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。 哪些是严重持续变态反应受试者的慢性变态反应性炎症的特征 发炎。嗜酸性粒细胞向组织运输的机制和后果很难研究。 人类受试者。因此，我们开发了一种新的小鼠模型，从 骨髓到组织对重复的过敏原挑战的反应，这是一个共享许多 人类持续的过敏性炎症的特征。 我们建议使用这个新的小鼠模型来研究嗜酸性粒细胞在血管新生血管中的交通 过敏性炎症的部位，一旦进入组织，就会导致血管生成和纤维化。特定的 AIMS#1和#2将重点研究嗜酸性粒细胞与血管新生血管内皮细胞的相互作用 皮肤室模型，可直接显示血管中荧光标记的嗜酸性粒细胞 在皮肤室里。嗜酸性粒细胞在血管新生血管中的黏附和血管通透性的变化 经抗血管内皮生长因子和其他血管生成细胞因子的中和性抗体处理的小鼠的定量 在持续的过敏性炎症部位表达。 在具体目标#3和#4中，我们建议确定不同的转化生长因子-β亚型的贡献。 从嗜酸性粒细胞到组织纤维化，以及从 骨髓组织向组织纤维化转变。 总体而言，这些研究将有助于确定持续的过敏性炎症对血管的作用 导致持续过敏部位持续组织肿胀和疤痕形成的组织变化 发炎。这些研究可能确定潜在的治疗靶点，以减少组织损伤。 以及患有严重持续过敏的受试者持续过敏性炎症部位的肿胀。

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.