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.

Pericytes, mesenchymal stem cells and their contributions to tissue repair

“…These studies have confirmed the validity of pericyte markers used in humans by showing co-localisation between transgenic markers used and αSMA, PDGFRβ and CD146 (Johnson et al, 2015;Lin et al, 2008;Rock et al, 2011).…”

“…Identification of pericyte markers in mice is based on the use of lineage tracing techniques in transgenic mice, including nestin-GFP, NG2-DsRed and coll1α1-GFP mice in models of tissue fibrosis (Birbrair et al, 2013d;Johnson et al, 2015;Lin et al, 2008;Rock et al, 2011). These studies have confirmed the validity of pericyte markers used in humans by showing co-localisation between transgenic markers used and αSMA, PDGFRβ and CD146 (Johnson et al, 2015;Lin et al, 2008;Rock et al, 2011).…”

Acid-Sensing Ion Channel 1a Contributes to Airway Hyperreactivity in Mice

“…As expected, OVA-sensitization induced AHR in wild-type mice (Fig 2B and 2C). The degree of AHR was consistent with previous reports in C57Bl/6 mice [55, 66]. In contrast, OVA-sensitization failed to elicit AHR in ASIC1a -/- mice.…”

ROS-induced endothelial stress contributes to pulmonary fibrosis through pericytes and Wnt signaling

“…A Andersson-Sjöland et al that inflammation may result in loss of microvascular pericyte coverage, 27,28 however as the inflammatory response in our model was relatively modest, this appeared unlikely. Yet, to investigate pericytes closer, we studied tissue from controls and 2w (when inflammation peaks) using TEM.…”