Tzouvelekis Argyris, Herazo-Maya Jose D, Slade Martin, Chu Jen-Hwa, Deiuliis Giuseppe, Ryu Changwan, Li Qin, Sakamoto Koji, Ibarra Gabriel, Pan Hongyi, Gulati Mridu, Antin-Ozerkis Danielle, Herzog Erica L, Kaminski Naftali
Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
Department of Occupational and Environmental Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
Respirology. 2017 Apr;22(3):486-493. doi: 10.1111/resp.12920. Epub 2016 Oct 19.
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis and variable clinical course. Although matrix metalloproteinase-7 (MMP-7) is emerging as an important IPF biomarker, reproducibility across studies is unclear. We aimed to determine whether a previously reported prognostic threshold for MMP-7 was predictive of mortality in an independent cohort of IPF patients.
MMP-7 concentrations obtained from heparinized plasma samples were determined by ELISA in 97 patients with IPF and 41 healthy controls. The association of the previously published heparin plasma MMP-7 threshold of 12.1 ng/mL with all-cause mortality or transplant-free survival (TFS) was determined, either as an independent biomarker or as part of the modified personal clinical and molecular mortality index (m-PCMI).
MMP-7 plasma concentrations were significantly higher in IPF patients compared to healthy controls (14.40 ± 6.55 ng/mL vs 6.03 ± 2.51 ng/mL, P < 0.001). The plasma MMP-7 threshold of 12.1 ng/mL was significantly associated with both all-cause mortality and TFS (unadjusted Cox proportional hazard ratio (HR) = 25.85 and 15.49, 95% CI: 10.91-61.23 and 5.41-44.34, respectively, P < 0.001). MMP-7 concentrations, split by 12.1 ng/mL, were significantly (P < 0.05) predictive of mortality and TFS after adjusting for age, gender, smoking and baseline pulmonary function parameters, in a multivariate Cox proportional hazards model. MMP-7 concentrations were negatively correlated with diffusing lung capacity of carbon monoxide (DL ) (r = -0.21, P = 0.02), and positively with a mortality risk scoring system (GAP) that combines age, gender, forced vital capacity (FVC) and DL (r = 0.32, P = 0.001).
This study confirms that MMP-7 concentrations could be used to accurately predict outcomes across cohorts and centres, when similar collection protocols are applied.
特发性肺纤维化（IPF）是一种预后不良且临床病程多变的进行性疾病。尽管基质金属蛋白酶-7（MMP-7）正逐渐成为一种重要的IPF生物标志物，但各研究间的可重复性尚不清楚。我们旨在确定先前报道的MMP-7预后阈值是否能预测独立IPF患者队列中的死亡率。
通过酶联免疫吸附测定法（ELISA）测定97例IPF患者和41例健康对照者肝素化血浆样本中的MMP-7浓度。确定先前公布的12.1 ng/mL肝素血浆MMP-7阈值与全因死亡率或无移植生存期（TFS）之间的关联，既作为独立生物标志物，也作为改良的个人临床和分子死亡率指数（m-PCMI）的一部分。
与健康对照者相比，IPF患者的血浆MMP-7浓度显著更高（14.40±6.55 ng/mL对6.03±2.51 ng/mL，P<0.001）。12.1 ng/mL的血浆MMP-7阈值与全因死亡率和TFS均显著相关（未调整的Cox比例风险比（HR）分别为25.85和15.49，95%置信区间：10.91-61.23和5.41-44.34，P<0.001）。在多变量Cox比例风险模型中，按12.1 ng/mL划分的MMP-7浓度在调整年龄、性别、吸烟和基线肺功能参数后，对死亡率和TFS具有显著（P<0.05）预测性。MMP-7浓度与一氧化碳弥散量（DL）呈负相关（r=-0.21，P=0.02），与结合年龄、性别、用力肺活量（FVC）和DL的死亡率风险评分系统（GAP）呈正相关（r=0.32，P=0.001）。
本研究证实，当应用相似的采集方案时，MMP-7浓度可用于准确预测不同队列和中心的预后。
