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Department of Pathobiology and Department of Pulmonary, Allergy and Critical Care Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195
Increased numbers of submucosal vessels are a consistent pathologic component of asthmatic airway remodeling. However, the relationship between new vessel formation and asthmatic inflammatory response is unknown. We hypothesized that angiogenesis is a primary event during the initiation of airway inflammation and is linked to the recruitment of bone marrow-derived endothelial progenitor cells (EPC). To test this hypothesis, circulating EPC and EPC-derived endothelial cell colony formation of individuals with asthma or allergic rhinitis and health controls was evaluated. Circulating EPC were increased in asthma, highly proliferative, and exhibited enhanced incorporation into endothelial cell tubes as compared with controls. In an acute allergen challenge murine asthma model, EPC mobilization occurred within hours of challenge and mobilized EPC were selectively recruited into the challenged lungs of sensitized animals, but not into other organs. EPC recruitment was Th1 and Th2 dependent and was temporally associated with an increased microvessel density that was noted within 48 h of allergen challenge, indicating an early switch to an angiogenic lung environment. A chronic allergen challenge model provided evidence that EPC recruitment to the lung persisted and was associated with increasing microvessel density over time. Thus, a Th1- and Th2-dependent angiogenic switch with EPC mobilization, recruitment, and increased lung vessel formation occurs early but becomes a sustained and cumulative component of the allergen-induced asthmatic response.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported National Institutes of Health Grants HL60917, HL69170, AI70649, HL081064, AI067816, and HL04449 and National Center for Research Resources Grant M01 RR018390.
2 Address correspondence and reprint requests to Dr. Serpil Erzurum, Lerner Research Institute, Cleveland Clinic, Department of Pathobiology, NC22, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail address: erzurus{at}ccf.org
3 Abbreviations used in this paper: EC, endothelial cell; BAL, bronchoalveolar lavage; Dil-AcLDL, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine-acetylated low density lipoprotein; EPC, endothelial progenitor cell; EPC-EC, EPC-derived EC; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; MVD, microvessel density; PC20, provocative concentration that causes a 20% fall in FEV1; VE, vascular endothelial; VEGF, VE growth factor; VEGFR2, VEGF receptor 2; VWF, von Willebrand factor.
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