Fibrocytes in human pulmonary fibrosis

描述（由申请人提供）：特发性肺纤维化（IPF）是一种以肺功能进行性下降和呼吸衰竭导致的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，而且由于我们无法预测有临床恶化风险的患者，新的治疗选择的研究受到阻碍。纤维细胞是一种新的骨髓来源的循环祖细胞群，在肺纤维化动物模型中已被证明可运输到肺部并促进纤维化，其数量与纤维化程度和人类肺纤维化的存活率相关。我们广泛的、长期的目标是了解纤维细胞对人类肺纤维化的贡献，并将这种病理机制作为一种治疗方式。我们的初步数据显示：1)与健康对照相比，纤维化间质性肺病患者肺和血浆中纤维细胞吸引趋化因子CXCL12水平显著升高，这与外周血和肺纤维细胞数量显著升高有关；2) Hermansky-Pudlak综合征（一种普遍在30岁时导致肺纤维化的遗传性疾病）患者的循环纤维细胞池也有类似的扩张；3)循环纤维细胞计数升高是IPF患者死亡的独立预测因子；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以及肺纤维化减少。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/或表型在临床检测到疾病进展之前识别出有疾病进展风险的患者，2)使用mTOR抑制剂西罗莫司治疗可减少循环纤维细胞的数量。我们提出验证这一假设的具体目的如下：1)在Hermansky-Pudlak综合征患者队列中，确定循环纤维细胞的数量和表型对肺纤维化发生和进展的预测价值。2)特发性肺纤维化患者循环纤维细胞的数量和表型与疾病严重程度的常规指标的序列相关性。3)在IPF患者中进行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，它们有可能确定一种新的生物标志物来预测IPF的疾病进展，并为针对纤维细胞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. PUBLIC HEALTH RELEVANCE: Idiopathic pulmonary fibrosis is progressive lung disease that typically results in death from respiratory failure within 3 years of diagnosis, and for which there is no effective treatment. Fibrocytes are a population of blood cells that, according to several lines of evidence, may be involved in damaging the lung in this illness. The proposed studies are relevant to public health in that they have the potential to define the number of these cells in the blood as a novel marker to identify patients with this illness who are at risk of deterioration, so that they can be targeted for testing new treatments. In addition, we propose to perform a small study of an existing drug in this illness, with the aim of targeting these cells therapeutically.