Systematic phenotyping and correlation of biomarkers with lung function and histology in lung fibrosis
Systematic phenotyping and correlation of biomarkers with lung function and histology in lung fibrosis
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DOI：
10.1152/ajplung.00183.2015
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发表时间：
2016-05-15
影响因子：
4.9
通讯作者：
Eickelberg, Oliver
中科院分区：
文献类型：
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作者：
Fernandez, Isis E.;Amarie, Oana V.;Eickelberg, Oliver
迄今为止，特发性肺纤维化（IPF）的表型和病程预测主要依赖于肺功能指标。最近有人提出将血液生物标志物用于特发性肺纤维化的诊断和结局预测，但它们与肺功能和组织学的相关性仍不清楚。在此，我们全面评估了液体活检中的生物标志物，并将其丰度与肺纤维化发作、进展和消退期间的肺功能和组织学相关联，旨在更准确地评估博来霉素诱导的肺纤维化临床前模型中的疾病进展。重要的是，在第14天观察到肺功能与纤维化组织学程度的最强相关性，而在第28天和第56天肺功能没有变化，即使组织学评估显示明显的纤维化病变。虽然基质金属蛋白酶-7（MMP-7），MMP-9和派-1显着升高，支气管肺泡灌洗液中的纤维化小鼠，只有可溶性ICAM-1（sI-CAM-1）的纤维化小鼠外周血中升高，并与纤维化的程度密切相关。重要的是，组织结合ICAM-1在肺匀浆中也升高，在增生的II型肺泡上皮细胞和内皮细胞中具有显著的染色。总之，我们表明肺功能下降不是组织学上明显的纤维化的先决条件，特别是在其发作或消退期间。sICAM-1的血浆水平与肺纤维化的程度密切相关，因此可以考虑用于肺纤维化临床前研究中个体内治疗研究的评估。
To date, phenotyping and disease course prediction in idiopathic pulmonary fibrosis (IPF) primarily relies on lung function measures. Blood biomarkers were recently proposed for diagnostic and outcome prediction in IPF, yet their correlation with lung function and histology remains unclear. Here, we comprehensively assessed biomarkers in liquid biopsies and correlated their abundance with lung function and histology during the onset, progression, and resolution of lung fibrosis, with the aim to more precisely evaluate disease progression in the preclinical model of bleomycin-induced pulmonary fibrosis in vivo. Importantly, the strongest correlation of lung function with histological extent of fibrosis was observed at day 14, whereas lung function was unchanged at days 28 and 56, even when histological assessment showed marked fibrotic lesions. Although matrix metalloproteinase-7 (MMP-7), MMP-9, and PAI-1 were significantly elevated in broncheoalveolar lavage of fibrotic mice, only soluble ICAM-1 (sI-CAM-1) was elevated in the peripheral blood of fibrotic mice and was strongly correlated with the extent of fibrosis. Importantly, tissue-bound ICAM-1 was also elevated in lung homogenates, with prominent staining in hyperplastic type II alveolar epithelial and endothelial cells. In summary, we show that lung function decline is not a prerequisite for histologically evident fibrosis, particularly during the onset or resolution thereof. Plasma levels of sICAM-1 strongly correlate with the extent of lung fibrosis, and may thus be considered for the assessment of intraindividual therapeutic studies in preclinical studies of pulmonary fibrosis.