CXCR2 Mediates the Recruitment of Endothelial Progenitor Cells During Allergic Airways Remodeling

Abstract

Airway remodeling is a central feature of asthma and includes the formation of new peribronchial blood vessels, which is termed angiogenesis. In a number of disease models, bone marrow-derived endothelial progenitor cells (EPCs) have been shown to contribute to the angiogenic response. In this study we set out to determine whether EPCs were recruited into the lungs in a model of allergic airways disease and to identify the factors regulating EPC trafficking in this model. We observed a significant increase in the number of peribronchial blood vessels at day 24, during the acute inflammatory phase of the model. This angiogenic response was associated with an increase in the quantity of EPCs recoverable from the lung. These EPCs formed colonies after 21 days in culture and were shown to express CD31, von Willebrand factor, and vascular endothelial growth factor (VEGF) receptor 2, but were negative for CD45 and CD14. The influx in EPCs was associated with a significant increase in the proangiogenic factors VEGF-A and the CXCR2 ligands, CXCL1 and CXCL2. However, we show directly that, while the CXCL1 and CXCL2 chemokines can recruit EPCs into the lungs of allergen-sensitized mice, VEGF-A was ineffective in this respect. Further, the blockade of CXCR2 significantly reduced EPC numbers in the lungs after allergen exposure and led to a decrease in the numbers of peribronchial blood vessels after allergen challenge with no effect on inflammation. The data presented here provide in vivo evidence that CXCR2 is critical for both EPC recruitment and the angiogenic response in this model of allergic inflammation of the airways. STEM

IL-17A, But Not IL-17F, Is Indispensable for Airway Vascular Remodeling Induced by Exaggerated Th17 Cell Responses in Prolonged Ovalbumin-Challenged Mice

“…CXCR2 is expressed by EPCs in both humans and rodents (27,28). Recently, it has been shown that the ligation of CXCR2 with its ligands, CXCL1 and CXCL2, is critical for EPC recruitment into the lung of allergen-sensitized mice (29). In our FIGURE 8.…”

Transglutaminase II/MicroRNA-218/-181a Loop Regulates Positive Feedback Relationship between Allergic Inflammation and Tumor Metastasis

“…tor cell recruitment and the angiogenic response in this model of allergic inflammation of the airways (45). Human mast cells are both a source and a target of angiogenic factors and therefore might play a role in inflammatory and neoplastic angiogenesis through the expression of several forms of VEGFs and their receptors (46).…”

CXCL1 Inhibits Airway Smooth Muscle Cell Migration through the Decoy Receptor Duffy Antigen Receptor for Chemokines

“…Moreover, depending on disease status, the concentrations of CXCL1 measured in biological fluids of humans or animal models do not exceed 10 ng/ml (18,54,55). Therefore, using a narrower range of concentrations of CXCL1 to examine its effect on ASMC migration may better reflect its biological significance in asthmatic airways remodeling.…”

“…Although primarily known as a potent inducer of neutrophil chemotaxis (16), CXCL1 was shown to induce cancer cell invasion (17) and endothelial (18) and epithelial cell migration (19). CXCL1 facilitates its signaling by binding to its putative receptor, the chemokine receptor CXCR2, although it also was found to bind to CXCR1, albeit with lower affinity (20).…”