Fibrocytes in the Pathogenesis of Sickle Cell Lung Disease

描述（由申请人提供）：镰状细胞病（SCD）伴相关镰状细胞肺损伤（SCLI）可导致慢性镰状细胞肺疾病（CSCLD）的发展。CSCLD的特征是慢性间质性肺疾病，伴有继发性肺动脉高压和纤维化。循环纤维细胞（CD 45 + Col 1+）的发现改变了我们对肺纤维化发病机制的看法。在临床前模型中，纤维细胞在介导肺纤维化中起作用。发现纤维细胞在IPF患者的循环和肺中升高，其循环水平的大小与这些患者的预后较差相关。将这些发现扩展到SCD，我们发现使用人SCD的临床前转基因小鼠模型，表达CXC趋化因子受体4（CXCR 4）的纤维细胞在促进与肺源性CXCL 12表达相关的肺纤维化中起重要作用。此外，我们发现，CXCR 4+纤维细胞在SCD患者的循环中升高。基于我们的初步数据，我们产生了一个总体假设，即纤维细胞在介导SCLI的发病机制和CSCLD的发展中起着关键作用。为了测试这一假设，我们设计了以下具体目标，以在分子、细胞、临床前动物模型和患者水平上评估纤维细胞生物学，以确定这些细胞是否有助于SCLI和CSCLD的发展：SCD小鼠中纤维细胞定位与纤维化和血管重塑的相关性，以及阐明CXCL 12/CXCR 4在SCLI发病过程中促进BM扩张、BM动员和这些细胞外渗到肺中的作用：2. mTOR抑制的测定导致CXCL 12/CXCR 4的下调和肺中纤维细胞外渗的损害，这与转基因SCD动物中SCLI发病过程中肺血管重塑和纤维化的减弱直接相关。3.确定纤维细胞数量和活化表型（即，(SMA+和pSmad 2/3+纤维细胞）与成人SCD患者的限制性肺病相关。本项目的长期目标是确定纤维细胞是促进SCLI发病机制的关键细胞。这些发现将支持这样的观点，即靶向纤维细胞的策略将导致新的疗法，以减弱其在CSCLD发病机制中的生物学作用。 公共卫生相关性：镰状细胞病是非洲裔美国人最常见的遗传性疾病。虽然改善镰状细胞病的患者护理已导致这些患者的存活率增加，但不幸的是，他们经历了慢性器官问题的频率增加，特别是与肺相关的问题。这些患者可能会患上慢性肺部疾病，与血压升高和肺部瘢痕组织形成有关。这项提案中的研究将集中在镰状细胞病患者循环中发现的一种特殊细胞的作用上，这种细胞可能导致我们在这些患者的肺部看到的问题。

DESCRIPTION (provided by applicant): Sickle cell disease (SCD) with associated sickle cell lung injury (SCLI) can lead to the development of chronic sickle cell lung disease (CSCLD). CSCLD is characterized as chronic interstitial lung disease with secondary pulmonary hypertension and fibrosis. The discovery of circulating fibrocytes (CD45+Col1+) has now changed our view on the pathogenesis of pulmonary fibrosis. Fibrocytes play a role in mediating pulmonary fibrosis in pre-clinical models. Fibrocytes are found elevated in the circulation and lungs of IPF patients, and the magnitude of their circulating levels is associated with a worse prognosis in these patients. Extending these findings to SCD, we found using a preclinical transgenic mouse model of human SCD that CXC chemokine receptor 4 (CXCR4) expressing fibrocytes play a significant role in promoting pulmonary fibrosis related to the expression of lung-derived CXCL12. In addition, we found that CXCR4+ fibrocytes were elevated in the circulation of patients with SCD. Based on our preliminary data, we generated an overall hypothesis that fibrocytes play a critical role in mediating the pathogenesis of SCLI and development of CSCLD. To test this postulate, we designed the following specific aims to assess fibrocyte biology at the molecular, cellular, pre-clinical animal model, and patient levels to determine if these cells contribute to SCLI and the development of CSCLD: 1. Correlation of fibrocyte localization in SCD mice with fibrosis and vascular remodeling, and elucidation of the role of CXCL12/CXCR4 in promoting BM expansion, BM mobilization, and extravasation of these cells into the lung during the pathogenesis of SCLI: 2. Determination of mTOR inhibition results in down-regulation of CXCL12/CXCR4 and impairment of fibrocyte extravasation in the lungs that directly correlates with attenuation of the pulmonary vascular remodeling and fibrosis during the pathogenesis of SCLI in transgenic SCD animals. 3. Determine whether fibrocyte number and activated phenotype (i.e., (SMA+ and pSmad2/3+ fibrocytes) are associated with restrictive lung disease in adult SCD patients. Long-term objectives of this project will establish that fibrocytes are critical cells in promoting the pathogenesis of SCLI. These findings will support the notion that strategies to target fibrocytes will lead to novel therapies to attenuate their biology in the pathogenesis of CSCLD. PUBLIC HEALTH RELEVANCE: Sickle cell disease is the most common inherited disorder in African-Americans. While improved patient care in Sickle cell disease has led to increased survival of these patients, they unfortunately experience an increase frequency of chronic organ problems, especially related to the lung. These patients can develop a chronic lung condition that is associated with elevated blood pressure and formation of scar tissue in their lungs. The studies in this proposal will focus on the role of a special cell found in the circulation of patients with sickle cell disease that may contribute to the problems we see in the lungs of these patients.