title: Pericytes contribute to airway remodeling in a mouse model of chronic allergic asthma.
abstract: Myofibroblast accumulation, subepithelial fibrosis, and vascular remodeling are complicating features of chronic asthma, but the mechanisms are not clear. Platelet-derived growth factors (PDGFs) regulate the fate and function of various mesenchymal cells and have been implicated as mediators of lung fibrosis. However, it is not known whether PDGF-BB signaling via PDGFRβ, which is critical for the recruitment of pericytes to blood vessels, plays a role in airway remodeling in chronic asthma. In the present study, we used a selective PDGFRβ inhibitor (CP-673451) to investigate the role of PDGFRβ signaling in the development of airway remodeling and lung dysfunction in an established mouse model of house dust mite-induced chronic allergic asthma. Unexpectedly, we found that pharmacological inhibition of PDGFRβ signaling in the context of chronic aeroallergen exposure led to exacerbated lung dysfunction and airway smooth muscle thickening. Further studies revealed that the inflammatory response to aeroallergen challenge in mice was associated with decreased PDGF-BB expression and the loss of pericytes from the airway microvasculature. In parallel, cells positive for pericyte markers accumulated in the subepithelial region of chronically inflamed airways. This process was exacerbated in animals treated with CP-673451. The results indicate that perturbed PDGF-BB/PDGFRβ signaling and pericyte accumulation in the airway wall may contribute to airway remodeling in chronic allergic asthma.
authors: Department of Medical Biochemistry and Biophysics, Matrix Division, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden; Leukocyte Biology Section, National Heart and Lung Institute, Sir Alexander Fleming Building, Imperial College London, London, United Kingdom; and jill.johnson@imperial.ac.uk.
authors: Jill R
authors: http://orcid.org/0000-0002-5149-0084
authors: JR
authors: Johnson
authors: Department of Medical Biochemistry and Biophysics, Matrix Division, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden;
authors: Erika
authors: E
authors: Folestad
authors: Leukocyte Biology Section, National Heart and Lung Institute, Sir Alexander Fleming Building, Imperial College London, London, United Kingdom; and.
authors: Jessica E
authors: JE
authors: Rowley
authors: Leukocyte Biology Section, National Heart and Lung Institute, Sir Alexander Fleming Building, Imperial College London, London, United Kingdom; and.
authors: Elisa M
authors: EM
authors: Noll
authors: Leukocyte Biology Section, National Heart and Lung Institute, Sir Alexander Fleming Building, Imperial College London, London, United Kingdom; and.
authors: Simone A
authors: SA
authors: Walker
authors: Leukocyte Biology Section, National Heart and Lung Institute, Sir Alexander Fleming Building, Imperial College London, London, United Kingdom; and.
authors: Clare M
authors: CM
authors: Lloyd
authors: Leukocyte Biology Section, National Heart and Lung Institute, Sir Alexander Fleming Building, Imperial College London, London, United Kingdom; and.
authors: Sara M
authors: SM
authors: Rankin
authors: Department of Medical Biochemistry and Biophysics, Matrix Division, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden; Lund University, Department of Laboratory Medicine Lund, Lund, Sweden.
authors: Kristian
authors: K
authors: Pietras
authors: Department of Medical Biochemistry and Biophysics, Matrix Division, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden;
authors: Ulf
authors: U
authors: Eriksson
authors: Department of Medical Biochemistry and Biophysics, Matrix Division, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden;
authors: Jonas
authors: J
authors: Fuxe
mesh_terms: D056151:Airway Remodeling; D000403:Airway Resistance; D000818:Animals; D001249:Asthma / Q000473:pathology* / Q000503:physiopathology; D000077214:Becaplermin; D001562:Benzimidazoles / Q000494:pharmacology; D001980:Bronchi / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002908:Chronic Disease; D004195:Disease Models, Animal; D004548:Elasticity; D005260:Female; D008810:Mice, Inbred C57BL; D009130:Muscle, Smooth / Q000473:pathology; D020286:Pericytes / Q000502:physiology*; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001562:Benzimidazoles; C497448:CP-673,451; D020574:Proto-Oncogene Proteins c-sis; D011804:Quinolines; D000077214:Becaplermin; D020797:Receptor, Platelet-Derived Growth Factor beta
keywords: airway hyperresponsiveness; asthma; house dust mite; pericyte; remodeling
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