Targeting HSC-derived Circulating Fibroblast Precursors in Pulmonary Fibrosis

靶向 HSC 衍生的循环成纤维细胞前体治疗肺纤维化

• 批准号: 9275406
• 负责人: AMANDA C. LARUE
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9275406
• 关键词: Age; Airborne Particulate Matter; Alveolar; Architecture; Autologous; Automobile Driving; Biological Markers; Blood Circulation; Bone Marrow; Breathing; Cell Transplantation; Cells; Chronic; Chronic lung disease; Clonal Hematopoietic Stem Cell; Clone Cells; DDR2 gene; Data; Development; Diagnosis; Disease; Disease Progression; Dust; Effector Cell; Environmental Hazards; Epithelial Cell Proliferation; Evaluation; Exposure to; Extracellular Matrix; FDA approved; Fibroblasts; Fibrosis; Flow Cytometry; Gases; Goals; Gulf War; Health; Hematopoietic stem cells; Heterogeneity; Human; In Vitro; Incidence; Lead; Lung; Lung diseases; Medical; Methods; Mission; Modeling; Molecular; Mus; Myofibroblast; PTPRC gene; Particulate; Patients; Phenotype; Physiologic pulse; Population; Population Heterogeneity; Pulmonary Fibrosis; Pulse Oximetry; Recruitment Activity; Respiration Disorders; Risk; Role; Silicon Dioxide; Soldier; Staining method; Stains; Testing; Therapeutic; Therapeutic Effect; Tissues; Transplantation; Treatment Effectiveness; Treatment Efficacy; Veterans; Xenograft Model; alveolar type II cell; base; effective therapy; enhanced green fluorescent protein; environmental chemical; hazard; human disease; improved; in vitro testing; in vivo; insight; microCT; monocyte; new therapeutic target; novel; paracrine; particle; peripheral blood; persistent symptom; progenitor; public health relevance; reconstitution; response; therapeutic target

DESCRIPTION (provided by applicant): Exposure to environmental and chemical hazards is thought to be a major contributing factor to Gulf War illness (GWI) (US Dept VA). Of particular concern for Gulf War Veterans is chronic inhalation of sand, dust and airborne particulates while in theater which pose significant risk for development of respiratory diseases including pulmonary fibrosis (PF). PF is a chronic lung disease characterized by accumulation of extracellular matrix (ECM), destruction of normal lung architecture, and decreased capacity for gas exchange. The activated fibroblast is the primary effector cell in PF. However, targeting activated fibroblasts is challenging due, in part, to the heterogeneity of the population. This heterogeneity is thought to reflect the multiple proposed origins of fibroblasts, making it essential to elucidate the role of fibroblasts from all origins i PF. Using mice whose bone marrow was reconstituted by a clonal population of cells derived from a single enhanced green fluorescent protein positive (EGFP+) hematopoietic stem cell (HSC), we have demonstrated an HSC origin for fibroblasts and activated fibroblasts in multiple tissues. We also identified a CD45+DDR2+ HSC-derived circulating fibroblast precursor (CFP) in peripheral blood of mice and humans that is related to the monocyte, gives rise to activated fibroblasts, produces pro-fibrotic factors, increases with disease, and can be therapeutically targeted. Using a silica model of PF that mimics particulate exposure in Veterans of the Gulf War, we have shown that CFPs increase in circulation with PF and traffic to the fibrotic lung. Together, our findings support the hypothesis that HSC-derived CFPs are critical to progression of PF and can be targeted to inhibit fibrotic progression. This will be tested using our novel clonal HSC cell transplantation method in conjunction with a silica instillation PF model in three Specific Aims. Aim 1 will temporally examine CFP contribution to silica-induced PF and potential of CFPs to serve as an early biomarker for disease and/or response to therapy (Aim 1). Studies in Aim 2 will elucidate mechanisms regulating participation, activation and pro-fibrotic effects of CFPs. Finally, we will examine the effect of therapeutically targeting this unique fibrotic progenitor using both mouse-to-mouse transplant and human-to-mouse xenograft models to demonstrate that inhibition of CFPs can reduce progression of silica-based fibrosis and is applicable to human disease (Aim 3). The proposed studies are paradigm shifting in that most studies focus on targeting the activated fibroblast or relatively mature fibrocyte in fibrosis, whie our data suggests that the more primitive CFP may provide a more effective therapeutic target. These studies are significant in that they are the first to conduct flow cytometric, immunohistochemical, molecular, and functional evaluation of HSC-derived CFPs and their contribution to PF. It is suggested that the number of Veterans diagnosed with Gulf War Illness, including respiratory diseases, is grossly underestimated. As GWI is better defined and the Veteran population serving in the Gulf ages, we expect to see an increased incidence of PF in the Veteran population. Studying early markers of PF is of great relevance to the VA mission as it will allow us to better detect early signs of PF in patients, potentially using CFPs as a biomarker, to dramatically improve effectiveness of treatment prior to loss of normal lung architecture and function. Therefore, these studies have the potential to directly impact Gulf War Veterans' health as well as have far-reaching application to Veterans with multiple types of fibrotic disease.

描述(由申请人提供)： 暴露在环境和化学危害中被认为是导致海湾战争疾病(GWI)的主要因素(美国退伍军人事务部)。海湾战争退伍军人特别关注的是在战区长期吸入沙子、灰尘和空气中的颗粒物，这对 发展呼吸系统疾病，包括肺纤维化(PF)。肺纤维化是一种慢性肺部疾病，以细胞外基质(ECM)积聚、正常肺结构破坏和气体交换能力降低为特征。活化的成纤维细胞是PF的主要效应细胞。然而，部分由于群体的异质性，靶向激活的成纤维细胞是具有挑战性的。这种异质性被认为反映了成纤维细胞的多种来源，因此有必要阐明所有来源的成纤维细胞在肺间质纤维化中的作用。利用单个增强型绿色荧光蛋白阳性(EGFP+)造血干细胞(HSC)的克隆性细胞群重建小鼠的骨髓，我们证明了多个组织中的成纤维细胞和激活的成纤维细胞来自HSC。我们还在小鼠和人类的外周血中发现了一种CD45+DDR2+HSC来源的循环成纤维细胞前体(CFP)，它与单核细胞有关，可以产生激活的成纤维细胞，产生促纤维化因子，随着疾病的增加而增加，并且可以作为治疗的靶点。使用模拟海湾战争退伍军人颗粒物暴露的肺泡灌洗液的二氧化硅模型，我们已经证明，随着肺泡灌洗液的循环和流向纤维化肺的流量增加，CFPs增加。总之，我们的发现支持这一假设，即HSC来源的CFPs对PF的进展至关重要，并且可以靶向抑制纤维化的进展。这将使用我们的新的克隆HSC细胞移植方法结合二氧化硅滴注PF模型在三个特定的目的进行测试。目标1将暂时检查CFP对二氧化硅诱导的PF的贡献，以及CFP作为疾病和/或治疗反应的早期生物标志物的潜力(目标1)。AIM 2中的研究将阐明参与、激活和促纤维化作用的调节机制 CFPS。最后，我们将使用小鼠到小鼠移植和人到小鼠异种移植模型来检验以这种独特的纤维化前体为靶点的治疗效果，以证明抑制CFPs可以减少基于二氧化硅的纤维化的进展，并适用于人类疾病(目标3)。所提出的研究是范式转换，因为大多数研究集中于纤维化中活化的成纤维细胞或相对成熟的成纤维细胞，而我们的数据表明，更原始的CFP可能提供更有效的治疗靶点。这些研究具有重要意义，因为它们首次对HSC来源的CFPs及其对PF的贡献进行了流式细胞术、免疫组织化学、分子和功能评估。有人建议，被诊断患有海湾战争疾病(包括呼吸系统疾病)的退伍军人人数被严重低估。随着GWI定义的更明确，以及在海湾服役的退伍军人群体的老龄化，我们预计退伍军人群体中PF的发病率将会增加。研究肺纤维化的早期标志物与VA任务具有重要的相关性，因为它将使我们能够更好地检测患者的肺纤维化的早期迹象，潜在地使用CFPS作为生物标志物，在失去正常肺结构和功能之前显著提高治疗效果。因此，这些研究有可能直接影响海湾战争退伍军人的健康，并对患有多种纤维化疾病的退伍军人具有深远的应用价值。

项目成果

Physical and elemental analysis of Middle East sands from recent combat zones.

对来自最近战区的中东沙子进行物理和元素分析。

• DOI: 10.1080/08958378.2020.1766602
• 发表时间: 2020
• 期刊: Inhalation toxicology
• 影响因子: 2.1
• 作者: McDonald,LindsayT;Christopher,StevenJ;Morton,SteveL;LaRue,AmandaC
• 通讯作者: LaRue,AmandaC

Experimental respiratory exposure to putative Gulf War toxins promotes persistent alveolar macrophage recruitment and pulmonary inflammation.

实验性呼吸道暴露于假定的海湾战争毒素会促进肺泡巨噬细胞持续招募和肺部炎症。

• DOI: 10.1016/j.lfs.2021.119839
• 发表时间: 2021
• 期刊: Life sciences
• 影响因子: 6.1
• 作者: Powers,AmyA;Jones,KatherineE;Eisenberg,SethH;Rigatti,LoraH;Ryan,JohnP;Luketich,JamesD;Lotze,MichaelT;LaRue,AmandaC;Dhupar,Rajeev;Soloff,AdamC
• 通讯作者: Soloff,AdamC