A prominent increase in blood vessel number, vascular remodeling and vascular leakage has been demonstrated in asthma. VEGF is also present in exaggerated quantities in asthmatic airways. However, the mechanisms that generate asthmatic vascular alterations, the role of VEGF in these alterations and the possibility that VEGF contributes to the pathogenesis of the inflammatory, immune, structural and physiologic responses that are characteristic of asthma has not been investigated. Studies designed to define the roles of VEGF in asthma demonstrated that: (1) VEGF is produced during innate immune responses elicited by viruses and is stimulated by IL-13; (2) VEGF165 induces asthma-like airway inflammation, edema, vascular remodeling, mucus metaplasia, fibrosis, myocyte hyperplasia and airways hyperresponsiveness (AHR) via IL-13-dependent and -independent pathways; (3) VEGF165 augments respiratory Th2 antigen sensitization while increasing the number, activation and function of pulmonary dendritic cells and (4) VEGF is produced by epithelial cells, macrophages and Th2 cells in antigen-induced inflammation where it plays a critical role inTh2 inflammation, cytokine elaboration and AHR. These studies led to the following hypotheses: 1. Angiogenesis and or angiogenic regulators play critical roles in Th2 inflammation and airway remodeling. 2. VEGF is a critical mediator in Th2 inflammation that: (a) induces inflammation, vascular and parenchymal remodeling and AHR; (b) serves as a link between innate and adaptive immunity by predisposing to Th2 sensitization and augmenting Th2 inflammation; (c) is produced by epithelial cells, macrophages and T cells and required for optimal IL-4 and IL-13 production and AHR at sites of adaptive Th2 inflammation; (d) is stimulated by and mediates many of the tissue effects of IL-13 and (e) mediates its effects via complex mechanisms that involve angiogenesis, vascular leak and immaturity, DC alterations, nitric oxide (NO) and or IL-13. To test this hypothesis we will:
Aim #1. Characterize the effects of VEGF, alone and in combination, with angiopoietin (Ang) -1 and Ang-2 in the murine lung/airway.
Aim #2. Characterize the roles of VEGF in antigen-induced Th2 inflammation, Th2 cell development and activation and the pathogenesis of the tissue effects of IL-13.
Aim #3. Characterize the importance of VEGF-induced neovascularization, vascular immaturity and leak, DC alterations, NO and IL-13 in the pathogenesis of the respiratory effects of VEGF.
Aim #4. Characterize the reversibility of the inflammatory, immune and remodeling effects of VEGF.
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