: Egan
mesh_terms: D056151:Airway Remodeling; D000818:Animals; D054357:Chemokine CXCL10 / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000276:immunology / Q000473:pathology*; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018181:Mice, Inbred CFTR; D018345:Mice, Knockout; D011014:Pneumonia / Q000276:immunology* / Q000473:pathology; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D008070:Lipopolysaccharides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: IFN-γ-induced protein 10; cystic fibrosis; inflammation