Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Valladolid, Spain; IOBA (Institute of Applied Ophthalmobiology), Universidad de Valladolid, Valladolid, Spain.
IOBA (Institute of Applied Ophthalmobiology), Universidad de Valladolid, Valladolid, Spain; Red Temática de Investigación Colaborativa en Oftalmología (OftaRed), Instituto de Salud Carlos III, Madrid, Spain.
Ocul Surf. 2019 Jul;17(3):502-515. doi: 10.1016/j.jtos.2019.03.009. Epub 2019 Mar 30.
To investigate response profiles in the lacrimal functional unit of dry eye disease (DED) and healthy volunteers after exposure to a controlled adverse desiccating environment (CADE) by identifying groups of individuals with similar clinical and molecular changes.
Clinical parameters and tear molecule levels of 20 mild-moderate DED patients and 20 healthy volunteers were evaluated pre- (baseline) and post-CADE exposure. Clustering based on relative change from baseline values was used to identify response profiles. One-vs-all logistic regression was used to identify baseline predictors for response clusters.
Four response profiles were identified. Cluster 1: tear break-up time (TBUT) decrease and matrix metalloproteinase 9 (MMP-9) increase. Cluster 2: marked increase in corneal staining, up-regulation of both MMP-9 and interleukin (IL)-6 levels, and down-regulation of epithelial growth factor (EGF). Cluster 3: increase in fractalkine, vascular endothelial growth factor (VEGF), MMP-9, IL-6, IL-8, IL-1 receptor antagonist (IL-1Ra) and RANTES (regulated on activation, normal T expressed and secreted) tear levels; and increased corneal staining and decreased TBUT and phenol red thread scores. Cluster 4: decreased single-item score dry eye questionnaire (SIDEQ) scores and increased corneal staining. Predictive models using baseline variables found that cluster membership depended on: corneal and conjunctival staining, SIDEQ score, interferon gamma-induced protein (IP)-10, VEGF, and IL-1Ra concentrations.
The response of both mild-moderate DED and healthy asymptomatic individuals to environmental stress (CADE) can be predicted based on baseline (pre-exposure) clinical and tear molecular parameters. Thus, identifying individuals with a predictable response could improve patient enrollment in DED clinical trials.
通过识别具有相似临床和分子变化的个体群体，研究干眼症 (DED) 患者和健康志愿者的泪液功能单位在暴露于受控干燥环境 (CADE) 后的反应特征。
在暴露于 CADE 之前（基线）和之后，评估 20 名轻度至中度 DED 患者和 20 名健康志愿者的临床参数和泪液分子水平。基于与基线值的相对变化进行聚类，以确定反应特征。使用一对一逻辑回归来确定反应群的基线预测因子。
确定了四个反应特征。聚类 1：泪膜破裂时间 (TBUT) 减少和基质金属蛋白酶 9 (MMP-9) 增加。聚类 2：角膜染色明显增加，MMP-9 和白细胞介素 (IL)-6 水平上调，上皮生长因子 (EGF) 下调。聚类 3： fractalkine、血管内皮生长因子 (VEGF)、MMP-9、IL-6、IL-8、IL-1 受体拮抗剂 (IL-1Ra) 和 RANTES（正常 T 细胞激活表达和分泌调节）的泪液水平增加；角膜染色增加，TBUT 和酚红线评分降低。聚类 4：SIDEQ 问卷（干性眼病问卷）单项评分降低，角膜染色增加。使用基线变量的预测模型发现，聚类成员取决于：角膜和结膜染色、SIDEQ 评分、干扰素γ诱导蛋白 (IP)-10、VEGF 和 IL-1Ra 浓度。
基于基线（暴露前）临床和泪液分子参数，可以预测轻度至中度 DED 患者和无症状健康个体对环境应激 (CADE) 的反应。因此，识别具有可预测反应的个体可以改善 DED 临床试验的患者入组。
