Prostanoids, Plasminogen Actication, and Personalized Therapeutics in IPF

描述(申请人提供)：特发性肺纤维化(IPF)是一种肺部疤痕疾病，缺乏有效的治疗方法，通常在几年内进展为呼吸衰竭和死亡。因此，迫切需要改善这一毁灭性疾病的结果，而实现这一目标的最大障碍是缺乏能够在未来5-10年内切实实施的适当治疗。理想情况下，我们希望在我们的治疗性医疗机构中有多种治疗方法可供选择：1)具有广泛的抗纤维化作用；2)具有可接受的安全性；3)目前可用或预计很快可用；4)可单独使用或与其他药物联合使用；5)可基于体外反应性预测指标以个性化的方式应用于个别患者。这项建议利用了申请团队15年的研究，这些研究对目前两种符合上述潜在治疗标准的抗纤维化物质的知识做出了很大贡献：即前列腺素EZ(PGE2)等前列腺素类物质和增强纤溶酶原激活系统的尿激酶剂等。虽然PGE2几乎抑制了正常肺成纤维细胞可能导致纤维化肺疾病的所有功能，但我们发现从大多数IPF患者分离的成纤维细胞系对这种前列腺素的常见抑制作用具有抵抗力。然而，我们已经确定了导致这种耐药性的两种不同的分子机制，其中一种可以通过DNA甲基化抑制剂的预处理来克服，另一种可以通过尿激酶的预处理来克服。因此，我们认为，患者来源的肺成纤维细胞的体外能力可被PGE2、尿激酶、甲基化抑制剂或其组合下调，以预测对这些相同方案的临床反应。迫在眉睫的可行性前景是基于这样一个事实，即前列腺素、尿激酶和甲基化抑制剂目前都被批准用于治疗人类疾病。对于这些研究，我们将使用从肺活检标本和来自50名具有良好特征的IPF患者的支气管肺泡灌洗液中分离的成纤维细胞，这些患者参与了我们的Grand Opportunity Comet研究。一组潜在的治疗剂，单独或联合使用，将用于治疗这两种细胞类型，以确定对细胞胶原合成和增殖的治疗效果。将比较每种细胞类型的反应模式，并将其与疾病的临床进展相关联。此外，还将评估这些相同方案改善博莱霉素诱导的小鼠肺纤维化的能力。这些互补的方法将确定改善或阻止IPF纤维化进展的最易处理的选择，并将在未来的临床试验中为患者提供一个单独定制治疗方案的框架。因此，学员I提供的是一系列治疗方法，可以考虑在随后的学员II申请中提出的试验中实施。相关性(见说明)：特发性肺纤维化(IPF)是一种致命的肺部疤痕疾病，目前还没有有效的治疗方法。前列腺素和尿激酶可对抗肺疤痕形成。这项提议将测试这些物质单独和联合使用的能力，以改善两种动物模型和IPF患者细胞中肺内疤痕的形成。这些研究将确定利用这些物质的抗纤维化潜力的最佳方法，用于未来对IPF患者的临床试验。

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a scarring disease of the lungs for which effective therapy is lacking and which usually progresses to respiratory failure and death within several years. The need to improve outcomes in this devastating disease is therefore urgent, and the single biggest barrier to accomplishing this is the lack of appropriate treatments that can realistically be implemented within the next 5-10 years. Ideally, we would like to have in our therapeutic armamentarium a selection of treatments that: 1) have broad anti-fibrotic actions; 2) have an acceptable safety profile; 3) are currently available or expected to be available soon; 4) could be used alone or in combination with others; and 5) could be applied in a personalized fashion to individual patients, based on in vitro predictors of responsiveness. This proposal capitalizes on 15 years of research by the applicant team which has contributed substantially to current knowledge about two anti-fibrotic substances that meet the above criteria for potential therapies: namely, prostanoids such as prostaglandin Ez (PGE2) and agents such as urokinase that augment the plasminogen activation system. Although PGE2 inhibits virtually all of the functions by which normal lung fibroblasts might contribute to fibrotic lung disease, we have found that fibroblast lines isolated from the majority of individuals with IPF are resistant to the usual suppressive actions of this prostanoid. However, we have identified two distinct molecular mechanisms accounting for such resistance, one of which can be overcome by pretreatment with inhibitors of DNA methylation and the other by pretreatment with urokinase. We thus propose that the in vitro capacity of patient-derived lung fibroblasts to be down-regulated by PGE2, urokinase, methylation inhibitors, or combinations thereof could predict clinical responses to these same regimens. The prospect of imminent feasibility is based on the fact that prostanoids, urokinase, and methylation inhibitors are all currently approved for the treatment of human disease. For these studies we will employ fibroblasts isolated from lung biopsy specimens and from bronchoalveolar lavage of 50 patients with well-characterized IPF participating in our Grand Opportunity COMET study. A panel of potential therapeutic agents, alone and in combination, will be used to treat both cell types in order to determine treatment effects on cellular collagen synthesis and proliferation. Response patterns will be compared for each cell type and will be correlated with clinical progression of disease. In addition, the ability of these same regimens to ameliorate bleomycin-induced pulmonary fibrosis in mice will be assessed. These complementary approaches will determine the most tractable options for ameliorating or halting progression of fibrosis in IPF and will provide a framework for individually tailoring treatment regimens for patients in future clinical trials. The deliverable from CADET I will therefore be a menu of therapies that can be considered for implementation in trials to be proposed in a subsequent CADET II application. RELEVANCE (See instructions): Idiopathic pulmonary fibrosis (IPF) is a lethal scarring disease of the lung for which no effective therapies are currently available. Prostanoids and urokinase oppose lung scarring. This proposal will test the ability of these substances, alone and in combination, to ameliorate scar formation in the lung in both animal models and in cells from patients with IPF. These studies will identify the optimal means of harnessing the anti-fibrotic potential of these substances for future clinical trials in patients with IPF.