Fibrocyte Phenotypes as Biomarkers in IPFnet Patients

描述(由申请人提供)： 特发性肺纤维化(IPF)是一种以进行性肺功能丧失和细胞外基质(ECM)沉积为终点的疾病。此外，许多IPF患者会因已知原因(如感染)或称为“急性加重”的特发性症状而急性恶化。循环中的骨髓源性细胞称为纤维细胞(由共有的白细胞和间质标记物识别)可能是IPF发病的调节因素。IPF患者的纤维细胞数量增加，小鼠纤维化研究表明，纤维细胞被趋化因子招募到肺中，2)纤维细胞过继转移使疾病恶化，3)纤维细胞募集与感染加重有关。因此，纤维细胞的绝对数或特定的纤维细胞表型可作为IPF的新生物标志物。IPF网络(IPFnet)是监督Panther试验的母公司。Panther试验是一项多中心、随机、双盲的安慰剂对照试验，旨在研究强的松+硫唑嘌呤+N-乙酰半胱氨酸(NAC)或NAC单独与安慰剂治疗轻中度IPF患者的疗效(每组130名患者随访67周)。第二个试验是分步试验，在患有严重疾病的IPF患者中测试西地那非，为期12周(治疗组和安慰剂组均有85名患者)。所有这些患者都将在诊断、生理、疾病进展和不良事件方面具有良好的特征。这项拨款建议的研究将利用这些试验中登记的大量和多样化的IPF患者群体以及随着时间的推移在每个患者身上收集的丰富的临床/生理数据来进行纵向和横断面研究，以表征纤维细胞数量和表型，努力提供与IPF自然历史和治疗反应之间的机制关联。此外，我们将比较IPF纤维细胞表型与疾病特异性对照患者的表型，包括慢性阻塞性肺疾病(COPD)和硬皮病患者以及正常志愿者。我们假设，纤维细胞的绝对数量或独特的纤维细胞表型(趋化因子受体表达、胶原合成能力、促纤维化介质的分泌或增殖)将与入院时的疾病严重程度、疾病进展速度、对治疗的反应和急性加重的发生相关。IPFnet指导委员会认识到这些机械性研究的价值，并完全支持这一申请。目的1)确定正常、COPD、硬皮病和特发性肺纤维化患者的纤维细胞绝对数或纤维细胞表型改变是否存在差异。目的2)探讨特发性肺间质纤维化(IPF)患者和对照组的纤维细胞数量变化或纤维细胞表型变化(S)是否能预测疾病的严重程度、生理变化或治疗反应。目的3)确定纤维细胞表型改变绝对数的改变(S)是否与急性恶化相关，或区分不明原因的急性加重和已知原因的急性加重。相关声明纤维细胞表型已被证实为小鼠纤维化模型中的生物标记物。我们提出的研究将首次提供纤维细胞表型作为人类纤维化肺疾病生物标记物的纵向和横断面分析。(摘要结束)

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a disease that culminates in progressive loss of pulmonary function and deposition of extracellular matrix (ECM). Additionally, many IPF patients will experience an acute worsening of symptoms due to known causes (e.g. infection) or of idiopathic nature termed "acute exacerbations". Circulating, bone-marrow-derived cells known as fibrocytes (identified by shared leukocyte and mesenchymal markers) may be regulators of IPF pathogenesis. Fibrocyte numbers are increased in patients with IPF and murine fibrosis studies have demonstrated that fibrocytes are 1) recruited to the lung by chemokines 2) adoptive transfer of fibrocytes worsen disease and 3) fibrocyte recruitment correlates with infectious exacerbations. Thus, absolute numbers of fibrocytes, or particular fibrocyte phenotypes, may serve as novel biomarkers in IPF. The IPF network (IPFnet) is the parent organization that will oversee the PANTHER trial which is a multi-center, randomized, double-blind placebo controlled trial to investigate the efficacy of prednisone + azathioprine + N-acetylcysteine (NAC) or NAC alone versus placebo in IPF patients with mild- moderate disease (130 patients in each arm followed up to 67 weeks). The second trial is the STEP trial to test sildenafil in IPF patients with severe disease over a 12 week period (85 patients in both the treatment and placebo arms). All these patients will be well characterized for diagnosis, physiology, disease progression and adverse events. The studies proposed in this grant would take advantage of the large and diverse IPF patient populations enrolled in these trials and the abundant clinical/physiological data collected over time on each patient to perform longitudinal and cross-sectional studies to characterize fibrocyte numbers and phenotypes in an effort to provide mechanistic correlations into the natural history of IPF and response to therapy. In addition, we will compare IPF fibrocyte phenotypes to those obtained from disease-specific control patients including patients with chronic obstructive pulmonary disease (COPD) and scleroderma as well as normal volunteers. We hypothesize that absolute numbers of fibrocytes, or distinctive fibrocyte phenotypes (chemokine receptor expression, collagen synthetic capacity, secretion of pro-fibrotic mediators or proliferation) will correlate with severity of disease at entry, rate of progression of disease, response to therapy and occurrence of acute exacerbations. The IPFnet steering committee recognizes the value of these mechanistic studies and fully supports this application. Aim 1) To determine whether absolute numbers of fibrocytes or alterations in fibrocyte phenotype differentiate between normal, COPD, scleroderma and IPF subjects. Aim 2) To determine whether changes in fibrocyte numbers or alterations in fibrocyte phenotype(s) predict severity of disease, changes in physiology or response to therapy in IPF and control patients. Aim 3) To determine whether changes in absolute numbers of alterations in fibrocyte phenotype(s) correlate with acute deteriorations or differentiate between acute exacerbations of known and unknown cause. Statement of Relevance Fibrocyte phenotypes have been validated as biomarkers in murine models of fibrosis. Our proposed studies would be the first to provide longitudinal and cross sectional analyses of fibrocyte phenotypes as biomarkers in human fibrotic lung disease. (End of Abstract)