Fibrocytes in the Pathogenesis of Sickle Cell Lung Disease

描述（由申请人提供）：镰状细胞病（SCD）伴镰状细胞肺损伤（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继发性肺动脉高压和纤维化。循环纤维细胞（CD45+Col1+）的发现现在已经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发挥作用。在IPF患者的循环和肺中发现纤维细胞升高，其循环水平的大小与这些患者的预后较差有关。将这些发现扩展到SCD，我们使用临床前转基因小鼠SCD模型发现，表达纤维细胞的CXC趋化因子受体4 （CXCR4）在促进肺纤维化中发挥重要作用，这与肺源性CXCL12的表达有关。此外，我们发现SCD患者循环中CXCR4+纤维细胞升高。基于我们的初步数据，我们提出了一个总体假设，即纤维细胞在介导SCLI的发病机制和CSCLD的发展中起关键作用。为了验证这一假设，我们设计了以下具体目标，从分子、细胞、临床前动物模型和患者水平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小鼠纤维细胞定位与纤维化和血管重构的相关性，以及CXCL12/CXCR4在SCLI发病过程中促进BM扩张、BM动员和这些细胞外渗漏到肺中的作用的阐明：mTOR抑制的测定导致CXCL12/CXCR4的下调和肺纤维细胞外压的损害，这与转基因SCD动物SCLI发病过程中肺血管重构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pSmad2/3+纤维细胞）是否与成人SCD患者的限制性肺部疾病相关。该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一种观点，即针对纤维细胞的策略将导致新的治疗方法，以减弱其在CSCLD发病机制中的生物学作用。

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.