Fibrocytes in human pulmonary fibrosis

描述(申请人提供)：特发性肺纤维化(IPF)是一种以肺功能进行性下降和因呼吸衰竭而过早死亡为特征的疾病。目前对这种疾病没有有效的治疗方法，由于我们无法预测有临床恶化风险的患者，对新治疗方案的研究受到阻碍。在肺纤维化动物模型中，纤维细胞是一种新的骨髓来源的循环祖细胞，其数量与肺纤维化的程度和生存有关。我们广泛而长期的目标是了解纤维细胞在人类肺纤维化中的作用，并将这一病理机制作为一种治疗方式。我们的初步数据显示：1)与健康对照组相比，纤维化间质性肺疾病患者肺和血浆中纤维细胞趋化因子CXCL12的水平显著升高，这与外周血和肺纤维细胞数量的显著增加有关；2)Hermansky-Pudlak综合征患者有类似的循环纤维细胞池的扩张；3)循环纤维细胞计数的增加是IPF死亡的独立预测因素；4)CXCR4是人纤维细胞上表达的主要趋化因子受体，其表达被mTOR抑制剂西罗莫司下调；5)在肺纤维化动物模型中，西罗莫司可导致血液和肺纤维细胞数量减少，肺纤维化减轻。我们的总体假设是，在肺纤维化患者中，1)循环纤维细胞的数量和/或表型在临床可检测到疾病进展之前就确定了患者的进展风险，以及2)mTOR抑制剂西罗莫司的治疗减少了循环纤维细胞的数量。我们建议在以下特定目标下验证这一假说：1)在一组Hermansky-Pudlak综合征患者中，确定循环纤维细胞的数量和表型对肺纤维化的发生和进展的预测价值。2)将特发性肺纤维化患者循环中纤维细胞的数量和表型与疾病严重程度的常规指标相关联。3)对IPF患者进行mTOR抑制剂西罗莫司的短期中试，以确定其对循环纤维细胞数量和表型的影响。所提出的研究的意义在于，他们有可能找到一种新的生物标记物来预测IPF的疾病进展，并为以纤维细胞为靶点的这种疾病的治疗奠定基础。

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is an illness characterized by progressive decline in lung function and premature death from respiratory failure. There is currently no effective therapy for this disease and the study of new therapeutic options is hampered by our inability to predict patients at risk for clinical deterioration. Fibrocytes are a novel population of bone marrow-derived circulating progenitor cells that have been shown to traffic to the lungs and contribute to fibrosis in animal models of pulmonary fibrosis, and whose numbers correlate with the degree of fibrosis and with survival in human pulmonary fibrosis. Our broad, long-term objective is to understand the contribution of fibrocytes to human pulmonary fibrosis and to target this pathological mechanism as a therapeutic modality. Our preliminary data show that: 1) as compared to healthy controls, patients with fibrotic interstitial lung disease have markedly increased levels of the fibrocyte-attracting chemokine, CXCL12, in both the lungs and plasma, which is associated with a marked elevation in the number of peripheral blood and lung fibrocytes; 2) patients with Hermansky-Pudlak syndrome, a genetic disorder that universally results in pulmonary fibrosis in the 3rd decade of life, have a similar expansion of the circulating fibrocyte pool; 3) The elevation of circulating fibrocyte count is an independent predictor of death in IPF; 4) CXCR4 is the major chemokine receptor expressed on human fibrocytes, and its expression is down-regulated by the mTOR inhibitor, sirolimus; and 5) in an animal model of pulmonary fibrosis, administration of sirolimus results in reduced number of blood and lung fibrocytes as well as reduced lung fibrosis. Our overall hypothesis is that in patients with pulmonary fibrosis, 1) the number and/or phenotype of circulating fibrocytes identify patients at risk of disease progression before the progression is detectable clinically, and 2) therapy with the mTOR inhibitor, sirolimus, reduces the number of circulating fibrocytes. We propose to test this hypothesis under the following specific aims: 1) To determine the predictive value of the number and phenotype of circulating fibrocytes for development and progression of pulmonary fibrosis in a cohort of patients with Hermansky-Pudlak syndrome. 2) To serially correlate the number and phenotype of circulating fibrocytes to conventional indices of disease severity in patients with idiopathic pulmonary fibrosis. 3) To perform a short-term pilot trial of the mTOR inhibitor, sirolimus, in patients with IPF to determine its effect on the number and phenotype of circulating fibrocytes. The significance of the proposed studies is that they have the potential to identify a novel biomarker to predict disease progression in IPF, and to lay the groundwork for a therapy for this illness that targets fibrocytes.