The Dorothy P. & Richard P. Simmons Center for Interstitial Lung Disease, Department of Medicine, University of Pittsburgh Medical Center, NW 628 MUH, 3459 5th Avenue, Pittsburgh, PA 15261, USA.
Am J Respir Crit Care Med. 2012 Jan 1;185(1):67-76. doi: 10.1164/rccm.201101-0058OC.
Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of unknown etiology with a variable and unpredictable course.
The aim of this study was to identify and validate plasma proteins that are predictive of outcome in IPF.
Plasma samples were available for 241 patients with IPF (140 derivation and 101 validation). In the derivation cohort, concentrations of 92 proteins were analyzed using a multiplex bead-based immunoassay and concentrations of matrix metalloproteinase (MMP)-7, MMP-1, and surfactant protein D were assessed by ELISA. In the validation cohort concentrations of intercellular adhesion molecule (ICAM)-1, IL-8, and vascular cell adhesion molecule (VCAM)-1 were assessed by bead-based multiplex assay, and S100A12 and MMP-7 by ELISA. Associations of biomarkers with mortality, transplant-free survival, and disease progression were tested in the derivation and validation cohorts using nonparametric methods of survival analysis and the Cox proportional hazards model, and an integrated risk prediction score was derived and tested.
High concentrations of MMP-7, ICAM-1, IL-8, VCAM-1, and S100A12 predicted poor overall survival, poor transplant-free survival, and poor progression-free survival in the derivation cohort. In the independent validation cohort high concentrations of all five were predictive of poor transplant-free survival; MMP-7, ICAM-1, and IL-8 of overall survival; and ICAM-1 of poor progression-free survival. The personal clinical and molecular mortality prediction index derived in the derivation cohort was highly predictive of mortality in the validation cohort.
Our results suggest that plasma proteins should be evaluated as a tool for prognosis determination in prioritization of patients for lung transplantation and stratification in drug studies.
特发性肺纤维化（IPF）是一种病因不明的致命肺部疾病，其病程具有多变性和不可预测性。
本研究旨在鉴定并验证可预测 IPF 患者结局的血浆蛋白。
本研究纳入了 241 例 IPF 患者（140 例来自于推导队列，101 例来自于验证队列）的血浆样本。在推导队列中，使用基于多重微珠的免疫分析法分析了 92 种蛋白的浓度，同时通过 ELISA 法评估了基质金属蛋白酶（MMP）-7、MMP-1 和表面活性蛋白 D 的浓度。在验证队列中，通过基于多重微珠的免疫分析法评估了细胞间黏附分子（ICAM）-1、白细胞介素（IL）-8 和血管细胞黏附分子（VCAM）-1 的浓度，通过 ELISA 法评估了 S100A12 和 MMP-7 的浓度。在推导和验证队列中，使用非参数生存分析方法和 Cox 比例风险模型检测了生物标志物与死亡率、无移植生存率和疾病进展的相关性，并推导和检验了综合风险预测评分。
在推导队列中，MMP-7、ICAM-1、IL-8、VCAM-1 和 S100A12 的高浓度预示着总体生存率、无移植生存率和无进展生存率较差。在独立的验证队列中，这 5 种标志物的高浓度均预示着无移植生存率较差；MMP-7、ICAM-1 和 IL-8 预示着总体生存率较差；而 ICAM-1 则预示着无进展生存率较差。在推导队列中得出的个人临床和分子死亡率预测指数在验证队列中具有高度的死亡率预测价值。
我们的研究结果表明，血浆蛋白可以作为一种工具，用于确定患者的预后，以优先考虑肺移植，并在药物研究中进行分层。
