Propranolol-mediated attenuation of MMP-9 excretion in infants with hemangiomas.
Propranolol-mediated attenuation of MMP-9 excretion in infants with hemangiomas.
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DOI：
10.1001/jamaoto.2013.4773
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发表时间：
2013-10
期刊：
影响因子：
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通讯作者：
Silpa S. Thaivalappil;N. Bauman;Amarel Saieg;Elizabeth Movius;K. Brown;D. Preciado
中科院分区：
文献类型：
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作者：
Silpa S. Thaivalappil;N. Bauman;Amarel Saieg;Elizabeth Movius;K. Brown;D. Preciado
婴儿血管瘤（IH）在组织受累的部位和程度上差异很大，但IH的生物学进展是非常独特和可预测的。普萘洛尔是一种有效的治疗症状性IH，但其作用机制仍然未知和研究不足。目的比较普萘洛尔与泼尼松龙治疗婴儿IH后的排泄蛋白。设计、地点和参与者：对2010年7月至2012年9月在一家三级儿科医院就诊的IH患者进行探索性尿蛋白质组学分析。参与者是在我们机构接受IH治疗的婴儿，他们参加了一项比较泼尼松龙与普萘洛尔的盲法随机试验。他们在入组时的年龄从14天到15个月不等。排除标准包括糖尿病、哮喘和/或心血管疾病（包括高血压或低血压）病史。从所有参与者中纵向收集尿液样本。将样品脱盐、浓缩和凝胶分级，并使用液相色谱串联质谱法鉴定蛋白质含量。蛋白质印迹分析和酶联免疫吸附试验（ELISA）进行验证质谱的结果。干预治疗普萘洛尔或泼尼松龙开始前6个月的年龄。主要结果和测量尿液样本中存在的蛋白质和尿蛋白水平随时间的变化。结果样本来自3例接受泼尼松龙治疗的患者，3例接受普萘洛尔治疗的患者和5例未接受IH治疗的对照组。蛋白质组学鉴定了1000多种尿蛋白。与泼尼松龙治疗的患者相比，普萘洛尔治疗的患者在增殖期尿液中分泌的基质金属蛋白酶9（MMP-9）减弱。这些发现用蛋白质印迹分析验证，并用ELISA定量，证实与泼尼松龙治疗的IH患者相比，心得安治疗的IH患者在生命的第一年中的平均尿MMP-9水平显著降低（0.118 vs 0.501 ng/mL; P = .03）或未经治疗的IH患者（0.118 vs 3.69 ng/mL; P = .02）。结论和相关性普萘洛尔治疗减少IH患者尿中MMP-9的排泄。基质金属蛋白酶9可能是IH普萘洛尔反应性的生物标志物，其信号通路可能代表该药物的分子靶点。
IMPORTANCE Infantile hemangiomas (IHs) vary substantially in localization and extent of tissue involvement, but IH biological progression is remarkably unique and predictable. Propranolol is an effective treatment for symptomatic IH, but its mechanism of action remains unknown and understudied. OBJECTIVE To compare excreted proteins in infants with IH being treated with propranolol vs prednisolone. DESIGN, SETTING, AND PARTICIPANTS Exploratory urine proteomics profiling of patients with IH from July 2010 to September 2012 at a tertiary pediatric hospital. Participants were infants with IH treated at our institution who were participating in a blinded, randomized trial comparing prednisolone vs propranolol. They ranged in age from 14 days to 15 months at enrollment. Exclusion criteria included a history of diabetes mellitus, asthma, and/or cardiovascular disease including hypertension or hypotension. Urine samples were longitudinally collected from all participants. Specimens were desalted, concentrated, and gel fractionated, and the protein content was identified using liquid chromatography tandem mass spectrometry. Western blot analyses and enzyme-linked immunosorbent assays (ELISAs) were performed to validate mass spectrometry findings. INTERVENTION Treatment with propranolol or prednisolone administered starting before the age of 6 months. MAIN OUTCOMES AND MEASURES Proteins present in urine samples and change in urinary levels of proteins over time. RESULTS Samples were obtained from 3 patients treated with prednisolone, 3 patients treated with propranolol, and 5 untreated controls with IH. More than 1000 urinary proteins were identified by proteomics. Patients treated with propranolol demonstrated attenuation of excreted matrix metalloproteinase 9 (MMP-9) in urine over the proliferative phase of the condition compared with prednisolone-treated patients. These findings were validated with Western blot analysis and quantified with ELISA, which confirmed mean urinary MMP-9 levels in the first year of life to be significantly lower in propranolol-treated patients with IH compared with prednisolone-treated patients with IH (0.118 vs 0.501 ng/mL; P = .03) or with nontreated patients with IH (0.118 vs 3.69 ng/mL; P = .02). CONCLUSIONS AND RELEVANCE Propranolol treatment decreases urinary excretion of MMP-9 in patients with IH. Matrix metalloproteinase 9 may be a biomarker for IH propranolol responsiveness, and its signaling pathways may represent the molecular target of this drug.