Peripheral Markers of Phenotypic Heterogeneity in COPD

COPD的分类仅仅基于用力呼气流量异常的程度，是 在个体化治疗干预措施以影响自然病史方面不充分且价值有限 这种疾病。我们的全球假说是“慢性阻塞性肺疾病是一组可定义的解剖学和 生理性疾病过程，每个过程都有自己的分子和细胞过程来决定 疾病的表现和进展。我们建议使用2个现有和成熟的队列 有效招募前吸烟者，并对800名受试者进行一项横断面研究，研究范围广泛 然后对其中450人进行2-3年的纵向随访。 (SA1)：使用定量CT(QCT)决定因素的气道重塑和肺气肿及其 与COPD的其他生理和功能指标相关联以确定独特的临床病理 疾病亚类或表型，以及(SA2)与外周血分子相关 以及具有独特临床和肺组织病理表型的细胞生物标记物。我们相信， 根据初步数据，免疫细胞功能、细胞因子表达和 遗传因素是不同的，可以用来区分独特的病理生理亚群 病人。我们的目的无非是为COPD重新分类提供正当理由，使其更具生物学意义 可以指导开发更有效的针对患者的治疗方法的相关类别。 在我们的(SA3)中，我们进一步探讨了我们的合作研究员J博士的实验室最近的观察结果 Hogg说，外周气道管腔粘液含量LC%与较差的存活率之间存在显著的相关性。 与这一过程相关的替代标记的发现可能具有巨大的重要性，因为 日期，我们一直无法确定LC%的严重程度与任何临床或 生理特征。我们假设：分子和细胞生物标记物和QCT变量 慢性阻塞性肺疾病，在肺移植前特征的重症患者亚组中，与 在肺组织中测量管腔内容物(LC)闭塞的严重程度 标准的形态测量技术。对这种情况的非侵入性替代品的识别，可能 对判断预后或针对个体化治疗有重大影响。

The classification of COPD based simply on magnitude of forced expiratory flow abnormality, is inadequate and of limited value in individualizing therapeutic interventions to influence the natural history of the disease. Our global hypothesis is that "COPD is a heterogeneous group of definable anatomic and physiologic disease processes, each with its own molecular and cellular processes that determine disease manifestation and progression." We propose to use 2 well established cohorts of current and former smokers to efficiently recruit and execute a cross sectional study of 800 subjects with a wide range of disease manifestation and then to follow 450 of them longitudinally over a 2-3 year course. (SA1): To use quantitative CT (QCT) determinants of airway remodeling and emphysema and their associations with other physiologic and functional indices of COPD to define unique clinicopathologic disease subclasses or phenotypes, and (SA2) To Associate Peripheral Blood Molecular and Cellular Biomarkers with Unique Clinical and Lung Histopathologic Phenotypes. We believe, based upon preliminary data, that ascertainable variation in immune cell function, cytokine expression, and genetic factors are different between and can be used to distinguish unique pathophysiologic subsets of patients. We aim nothing short of providing justification for reclassification of COPD into more biologically relevant categories that could direct development of more effective patient specific therapies. In our (SA3) we further explore the recent observations from the laboratory of our co-investigator, Dr. J Hogg, of a dramatic association between peripheral airway luminal mucous content LC% and poor survival. Findings of surrogate markers associated with this process could have immense importance because, to date, we have been unable to identify an association between the severity of LC% and any clinical or physiologic feature. We hypothesize that: Molecular and cellular biomarkers and QCT variables of COPD, in a subgroup of severe patients characterized prior to lung transplantation, are associated with severity of luminal content (LC) occlusion of peripheral airways measured in lung tissue using standard morphometric techniques. Identification of non-invasive surrogates for this condition, could have major implications in determining prognosis or targeting individual therapy.