Role of CXCR2-mediated cell trafficking in pulmonary vascular remodeling

项目总结 目前尚不清楚CXCR2在髓系或内皮细胞中的表达对髓系来源的抑制有何作用 细胞(MDSC)募集到肺，随后发生肺血管重塑。有一个迫切的需要 为了弥合这一知识差距，因为在完成之前，CXCR2的免疫治疗调控- 对血管重塑和肺动脉高压(PH)的发展的影响可能会持续到 伸手。这里的总体目标是通过趋化因子受体确定MDSC招募的贡献。 CXCR2，由循环髓系细胞或肺血管内皮细胞表达。中央高铁- 假设组织特异性CXCR2的表达是中性粒细胞(PMN)-MDSC募集所必需的 对肺血管系统和肺高压的发展有重要影响。这一假说的科学前提是 根据初步数据表明，表达CXCR2的MDSCs是发育所必需的。 肺血管疾病动物模型中PH的研究进展以及这种循环细胞群的存在 特发性肺纤维化(IPF)合并PH患者的全血水平明显高于IPF患者。 无肺压升高的病人。拟议研究的理由是，一旦完成， 未来的研究可以利用佛罗里达大学在组织方面的专业知识- 通过使用纳米颗粒技术或CXCR2定向的现有CXCR2抑制剂的特定递送 利用AAV载体进行基因治疗。作为拟议工作的结果，预期结果是垂直的 CXCR2在血管重塑中的作用研究进展 为未来详细研究MDSC介导的与慢性肺相关的PH发生机制奠定基础 疾病，如IPF。预计结果将产生积极的翻译影响，因为很可能 已确定的组织特异性CXCR2影响将为免疫治疗干预提供靶点。该中心- TRAL假说将通过追求以下具体目标来检验：1)检验CXCR2表达- 通过PMN-MDSC的Sion促进PH的发生；2)验证血管内皮细胞的假说 CXCR2的表达对PH中MDSC的募集具有保护作用。第一个目标是野生型和转基因小鼠 在髓系细胞(LysM.Cre-CXCR2fl/fl，mCXCR2小鼠)中组织特异性缺失CXCR2将是 用于在两个模型中确定减弱的MDSC贩运对PH的发展的影响 疾病(博莱霉素引起的肺纤维化和慢性缺氧)。在第二个目标中，转基因小鼠 血管内皮细胞(VECad.Cre-CXCR2fl/fl，eCXCR2小鼠)中CXCR2的组织特异性缺失将是 用于博莱霉素和PH的缺氧模型。这些研究的贡献将是重大的，因为它 代表了一种通过防止CXCR2介导的转运到肺来改善临床结果的战略。 这项拟议的研究具有创新性，因为它代表了通过转移重点来改变现状 从血管扩张剂治疗到免疫调节调节剂MDSCs，在PH的病理生物学中。

PROJECT SUMMARY It is unknown how myeloid or endothelial cell expression of CXCR2 contributes to myeloid-derived suppressor cell (MDSC) recruitment to the lungs, with subsequent pulmonary vascular remodeling. There is an urgent need to close this gap in knowledge because, until accomplished, immunotherapeutic modulation of CXCR2 contribu- tion to the development of vascular remodeling, and pulmonary hypertension (PH), will likely remain beyond reach. The overall objective here is to define the contribution of MDSC recruitment through chemokine receptor CXCR2, expressed by either circulating myeloid cells or the pulmonary vascular endothelium. The central hy- pothesis is that tissue specific CXCR2 expression is necessary for polymorphonuclear (PMN)-MDSC recruitment to the pulmonary vasculature and PH development. The scientific premise for this hypothesis has been formu- lated on the basis of preliminary data demonstrating that MDSCs expressing CXCR2 are necessary for devel- opment of PH in animal models of pulmonary vascular disease, and that this circulating cell population is present to a higher degree in whole blood of idiopathic pulmonary fibrosis (IPF) patients with PH, compared to IPF pa- tients without elevated pulmonary pressures. The rationale for the proposed research is that, upon completion of experiments, future studies can be proposed taking advantage of University of Florida expertise in tissue- specific delivery of either existing CXCR2 inhibitors though use of nanoparticle technology, or CXCR2 directed gene-therapy utilizing AAV vectors. Expected outcomes, as a consequence of proposed work, are a vertical advancement in the understanding of CXCR2 contribution to vascular remodeling, additionally establishing a foundation for future studies detailing mechanisms of MDSC mediated PH development related to chronic lung disease, such as IPF. The results are expected to have positive translational impact because it is probable that the identified tissue-specific CXCR2 influence will provide targets for immunotherapeutic interventions. The cen- tral hypothesis will be tested by pursuing the following specific aims: 1) test the hypothesis that CXCR2 expres- sion by PMN-MDSC promotes development of PH, and 2) test the hypothesis that vascular endothelial cell CXCR2 expression is protective against MDSC recruitment in PH. In the first aim, wild type and transgenic mice with tissue-specific deletion of CXCR2 in myeloid-derived cells (LysM.Cre-CXCR2fl/fl, mCXCR2 mice) will be used to determine the effect that attenuated MDSC trafficking will have on the development of PH in two models of disease (bleomycin-induced pulmonary fibrosis and chronic hypoxia). In the second aim, transgenic mice with tissue-specific deletion of CXCR2 in vascular endothelial cells (VECad.Cre-CXCR2fl/fl, eCXCR2 mice) will be used in the bleomycin and hypoxia models of PH. The contribution of these studies will be significant because it represents a strategy to improve clinical outcomes through prevention of CXCR2-mediated trafficking to the lung. The proposed research is innovative because it represents a departure from the status quo by shifting focus from vasodilator therapy to an immunoregulatory mediator, MDSCs, in the pathobiology of PH.