Chemokine-mediated angiogenesis: an essential link in the evolution of airway fibrosis?
Ivor S. Douglas, Mark R. Nicolls
Ivor S. Douglas, Mark R. Nicolls
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Commentary

Chemokine-mediated angiogenesis: an essential link in the evolution of airway fibrosis?

Abstract

Angiogenesis may be an important factor in the development of fibrotic lung disease. Prior studies have strongly suggested a role for angiogenic vascular remodeling in pulmonary fibrosis, and emerging evidence indicates that new vessel formation is critical in airway fibrosis. Bronchiolitis obliterans syndrome is a fibrotic occlusion of distal airways that is largely responsible for the morbidity and mortality of patients after lung transplantation. In this issue, Belperio et al. demonstrate a role for CXC chemokine receptor 2 in the regulation of angiogenesis-mediated airway fibroproliferation. By integrating an understanding of neovascularization into the study of events that occur between inflammation and fibrosis, it becomes increasingly possible to rationally design therapies that can halt conditions of maladaptive fibrosis.

Authors

Ivor S. Douglas, Mark R. Nicolls

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Figure 1

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Evolution of BOS from airway injury to angiofibroproliferation. (A) The ...
Evolution of BOS from airway injury to angiofibroproliferation. (A) The progression of airway pathology from initial injury to luminal and subepithelial fibrosis begins with cellular infiltration consisting of macrophages (a significant source of CXCL2), neutrophils, and subsequently T lymphocytes. Infiltrating cells and injured lung parenchyma (e.g., epithelial cells, vascular endothelial cells) liberate a variety of cytokines, oxidants, and chemokines. One prominently expressed chemokine, CXCL2, binds to receptors on neutrophils and vascular endothelium, simultaneously promoting a neutrophil influx and angiogenesis. Following cellular infiltration, the respiratory epithelium is likely injured, and pseudostratified columnar epithelium undergoes apoptosis and is transformed into a flattened, dysplastic monolayer that covers the basement membrane. (B) During a period when the epithelium is undergoing progressive injury, angiogenesis likely occurs through a CXCR2-dependent, VEGF-independent process (2). While the mechanism by which angiogenesis contributes to progressive airway fibrosis has not yet been fully elucidated, it is possible that increased vascularity facilitates the delivery of growth factors that promote tissue remodeling (e.g., platelet-derived growth factor-2 [PDGF2]) or cells that differentiate to produce collagen (e.g., fibrocytes). The concurrent and persistent immune epithelial injury may result in epithelial-myofibroblast crosstalk that promotes new collagen synthesis (22) through paracrine growth factor signaling and epithelial-to-mesenchymal transition (EMT). As subepithelial fibrosis increases and the respiratory epithelium becomes less distinct, increased deposition in the airway lumen of type I and III collagen occurs. Eventually, this fibrosis culminates as BOS, a physiologically significant occlusion of the airways in lung transplant recipients, which is the hallmark of chronic lung transplant rejection. PMN, polymorphonuclear neutrophil; ET-1, endothelin-1; EGF, epidermal growth factor.