title: Airway remodeling is absent in CCR1-/- mice during chronic fungal allergic airway disease.
abstract: Asthmatic-like reactions characterized by elevated IgE, Th2 cytokines, C-C chemokines, eosinophilic inflammation, and persistent airway hyperresponsiveness follow pulmonary exposure to the spores or conidia from Aspergillus fumigatus fungus in sensitized individuals. In addition to these features, subepithelial fibrosis and goblet cell hyperplasia characterizes fungal-induced allergic airway disease in mice. Because lung concentrations of macrophage inflammatory protein-1alpha and RANTES were significantly elevated after A. fumigatus-sensitized mice received an intrapulmonary challenge with A. fumigatus spores or conidia, the present study addressed the role of their receptor, C-C chemokine receptor 1 (CCR1), in this model. A. fumigatus-sensitized CCR1 wild-type (+/+) and CCR1 knockout (-/-) mice exhibited similar increases in serum IgE and polymorphonuclear leukocyte numbers in the bronchoalveolar lavage. Airway hyperresponsiveness was prominent in both groups of mice at 30 days after an intrapulmonary challenge with A. fumigatus spores or conidia. However, whole lung levels of IFN-gamma were significantly higher whereas IL-4, IL-13, and Th2-inducible chemokines such as C10, eotaxin, and macrophage-derived chemokine were significantly lower in whole lung samples from CCR1-/- mice compared with CCR1+/+ mice at 30 days after the conidia challenge. Likewise, significantly fewer goblet cells and less subepithelial fibrosis were observed around large airways in CCR1-/- mice at the same time after the conidia challenge. Thus, these findings demonstrate that CCR1 is a major contributor to the airway remodeling responses that arise from A. fumigatus-induced allergic airway disease.
authors.affiliation: Department of Pathology and Division of Pulmonary and Critical Care, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: K
authors.initials: K
authors.lastname: Blease
authors.forename: B
authors.initials: B
authors.lastname: Mehrad
authors.forename: T J
authors.initials: TJ
authors.lastname: Standiford
authors.forename: N W
authors.initials: NW
authors.lastname: Lukacs
authors.forename: S L
authors.initials: SL
authors.lastname: Kunkel
authors.forename: S W
authors.initials: SW
authors.lastname: Chensue
authors.forename: B
authors.initials: B
authors.lastname: Lu
authors.forename: C J
authors.initials: CJ
authors.lastname: Gerard
authors.forename: C M
authors.initials: CM
authors.lastname: Hogaboam
mesh_terms: D000818:Animals; D001229:Aspergillosis, Allergic Bronchopulmonary / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D001232:Aspergillus fumigatus / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000209:etiology / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000378:metabolism; D018925:Chemokines / Q000096:biosynthesis; D002908:Chronic Disease; D016207:Cytokines / Q000378:metabolism / Q000502:physiology; D007073:Immunoglobulin E / Q000097:blood; D007371:Interferon-gamma / Q000378:metabolism; D008168:Lung / Q000737:chemistry / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018655:Lymphocyte Count; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000819:agonists / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D013172:Spores, Fungal / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: C515301:Ccr1 protein, mouse; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D018925:Chemokines; D016207:Cytokines; D019402:Macrophage Inflammatory Proteins; D012333:RNA, Messenger; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D007073:Immunoglobulin E; D007371:Interferon-gamma