Eosinophil trafficking and chronic tissue damage induced by allergic inflammation

嗜酸性粒细胞从骨髓到组织的运输可能导致组织损伤和重塑 这是患有严重持续过敏性疾病的人类受试者中慢性过敏性炎症的特征 炎症嗜酸性粒细胞运输到组织的机制和后果是很难研究的， 人类实验对象因此，我们开发了一种新的小鼠模型，持续的嗜酸性粒细胞贩运从 骨髓到组织中的反应，这是一个模型，共享许多 在人类中具有持续的过敏性炎症特征。 我们建议使用这种新的小鼠模型来研究嗜酸性粒细胞如何在血管生成血管中运输， 过敏性炎症的部位，一旦进入组织有助于血管生成和纤维化。具体 目的#1和#2将重点研究嗜酸性粒细胞与血管生成血管内皮细胞的相互作用， 皮肤腔室模型，可直接观察血管中荧光标记的嗜酸性粒细胞 在皮肤舱里。嗜酸性粒细胞在血管生成血管中的粘附和血管通透性的变化将是 在用针对VEGF和其他血管生成细胞因子的中和Ab处理的小鼠中定量， 在持续的过敏性炎症部位表达。 在具体目标#3和#4中，我们建议确定TGF-β的不同亚型的贡献， 来源于嗜酸性粒细胞的组织纤维化，以及来源于嗜酸性粒细胞的成纤维细胞祖细胞运输的重要性 从骨髓组织到组织纤维化。 总的来说，这些研究将有助于确定持续的过敏性炎症对血管的作用， 组织变化，导致持续过敏部位持续组织肿胀和瘢痕形成 炎症这些研究可能会发现潜在的治疗靶点，可以减少组织损伤 以及在患有严重持续变态反应的人类受试者中持续变态反应性炎症部位的肿胀。

Trafficking of eosinophils from the bone marrow to tissues may contribute to tissue damage and remodeling which are features of chronic allergic inflammation in human subjects with severe ongoing allergic inflammation. The mechanism and consequence of eosinophil trafficking to tissues is difficult to study in human subjects. We have therefore developed a novel mouse model of sustained eosinophil trafficking from bone marrow to tissues in response to repetitive allergen challenge which is a model that shares many features with ongoing allergic inflammation in humans. We propose to use this novel mouse model to investigate how eosinophils traffic in angiogenic vesselsat sites of allergic inflammation, and once in the tissues contribute to angiogenesis and fibrosis. Specific aims#1 and #2 will focus on studying the interaction of eosinophils with endothelium in angiogenic vessels in a skin chamber model which allows direct visualization of fluorescently labeled eosinophils in bloodvessels in the skin chamber. Eosinophil adhesion in angiogenic vessels and vascular permeability changes will be quantitated in mice treated with neutralizing Abs to VEGF and other angiogenic cytokines identified to be expressed at sites of ongoing allergic inflammation. In specific aims #3 and #4, we propose to determine the contribution of different isoforms of TGF-beta derived from eosinophils to tissue fibrosis, as well as the importance of fibroblast progenitor trafficking from the bone marrow tissue to tissue fibrosis. Overall these studies will help to determine the role of ongoing allergic inflammation to blood vesseland tissue changes which result in persistent tissue swelling and scarring at sites of ongoing allergic inflammation. These studies may identify potential therapeutic targets which can reduce the tissuedamage and swelling at sites of ongoing allergic inflammation in human subjects with severe ongoing allergies.