Stolk Jan, Veldhuisen Barbara, Annovazzi Laura, Zanone Chiara, Versteeg Elly M, van Kuppevelt Toine H, Berden Jo H M, Nieuwenhuizen Willem, Iadarola Paolo, Luisetti Maurizio
Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands.
Respir Res. 2005 May 31;6(1):47. doi: 10.1186/1465-9921-6-47.
The burden of proteinases from inflammatory cells in the lung of subjects with type Pi ZZ of alpha-1-antitrypsin deficiency is higher than in those without the deficiency. Cross-sectional studies have shown increased levels of biomarkers of extracellular matrix degradation in vivo. Longitudinal variability of these biomarkers is unknown but desirable for clinical studies with proteinase inhibitors.
We measured three different types of biomarkers, including desmosines, elastase-formed fibrinogen fragments and heparan sulfate epitope JM403, in plasma and urine for a period of 7 weeks in a group of 12 patients who participated in a placebo-controlled study to assess the safety of a single inhalation of hyaluronic acid.
Effect of study medication on any of the biomarkers was not seen. Baseline desmosines in plasma and urine correlated with baseline CO diffusion capacity (R = 0.81, p = 0.01 and R = 0.65, p = 0.05). Mean coefficient of variation within patients (CVi) for plasma and urine desmosines was 18.7 to 13.5%, respectively. Change in urinary desmosine levels correlated significantly with change in plasma desmosine levels (R = 0.84, p < 0.01). Mean CVi for fibrinogen fragments in plasma was 20.5% and for JM403 in urine was 27.8%. No correlations were found between fibrinogen fragments or JM403 epitope and desmosines.
We found acceptable variability in our study parameters, indicating the feasibility of their use in an evaluation of biochemical efficacy of alpha-1-antitrypsin augmentation therapy in Pi Z subjects.
α-1抗胰蛋白酶缺乏症Pi ZZ型患者肺部炎症细胞中的蛋白酶负荷高于无此缺乏症的患者。横断面研究表明，体内细胞外基质降解生物标志物水平升高。这些生物标志物的纵向变异性尚不清楚，但对于蛋白酶抑制剂的临床研究而言是可取的。
我们在一组12名参与安慰剂对照研究以评估单次吸入透明质酸安全性的患者中，在7周内测量了血浆和尿液中的三种不同类型生物标志物，包括锁链素、弹性蛋白酶形成的纤维蛋白原片段和硫酸乙酰肝素表位JM403。
未观察到研究药物对任何生物标志物的影响。血浆和尿液中的基线锁链素与基线一氧化碳弥散能力相关（R = 0.81，p = 0.01；R = 0.65，p = 0.05）。患者体内血浆和尿液锁链素的平均变异系数（CVi）分别为18.7%至13.5%。尿锁链素水平的变化与血浆锁链素水平的变化显著相关（R = 0.84，p < 0.01）。血浆中纤维蛋白原片段的平均CVi为20.5%，尿液中JM403的平均CVi为27.8%。未发现纤维蛋白原片段或JM403表位与锁链素之间存在相关性。
我们在研究参数中发现了可接受的变异性，表明其可用于评估Pi Z受试者α-1抗胰蛋白酶增强疗法的生化疗效。
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