Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) play important roles in the turnover of extracellular matrix and in the pathogenesis of idiopathic pulmonary fibrosis (IPF). This study aimed to determine the utility of circulating MMPs and TIMPs in distinguishing patients with IPF from controls and to explore associations between MMPs/TIMPs and measures of disease severity in patients with IPF. The IPF cohort (n = 300) came from the IPF-PRO Registry, an observational multicenter registry of patients with IPF that was diagnosed or confirmed at the enrolling center in the past 6 months. Controls (n = 100) without known lung disease came from a population-based registry. Generalized linear models were used to compare circulating concentrations of MMPs 1, 2, 3, 7, 8, 9, 12, and 13 and TIMPs 1, 2, and 4 between patients with IPF and controls, and to investigate associations between circulating levels of these proteins and measures of IPF severity. Multivariable models were fit to identify the MMP/TIMPs that best distinguished patients with IPF from controls. All the MMP/TIMPs analyzed were present at significantly higher levels in patients with IPF compared with controls except for TIMP2. Multivariable analyses selected MMP8, MMP9 and TIMP1 as top candidates for distinguishing patients with IPF from controls. Higher concentrations of MMP7, MMP12, MMP13 and TIMP4 were significantly associated with lower diffusion capacity of the lung for carbon monoxide (DLCO) % predicted and higher composite physiologic index (worse disease). MMP9 was associated with the composite physiologic index. No MMP/TIMPs were associated with forced vital capacity % predicted. Circulating MMPs and TIMPs were broadly elevated among patients with IPF. Select MMP/TIMPs strongly associated with measures of disease severity. Our results identify potential MMP/TIMP targets for further development as disease-related biomarkers.

中文翻译：

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多中心 IPF-PRO 注册队列中特发性肺纤维化患者的循环基质金属蛋白酶和组织金属蛋白酶抑制剂。

基质金属蛋白酶 (MMP) 和 MMP 组织抑制剂 (TIMP) 在细胞外基质的更新和特发性肺纤维化 (IPF) 的发病机制中起重要作用。本研究旨在确定循环 MMP 和 TIMP 在区分 IPF 患者和对照组中的效用，并探讨 MMP/TIMP 与 IPF 患者疾病严重程度测量之间的关联。IPF 队列 (n = 300) 来自 IPF-PRO 登记处，这是一个针对过去 6 个月在登记中心诊断或确诊的 IPF 患者的观察性多中心登记处。没有已知肺部疾病的对照 (n = 100) 来自基于人群的登记。广义线性模型用于比较 MMP 1、2、3、7、8、9、12 和 13 以及 TIMP 1、2、和 4 在 IPF 患者和对照组之间，并研究这些蛋白质的循环水平与 IPF 严重程度测量之间的关联。多变量模型适用于识别最能区分 IPF 患者和对照组的 MMP/TIMP。除 TIMP2 外，所有分析的 MMP/TIMP 在 IPF 患者中的水平均显着高于对照组。多变量分析选择 MMP8、MMP9 和 TIMP1 作为区分 IPF 患者和对照组的最佳候选者。较高浓度的 MMP7、MMP12、MMP13 和 TIMP4 与较低的肺一氧化碳扩散能力 (DLCO) 预测百分比和较高的复合生理指数（更严重的疾病）显着相关。MMP9与复合生理指标相关。没有 MMP/TIMP 与用力肺活量 % 预测相关。IPF 患者的循环 MMP 和 TIMP 普遍升高。选择与疾病严重程度测量密切相关的 MMP/TIMP。我们的结果确定了潜在的 MMP/TIMP 目标以进一步开发为疾病相关的生物标志物。