title: Microfibrillar-associated protein 4 modulates airway smooth muscle cell phenotype in experimental asthma.
abstract: BACKGROUND
  Recently, several proteins of the extracellular matrix have been characterised as active contributors to allergic airway disease. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein abundant in the lung, whose biological functions remain poorly understood. In the current study we investigated the role of MFAP4 in experimental allergic asthma.
  
  
  METHODS
  MFAP4-deficient mice were subjected to alum/ovalbumin and house dust mite induced models of allergic airway disease. In addition, human healthy and asthmatic primary bronchial smooth muscle cell cultures were used to evaluate MFAP4-dependent airway smooth muscle responses.
  
  
  RESULTS
  MFAP4 deficiency attenuated classical hallmarks of asthma, such as eosinophilic inflammation, eotaxin production, airway remodelling and hyperresponsiveness. In wild-type mice, serum MFAP4 was increased after disease development and correlated with local eotaxin levels. MFAP4 was expressed in human bronchial smooth muscle cells and its expression was upregulated in asthmatic cells. Regarding the underlying mechanism, we showed that MFAP4 interacted with integrin αvβ5 and promoted asthmatic bronchial smooth muscle cell proliferation and CCL11 release dependent on phosphatidyloinositol-3-kinase but not extracellular signal-regulated kinase pathway.
  
  
  CONCLUSIONS
  MFAP4 promoted the development of asthmatic airway disease in vivo and pro-asthmatic functions of bronchial smooth muscle cells in vitro. Collectively, our results identify MFAP4 as a novel contributor to experimental asthma, acting through modulation of airway smooth muscle cells.
authors.affiliation: Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Pilecki
authors.affiliation: Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Schlosser
authors.affiliation: Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Helle
authors.initials: H
authors.lastname: Wulf-Johansson
authors.affiliation: Department of Pharmacology, Bordeaux University, Cardio-thoracic Research Centre, U1045, Bordeaux, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Trian
authors.affiliation: Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Jesper B
authors.initials: JB
authors.lastname: Moeller
authors.affiliation: Department of Pathology, Odense University Hospital, Odense, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Marcussen
authors.affiliation: German Research Center for Environmental Health, German Mouse Clinic and Institute of Experimental Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany Department of Dermatology and Allergology am Biederstein, University Hospital Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Aguilar-Pimentel
authors.affiliation: German Research Center for Environmental Health, German Mouse Clinic and Institute of Experimental Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technical University Munich, Freising-Weihenstephan, Germany.
authors.forename: Martin Hrabe
authors.initials: MH
authors.lastname: de Angelis
authors.affiliation: Department of Respiratory Medicine, Gentofte Hospital, Hellerup, Denmark Manchester Academic Health Science Centre, University Hospital South Manchester NHS Foundation Trust, Manchester, UK.
authors.forename: Jorgen
authors.initials: J
authors.lastname: Vestbo
authors.affiliation: Department of Pharmacology, Bordeaux University, Cardio-thoracic Research Centre, U1045, Bordeaux, France Department of Lung Function Testing, Department of Thoracic Chirurgy, Department of Anatomy and Pathology, CHU Bordeaux Teaching Hospital, Pessac, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Berger
authors.affiliation: Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Uffe
authors.initials: U
authors.lastname: Holmskov
authors.affiliation: Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Grith L
authors.initials: GL
authors.lastname: Sorensen
mesh_terms: D000818:Animals; D001249:Asthma / Q000378:metabolism*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D002448:Cell Adhesion; D018929:Cell Culture Techniques; D049109:Cell Proliferation; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000378:metabolism*; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D002352:Carrier Proteins; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C400752:MFAP4 protein, human; C000600072:MFAP4 protein, mouse
keywords: Asthma Mechanisms