Identification of novel non-invasive biomarkers of urinary chronic pelvic pain syndrome: findings from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network.
Identification of novel non-invasive biomarkers of urinary chronic pelvic pain syndrome: findings from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network.
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DOI：
10.1111/bju.13832
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发表时间：
2017-07
影响因子：
4.5
通讯作者：
MAPP Research Network
中科院分区：
文献类型：
--
作者：
Dagher A;Curatolo A;Sachdev M;Stephens AJ;Mullins C;Landis JR;van Bokhoven A;El-Hayek A;Froehlich JW;Briscoe AC;Roy R;Yang J;Pontari MA;Zurakowski D;Lee RS;Moses MA;MAPP Research Network
目的探讨泌尿系统慢性盆腔疼痛综合征（UCPPS）的一系列候选标志物，根据其可能参与的潜在生物学过程进行选择，从而为病理生理学提供新的见解，并为扩大临床和机制研究提供靶点。方法：基线尿液样本来自慢性骨盆疼痛多学科研究方法（MAPP）研究网络中患有UCPPS的参与者（n= 259）、阳性对照（PCs；无骨盆疼痛的慢性疼痛，n= 107）和健康对照（hc,n= 125），分析是否存在文献中认为与UCPPS相关的蛋白质。基质金属蛋白酶（MMP）‐2、MMP‐9、MMP‐9/中性粒细胞明胶酶相关脂钙蛋白（NGAL）复合物（也称为脂钙蛋白2）、血管内皮生长因子（VEGF）、VEGF受体1 （VEGF‐R1）和NGAL均采用单特异性酶联免疫吸附法测定和定量。使用Student'st - test比较不同性别的UCPPS、PC和HC组的对数转化浓度（pg/mL或ng/mL）和归一化的总蛋白浓度（pg/μg），并调整p值以进行多重比较。多变量逻辑回归和受试者操作特征曲线评估了生物标志物在区分UCPPS参与者和对照组参与者方面的效用。通过线性回归评估蛋白质与症状严重程度的关系。结果男性患者血清VEGF、VEGF‐R1和MMP‐9正常化浓度（pg/μg）和女性患者血清VEGF浓度（pg/mL）与UCPPS和HC相关。这些蛋白在UCPPS参与者和hc之间仅提供了边际区别。在患有UCCPS的男性中，疼痛严重程度与MMP‐9和MMP‐9/NGAL复合物的浓度显著正相关，尿的严重程度与MMP‐9、MMP‐9/NGAL复合物和VEGF‐R1显著正相关。在患有UCPPS的女性中，疼痛和泌尿症状严重程度与MMP‐9/NGAL复合物的正常化浓度升高相关，而疼痛严重程度单独与VEGF的正常化浓度升高相关，而泌尿症状严重程度单独与MMP‐2的正常化浓度升高相关。UCPPS患者的疼痛严重程度与除NGAL外的所有生物标志物浓度呈显著正相关，尿液严重程度与除VEGF‐R1外的所有浓度呈显著正相关。结论MMP‐9、MMP‐9/NGAL复合物和VEGF‐R1水平的改变与男性和女性的所有生物标志物的改变与UCPPS的临床症状相关。所有评估的候选标记物都不能有效地区分UCPPS患者和对照组。升高的VEGF、MMP - 9和VEGF - R1水平在男性和女性中可能为UCPPS的病理生理提供潜在的新见解。
ObjectiveTo examine a series of candidate markers for urological chronic pelvic pain syndrome (UCPPS), selected based on their proposed involvement in underlying biological processes so as to provide new insights into pathophysiology and suggest targets for expanded clinical and mechanistic studies.MethodsBaseline urine samples from Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study participants with UCPPS (n= 259), positive controls (PCs; chronic pain without pelvic pain,n= 107) and healthy controls (HCs,n= 125) were analysed for the presence of proteins that are suggested in the literature to be associated with UCPPS. Matrix metalloproteinase (MMP)‐2, MMP‐9, MMP‐9/neutrophil gelatinase‐associated lipocalin (NGAL) complex (also known as Lipocalin 2), vascular endothelial growth factor (VEGF), VEGF receptor 1 (VEGF‐R1) and NGAL were assayed and quantitated using mono‐specific enzyme‐linked immunosorbent assays for each protein. Log‐transformed concentration (pg/mL or ng/mL) and concentration normalized to total protein (pg/μg) values were compared among the UCPPS, PC and HC groups within sex using the Student'st‐test, withPvalues adjusted for multiple comparisons. Multivariable logistic regression and receiver‐operating characteristic curves assessed the utility of the biomarkers in distinguishing participants with UCPPS and control participants. Associations of protein with symptom severity were assessed by linear regression.ResultsSignificantly higher normalized concentrations (pg/μg) of VEGF, VEGF‐R1 and MMP‐9 in men and VEGF concentration (pg/mL) in women were associated with UCPPS vs HC. These proteins provided only marginal discrimination between UCPPS participants and HCs. In men with UCCPS, pain severity was significantly positively associated with concentrations of MMP‐9 and MMP‐9/NGAL complex, and urinary severity was significantly positively associated with MMP‐9, MMP‐9/NGAL complex and VEGF‐R1. In women with UCPPS, pain and urinary symptom severity were associated with increased normalized concentrations of MMP‐9/NGAL complex, while pain severity alone was associated with increased normalized concentrations of VEGF, and urinary severity alone was associated with increased normalized concentrations of MMP‐2. Pain severity in women with UCPPS was significantly positively associated with concentrations of all biomarkers except NGAL, and urinary severity with all concentrations except VEGF‐R1.ConclusionAltered levels of MMP‐9, MMP‐9/NGAL complex and VEGF‐R1 in men, and all biomarkers in women, were associated with clinical symptoms of UCPPS. None of the evaluated candidate markers usefully discriminated UCPPS patients from controls. Elevated VEGF, MMP‐9 and VEGF‐R1 levels in men and VEGF levels in women may provide potential new insights into the pathophysiology of UCPPS.
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