Pericytes contribute to airway remodeling in a mouse model of chronic allergic asthma

Jill R Johnson,Jonas Fuxe,Elisa M Noll,Clare M Lloyd,Simone A Walker,Ulf Eriksson,Erika Folestad,Kristian Pietras,Jessica E Rowley,Sara M Rankin

doi:10.1152/ajplung.00286.2014

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.

Highlights

ASTHMA IS A HETEROGENIC DISEASE that currently affects 300 million people worldwide [34]
Impaired pericyte coverage of blood vessels is seen in PDGFBB-deficient mice and in diseases like cancer and is associated with vascular leakage and edema [2, 4, 32]. In light of these findings, and since tyrosine kinase inhibitors such as masitinib are currently being investigated as asthma therapies [16], we elected to investigate the impact of PDGFR␤ inhibition on airway and vascular smooth muscle (VSM) cells/pericytes in a mouse model of chronic aeroallergen exposure driven by exposure to house dust mite (HDM) extract via the respiratory
Chronic allergic asthma is a complex disease provoked by aeroallergen exposure, which promotes Th2-polarized airway inflammation [13] and airway remodeling [1], for which a number of possible underlying mechanisms have been proposed [7, 12, 19, 20, 22, 26, 30]

Summary

Introduction

ASTHMA IS A HETEROGENIC DISEASE that currently affects 300 million people worldwide [34]. Impaired pericyte coverage of blood vessels is seen in PDGFBB-deficient mice and in diseases like cancer and is associated with vascular leakage and edema [2, 4, 32] In light of these findings, and since tyrosine kinase inhibitors such as masitinib are currently being investigated as asthma therapies [16], we elected to investigate the impact of PDGFR␤ inhibition on airway and VSM cells/pericytes in a mouse model of chronic aeroallergen exposure driven by exposure to house dust mite (HDM) extract via the respiratory. Chronic respiratory HDM exposure leads to Th2-polarized airway inflammation, remodeling of the airway wall and bronchial hyperreactivity, and recapitulates many of the features of clinical asthma [21] Using this paradigm, we investigated the role of PDGFR␤ signaling and the downstream effects of inhibiting this receptor during chronic HDM exposure on airway remodeling and lung dysfunction

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