Role of CXCR2-mediated cell trafficking in pulmonary vascular remodeling

项目摘要 目前尚不清楚CXCR2的髓样或内皮细胞表达如何促进髓源性抑制因子的表达。 细胞（MDSC）募集到肺，随后肺血管重塑。迫切需要 填补这一知识空白，因为，直到完成，免疫调节CXCR2贡献， 对于血管重塑和肺动脉高压（PH）的发展， 到达。本研究的总体目标是确定MDSC通过趋化因子受体募集的作用， CXCR2，由循环髓样细胞或肺血管内皮细胞表达。中央卫生- 假设组织特异性CXCR2表达是多形核白细胞（PMN）-MDSC募集所必需的 肺血管和PH发展的影响。这个假设的科学前提是公式- 基于初步数据，表明表达CXCR2的MDSC是发育所必需的， 肺血管疾病动物模型中PH的增加，并且存在这种循环细胞群， 与IPF患者相比，PH的特发性肺纤维化（IPF）患者的全血中， 没有肺动脉压升高的患者。拟议研究的理由是，在完成后， 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的现有CXCR2抑制剂的特异性递送，或CXCR2定向的 利用AAV载体的基因治疗。作为拟议工作的结果，预期成果是纵向的， 在理解CXCR2对血管重塑的贡献方面取得了进展，另外还建立了一个 为进一步研究MDSC介导的与慢性肺相关的PH发展机制奠定了基础 疾病，如IPF。预计结果将产生积极的翻译影响，因为很可能， 所鉴定的组织特异性CXCR2影响将为免疫干预提供靶点。中心- 将通过追求以下具体目标来检验该假设：1）检验CXCR2表达的假设， PMN-MDSC的作用促进PH的发展; 2）验证血管内皮细胞 CXCR2表达对PH中MDSC募集具有保护作用。 在骨髓来源的细胞（LysM. Cre-CXCR2fl/fl，mCXCR2小鼠）中具有CXCR2的组织特异性缺失， 用于在两种模型中确定减毒MDSC运输对PH发展的影响 疾病（博来霉素诱导的肺纤维化和慢性缺氧）。在第二个目标中， 血管内皮细胞中CXCR2的组织特异性缺失（VECad. Cre-CXCR2fl/fl，eCXCR2小鼠）将被 这些研究的贡献将是显着的，因为它 代表了通过预防CXCR2介导的向肺的运输来改善临床结果的策略。 拟议中的研究是创新的，因为它代表了通过转移重点而脱离现状的做法 从血管扩张剂治疗到免疫调节介质MDSC，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.