Increased plasma matrix metalloproteinase-9 levels in migraineurs

BACKGROUND AND OBJECTIVE: Cortical spreading depression and neurogenic inflammation have been hypothesized to be key steps in the development of migraine headache. Recent studies have highlighted matrix metalloproteinase-9 (MMP-9) in cortical spreading depression, neurogenic inflammation, and cerebral ischemia. To seek their possible association, we investigated plasma MMP-9 levels in migraineurs during headache-free periods. METHODS: Plasma MMP-9 levels in 84 migraine subjects and 61 controls were determined by enzyme-linked immunosorbent assay. In addition, 23 patients with tension type headache were included in the study as comparative subjects. RESULTS: The MMP-9 levels in migraineurs (42.5+/-4.6 ng/mL, mean+/-SE) were significantly higher than those in controls (25.4+/-2.7 ng/mL, P< .005). Those levels in tension type headache subjects (24.6+/-4.8 ng/mL) did not differ from those in controls. There was no significant difference between subjects having migraine with aura and those without aura. The MMP-9 levels did not correlate with age, duration of illness, frequency of migraine attack, duration of headache attack, or medication for headache. Mean plasma MMP-9 levels were the highest in subjects from whom blood samples were taken 2-4 days after their latest attack. CONCLUSIONS: The degradation of extracellular matrix showing the increase of MMP-9 in migraineurs may be associated with an abnormality in their blood vessel permeability. MPP-9 plays some role in migraine pathophysiology. Further studies of MMPs are necessary to elucidate their role.     

Neurogenic model of migraine

Activation of peripheral trigeminal fibers induces neurogenic inflammation in rat dura mater, as well as vascular and mast cell changes. These changes parallel an increase of vasodilating and permeability promoting peptides in venous effluent of the cephalic circulation. The experimental model of electrical trigeminal ganglion stimulation or systemic capsaicin administration has proven effective in detecting cellular activation in brainstem trigeminal nuclei. Animal experimental models of trigeminovascular activation and the effects of antimigraine drugs on functional and morphological consequences of such activation provide the background for further models and for developing pharmacological strategies in this field.     

Medical applications of transforming growth factor-beta

Transforming growth factor-beta (TGF-beta) proteins and their antagonists have entered clinical trials. These multi-functional regulators of cell growth and differentiation induce extracellular matrix proteins and suppress the immune system making TGF-betas useful in treatment of wounds with impaired healing, mucositis, fractures, ischemia-reperfusion injuries, and autoimmune disease. In diseases such as keloids, glomerulonephritis and pulmonary fibrosis, excessive expression of TGF-beta has been implicated as being responsible for accumulation of detrimental scar tissue. In these conditions, agents that block TGF-beta have prevented or reversed disease. Similarly, in carcinogenesis, blocking TGF-beta activity may be valuable in stimulating an immune response towards metastasis. As these blocking agents receive approval, we will likely have new therapies for previously recalcitrant diseases.     

An alpha 2-macroglobulin receptor-dependent mechanism for the plasma clearance of transforming growth factor-beta 1 in mice.

Radioiodinated transforming growth factor-beta 1 (TGF-beta 1) bound to the plasma proteinase inhibitor, alpha 2-macroglobulin (alpha 2M), as determined by chromatography on Superose-6 and native polyacrylamide gel electrophoresis. When alpha 2M conformational change was induced with methylamine, 125I-TGF-beta 1 binding significantly increased. Intravenously injected 125I-TGF-beta 1 cleared from the circulation of mice rapidly at first; however, intravascular radioactivity stabilized near 20% of the initial level. At necropsy, radioactivity was recovered predominantly in the liver (65%); however, the density of radioactivity (disintegrations per minute/g organ wt) was highest in the lungs. Markedly different results were obtained with purified 125I-TGF-beta 1-alpha 2M-methylamine complex. Clearance of the complex occurred as a first-order process with a t1/2 of 4 min. Greater than 90% of the radioactivity was recovered in the liver. The clearance and distribution of 125I-TGF-beta 1-alpha 2M-methylamine were equivalent to those observed with 125I-alpha 2M-methylamine and 125I-alpha 2M-trypsin. The latter two radioligands clear via specific alpha 2M receptors in the liver. Large molar excesses of alpha 2M-trypsin or alpha 2M-methylamine competed with 125I-TGF-beta 1-alpha 2M-methylamine for plasma clearance. Native alpha 2M, which does not bind to the alpha 2M receptor, did not compete. The receptor binding domain of alpha 2M-methylamine was blocked by chemical modification or enzyme treatment. The resulting alpha 2M preparations still bound 125I-TGF-beta 1; however, the complexes did not clear when injected intravenously in mice. The studies presented here demonstrate that alpha 2M can mediate the plasma clearance of a growth factor via the alpha 2M receptor system. We propose that alpha 2M, the alpha 2M receptor, and proteinases may function as a concerted system to regulate TGF-beta 1 activity and the activity of related factors in vivo.     

小鼠心肌转化生长因子β1表达与依普利酮的影响

目的:观察高选择性醛固酮受体拮抗剂依普利酮对鸟苷酸环化酶偶联受体-A基因敲除小鼠心肌转化生长因子β1表达的影响,并对其逆转心室重构的分子机制进行探讨.方法:实验于2005-06/2006-04 在河北省人民医院心内科、日本奈良县立医科大学第一内科完成.①实验材料:鸟苷酸环化酶偶联受体-A基因敲除小鼠20只由日本国立循环器病中心岸本一郎教授馈赠,雄性,12周龄,基因背景为清洁级C57BL/6小鼠,随机数字表法分为空白对照组6只、依普利酮组7只、肼苯哒嗪组7只.另取同龄野生型小鼠7只作为野生组.实验过程中对动物的处置符合动物伦理学标准.②实验方法:依普利酮组每天通过饲料给予100 mg/kg依普利酮,肼苯哒嗪组每天通过饮用水给予10 mg/kg肼苯哒嗪,均给药4周.空白对照组与野生组不进行任何干预.③实验评估:每周检测小鼠尾动脉收缩压及体质量.各组小鼠于16周龄时采用腹主动脉抽血法处死,称取心脏重量,计算心脏重量与体质量的比值.心脏切片行Masson三色染色,并利用图像分析系统测量心肌胶原容积分数、心肌血管周围胶原面积和管腔面积之比.实时定量PCR法检测心室胶原纤维Ⅰ、胶原纤维Ⅲ、心肌转化生长因子β1 mRNA在心肌组织的表达.结果:①心室重构指标检测:与野生组比较,空白对照组收缩压、心脏重量/体质量、心肌胶原容积分数、心肌血管周围胶原面积/管腔面积均显著升高(P ＜ 0.01).与空白对照组比较,依普利酮组上述4项指标均显著下降(P ＜ 0.05或0.01);肼苯哒嗪组收缩压明显下降(P ＜ 0.01),心脏重量/体质量、心肌胶原容积分数、心肌血管周围胶原面积/管腔面积则明显升高(P ＜ 0.05).②心肌纤维化情况: 与空白对照组比较,依普利酮治疗4周后小鼠心肌纤维化得到改善,心脏重量/体质量、心肌胶原容积分数、心肌血管周围胶原面积/管腔面积3项量化指标均降低;肼苯哒嗪治疗4周后表现为心肌纤维化加重,3项量化指标相应增加.③心肌胶原纤维Ⅰ、胶原纤维Ⅲ及心肌转化生长因子β1 mRNA的表达:与空白对照组比较,依普利酮治疗4周后小鼠胶原纤维Ⅰ、胶原纤维Ⅲ及心肌转化生长因子β1的mRNA表达均下降;肼苯哒嗪治疗4周后三者mRNA的表达均升高.结论:依普利酮可独立于血压改善小鼠心肌纤维化和心室重构,其作用机制可能与抑制心室肌高表达的心肌转化生长因子β1有关.     

Nrf2/ARE信号通路激活对偏头痛大鼠神经源性炎症的影响

目的探讨核因子E2相关因子2/抗反应元件(Nrf2/ARE)通路激活对硝酸甘油(NTG)诱导的偏头痛模型大鼠神经源性炎症的影响。方法将大鼠随机分为NS组、莱菔硫烷(SFN)+NS组、NTG组、H₂O+NTG组及SFN+NTG组,6只/组。拍摄大鼠挠头视频,应用ELISA检测颈静脉血CGRP浓度,应用Western Blot检测大鼠硬脑膜Nrf2、HO1、NQO1、NF-κB、TNF-α及IL-1β的表达。结果SFN+NTG组各时间段大鼠挠头次数少于H₂O+NTG组(P<0.01)。SFN+NTG组的核Nrf2及下游HO1、NQO1蛋白的表达均高于NTG组与H₂O+NTG组,颈静脉血CGRP浓度低于H₂O+NTG组,硬脑膜NF-κB及TNF-α、IL-1β表达均低于NTG组与H₂O+NTG组(P<0.01)。结论Nrf2/ARE信号通路的激活可减少NTG诱导的偏头痛大鼠挠头次数,降低颈静脉CGRP的浓度,抑制硬脑膜炎症因子的表达,发挥神经保护作用。     

Increased C-reactive protein in young adult patients with migraine

Interictal serum C-reactive protein (CRP) was measured in 50 young adult patients with migraine and compared with 50 controls. The median CRP level was 1.42 mg/l in patients with migraine and 0.90 mg/l in controls (P = 0.03). This finding supports the role of inflammation in migraine, but needs confirmation in larger controlled studies. Prospective studies may establish whether measurements of CRP can identify patients with migraine at risk for cardiovascular events.     

Increased plasma histamine levels in migraine patients

Whole blood and plasma histamine levels, peripheral basophil and eosinophil counts and serum immunoglobulins have been measured in a group of eighteen patients with migraine in remission and in twelve of these patients during a headache attack. Plasma histamine levels were significantly elevated (P less than 0.0005) in patients with migraine both during headache attacks and symptom-free periods.     

肺纤维化模型大鼠肺组织中转化生长因子β1及转化生长因子β1mRNA的表达及黄芪莪术合剂的干预效应

目的:分析中药黄芪莪术合剂对博莱霉素所致大鼠肺间质纤维化的干预作用。方法:实验于2002-10/2003-02在天津中医药大学动物实验室完成。①健康SD大白鼠60只,正常饲养1周后,随机分为正常对照组6只、模型组18只、黄芪莪术合剂组18只、强的松组18只。②经气管滴入博莱霉素复制肺纤维化大鼠模型,黄芪莪术合剂组给予40.5mg/L黄芪莪术合剂,强的松组给予0.63g/L强的松盐水溶液,均采用灌胃方式给药,每次1.5mL,1次/d。正常对照组、模型组给予等量生理盐水。③模型组、黄芪莪术合剂组、强的松组分别于造模第3,7,21天每组6只麻醉下取右肺下叶组织后处死,正常对照组于第3天麻醉下取右肺下叶组织后处死。④采用免疫组织化学方法和原位杂交方法检测肺组织转化生长因子β1及转化生长因子β1mRNA的表达。结果:进入结果分析大鼠55只,中途脱落5只。①转化生长因子β1表达:造模第3,7,21天模型组高于正常对照组(P<0.01),黄芪莪术合剂组和强的松组明显低于模型组(P<0.01～0.05)。造模第3,21天强的松治疗组低于黄芪莪术合剂治疗组(P<0.05)。②转化生长因子β1mRNA表达:造模第3,7,21天模型组高于正常对照组,黄芪莪术合剂组和强的松组明显低于模型组(P<0.01);第7天时,强的松治疗组低于黄芪莪术合剂治疗组,第21天时黄芪莪术合剂治疗组低于强的松治疗组,差异均有显著性意义(P<0.05)。结论:中药黄芪莪术合剂具有显著抑制博莱霉素致大鼠肺纤维化的作用,抑制转化生长因子β1及转化生长因子β1mRNA的表达是其可能的机制之一。     

Hypertrophic stimuli induce transforming growth factor-beta 1 expression in rat ventricular myocytes.

Transforming growth factor-beta 1 (TGF-beta 1) is a peptide growth factor that may play a role in the myocardial response to hypertrophic stimuli. However, the cellular distribution, mechanism of induction, and source of increased TGF-beta 1 in response to hypertrophic stimuli are not known. We tested the hypothesis that the cardiac myocyte responds to hypertrophic stimuli with the increased expression of TGF-beta 1. In adult rat ventricular myocardium freshly dissociated into myocyte and nonmyocyte cellular fractions, the preponderance of TGF-beta 1 mRNA visualized by Northern hybridization was in the nonmyocyte fraction. Abdominal aortic constriction (7 d) and subcutaneous norepinephrine infusion (36 h) each caused ventricular hypertrophy associated with 3.1-fold and 3.8-fold increases, respectively, in TGF-beta 1 mRNA in the myocyte fraction, but had no effect on the level of TGF-beta 1 mRNA in the nonmyocyte fraction. In ventricular myocytes, norepinephrine likewise caused a 4.1-fold increase in TGF-beta 1 mRNA associated with an increase in TGF-beta bioactivity. This induction of TGF-beta 1 mRNA occurred at norepinephrine concentrations as low as 1 nM and was blocked by prazosin, but not propranolol. NE did not increase the TGF-beta 1 mRNA level in nonmyocytes, primarily fibroblasts, cultured from neonatal rat ventricle. Thus, the cardiac myocyte responds to two hypertrophic stimuli, pressure overload and norepinephrine, with the induction of TGF-beta 1. These data support the view that TGF-beta 1, released by myocytes and acting in an autocrine and/or paracrine manner, is involved in myocardial remodeling by hypertrophic stimuli.     

环孢素干预小肠移植物中转化生长因子β1的表达

背景:小肠移植慢性排斥反应的发生是影响其长远预后的重要因素。目的:观察环孢素对于小肠移植物中转化生长因子β1表达的影响。方法:近交系F344(RT11vr)大鼠和Lewis(RT11)大鼠作为小肠移植的供体和受体,利用显微外科技术构建异系大鼠小肠移植模型,分别在建模后7,28,60d进行移植物活检,常规病理学检测,应用Real time-PCR技术检测移植物内转化生长因子β1因子mRNA转录水平,并采用免疫组织化学方法对转化生长因子β1的表达进行定位。结果与结论:在建模后7-28d应用环孢素的过程中转化生长因子β1mRNA转录水平呈现明显减低趋势;在28-60d,停用环孢素后该因子表达则明显升高。说明环孢素对于异系小肠移植中转化生长因子β1的表达有一定的抑制作用。     

转化生长因子β1基因型与移植肾的慢性排斥反应

背景：免疫损伤是慢性排斥反应的主要发病机制，与多种免疫相关基因多态性有关，尤其是转化生长因子β1基因多态性更显重要。目前关于转化生长因子β1基因多态性与移植肾慢性排斥反应的关系，不同的学者研究结果各异。 目的：分析供、受者转化生长因子β1基因型与移植肾慢性排斥反应的关系。 设计：前瞻性病例分析。 单位：解放军南京军区福州总医院泌尿外科，全军器官移植中心。 对象：选择2000-06／2001-05在解放军南京军区福州总医院首次施行尸肾移植的受者144例和其中114例的供者65例（另30例缺乏供者血液标本）。手术方案得到医院伦理道德委员会批准。 方法：用序列特异引物聚合酶链反应方法，在肾移植前对肾移植受者（n=144）和其中114例的供者（n=65）进行转化生长因子β1基因型检测。术后对受者进行5年随访，追踪移植肾慢性排斥反应发生情况，分析受者基因型、供者基因型及供、受者基因型组合对移植肾功能的影响。 主要观察指标：①转化生长因子β1不同基因型的肾移植供、受者慢性排斥反应的发生率。②肾移植供、受者转化生长因子β1不同基因型组合慢性排斥反应的发生率。 结果：①高分泌基因型组受者的慢性排斥反应发生率高于中低分泌基因型组（x^2=10．091，P〈0．01）;两组移植肾慢性排斥反应发生率差异无显著性意义（x^2=0．002，P〉0．05）。②供、受者均为高分泌基因型组合的受者移植肾慢性排斥反应发生率高于所有其他基因型组合者（x^2=4．352，P〈0．05）；供、受者均为中低分泌基因型的受者慢性排斥反应发生率低于所有其他基因型组合者（x^2=4．134，P〈0．05）。 结论：肾移植术前同时检测移植供、受者转化生长因子β1基因多态性，有助于术前准确预测和评价移植后远期效果，指导术前做出合理的供、受者匹配。     

Specific binding of endocrine transforming growth factor-beta 1 to vascular endothelium.

The presentation of recombinant biologically active 125I-TGF-beta 1 via the bloodstream to potential target cells in mice and rats was evaluated by quantitative light and electron microscope radioautography. Specificity was evaluated by in vivo competition with excess unlabeled TGF-beta 1, and integrity of the ligand at the binding site was demonstrated by trichloroacetic acid precipitation after extraction from tissues. The distribution of radiolabel at 2.5, 15, 30, 45, and 60 min after 125I-TGF-beta 1 injection revealed radiolabel principally over microvasculature endothelium but at times > 2.5 min over endothelial endocytic components indicative of internalization. Nonspecific binding of 125I-TGF-beta 1 to the apex of the proximal convoluted tubule of the kidney indicated it as the likely site of rapid clearance of TGF-beta 1 from the circulation, while a comparison of the binding of 125I-TGF-beta 1 (endothelial) to that of 125I-TGF-beta 1 complexed with alpha 2-macroglobulin-methylamine (liver parenchyma) indicated that clearance of TGF-beta 1 complexed alpha 2-macroglobulin was likely via the hepatic alpha 2-macroglobulin receptor. The endothelial TGF-beta receptors uncovered here are likely involved in the local regulatory mechanism of leukocyte and monocyte adhesion and tissue infiltration regulated by endocrine TGF-beta 1.     

转化生长因子β1在增殖性玻璃体视网膜病变中的作用

目的转化生长因子β具有调控细胞的生长和分化、细胞的黏附和迁移、细胞外基质的产生和纤维化等一系列生物过程的作用.已有不少研究发现转化生长因子β参与增殖性玻璃体视网膜病变的发生发展过程,导致视功能的严重损伤.资料来源应用计算机检索Medline及Highwire1990-01/2004-08的转化生长因子β在增殖性玻璃体视网膜病变中作用的相关文章,检索词为"TGF,Proliferative Vitreoretinopathy",并限定文章语言种类为English.同时计算机检索维普中文科技期刊数据库1998-01/2004-08的转化生长因子β在增殖性玻璃体视网膜病变中作用的相关文章,检索词为"转化生长因子β,增殖性玻璃体视网膜病变".资料选择对资料进行初审,选取有关转化生长因子β的生物学物性及其在增殖性玻璃体视网膜病变发生发展的过程中所起作用的文献.资料提炼共收集到26篇相关文献.资料综合对收集的文献按几个部分进行归类如介绍转化生长因子β的生物学特性、相关受体和增殖性玻璃体视网膜病变发生机制.结论增殖性玻璃体视网膜病变是糖尿病视网膜病变、玻璃体出血、裂孔源性视网膜脱离等眼底疾病的致视功能丧失严重并发症,近年来已成为眼科研究热点之一.对于参与其发生发展的转化生长因子β及其他相关生长因子需做进一步的分子生物学方面的深入研究,以期为早期干预保护视功能奠定理论依据.     

Antibodies against transforming growth factor-beta 1 suppress intimal hyperplasia in a rat model.

Intimal hyperplasia is induced by therapeutic vascular interventions and often results in clinically important narrowing of the vascular lumen. Examination of the role of TGF-beta 1 in a rat carotid artery injury model confirmed the presence of a previously reported increase in TGF-beta 1 mRNA in the media of injured arteries. Administration of neutralizing anti- TGF-beta 1 antibodies significantly (P < 0.05) reduced the size of the intimal lesions that developed after carotid balloon injury. A control antibody had no effect. The intimal/medial area ratio was also reduced in the anti-TGF-beta 1 group relative to controls (P < 0.01). Immunohistochemical staining showed that two TGF-beta 1-induced extracellular matrix components, EDA + fibronectin and versican, were greatly increased in the untreated neointimal lesions, but were almost completely absent from the lesions of the anti-TGF-beta 1-treated animals. We conclude that TGF-beta 1 is causally involved in the development of intimal hyperplasia, and that anti-TGF-beta 1 agents may be useful in achieving at least partial control of this condition.     

冷冻异体神经移植中宿主局部应用转化生长因子β1质粒的研究

背景:异体神经移植修复神经缺损,降低免疫排斥反应是关键问题之一,目前主要手段是降低移植神经段的抗原性和全身使用免疫抑制剂。目的:观察经反复冻融处理的冷藏异体神经移植,局部使用转化生长因子β1质粒处理的效果。设计:随机对照动物实验。单位:华中科技大学同济医学院附属协和医院手外科。材料:实验于2003-01/2004-12在华中科技大学同济医学院完成,选择健康成年不同窝的Wistar大鼠40只,随机分为实验组和对照组,每组各20只。方法:制备转化生长因子β1质粒及冷冻的异体坐骨神经。实验组和对照组大鼠将坐骨神经在梨状肌孔下0.5cm处,切除2.0cm,神经缺损用预制冷冻的异体神经2.0cm移植修复,实验组局部肌肉及神经两断端注射转化生长因子β1质粒,对照组注射等量的生理盐水。分别于6,12周各组10只大鼠取材、切片、染色并进行轴索计数和统计学分析。结果:在实验过程中无动物死亡,均进入结果分析。6周时对照组神经移植段轴索间有轻度水肿,实验组轴索间基本无水肿,再生神经数量接近正常;12周时,实验组整个神经移植段基本被再生轴突充满,有髓纤维排列整齐,轴突和髓鞘发育良好,实验组再生轴突数显著高于对照组,差别具有极显著性[(98.6±4.8),(75.8±5.1)个/μm2,t=2.962,P<0.01]。结论:反复冻融冷藏保存可降低异体神经的抗原性,具有修复神经缺损的可能性。局部使用转化生长因子β1质粒,可在局部发挥免疫抑制作用,降低宿主的免疫排斥反应。     

血清转化生长因子β1水平变化与2型糖尿病肾病的相关性

目的:通过检测不同时期2型糖尿病肾病患者血清转化生长因子β1以及尿中蛋白含量的变化,探讨其与2型糖尿病肾脏病变之间的关系。方法:①实验对象:选择2003-01/2005-12广东省人民医院收治的糖尿病患者126例(糖尿病组),符合1999年WHO诊断标准。根据糖尿病患者尿白蛋白排泄率分为2型糖尿病无肾病组36例;2型糖尿病早期肾病组45例;2型糖尿病临床肾病组45例。另选择健康体检人群40例为正常对照组。糖尿病患者进入试验前空腹血糖控制在10.0mmol/L以下持续1个月以上,降血糖药物继续服用,凡有高血压者继续给予抗高血压药物治疗,控制血压于正常范围;停用其他所有改善血液黏稠度、抗血小板等药物至少2周进入试验期。所有参与者对实验知情同意。②实验方法和评估:于晨起空腹抽取静脉血,抽血后开始留24h尿,血糖采用葡萄糖氧化酶法测定;三酰甘油、低密度脂蛋白、高密度脂蛋白、肌酐采用全自动生化分析仪测定;糖化血红蛋白用乳胶免疫凝集抑制法测定;胰岛素用放免法测定,并计算胰岛素敏感指数,取自然对数。用ELISA法测定不同时期糖尿病肾病患者血清转化生长因子β1水平,以黄柳酸比浊法测定24h尿中总蛋白含量。结果:所有参与者均进入结果分析。①基础检测指标:3组糖尿病患者的空腹血糖、餐后120min血糖、空腹胰岛素、餐后120min胰岛素、血肌酐均高于正常对照组(P<0.05)。糖尿病早期肾病组病程、血肌酐水平高于糖尿病无肾病组(P<0.05),糖尿病临床肾病组病程、血肌酐水平高于糖尿病早期肾病组(P<0.05)。②尿中蛋白含量、血中转化生长因子β1水平:2型糖尿病早期肾病组和2型糖尿病临床肾病组尿中蛋白含量、血中转化生长因子β1水平明显高于正常对照组(P<0.01)和2型糖尿病无肾病组(P<0.05)。结论:血清转化生长因子β1水平可反映2型糖尿病肾病变程度,是评价2型糖尿病肾病进展的有用标记物。     

Urinary transforming growth factor-beta1 and alpha1-microglobulin in children and adolescents with type 1 diabetes

OBJECTIVE: Transforming growth factor (TGF)-beta1 is an important mediator in the pathogenesis of diabetic nephropathy. Urinary TGF-beta1 reflects TGF-beta1 production in the kidney, and alpha1-microglobulin tubular dysfunction. These 2 markers were studied in the early phases of type 1 diabetes. RESEARCH DESIGN AND METHODS: There were 113 type 1 diabetic children and adolescents (mean +/- SD: age 14.1 +/- 2.9 years, and diabetes duration 7.4 +/- 2.9 years, HbA1c 9.3 +/- 1.5%) and 39 healthy subjects (age 13.8 +/- 2.8 years) who participated in the study. Of the diabetic patients, 105 were normoalbuminuric (2-3 consecutive overnight urinary albumin excretion rates [AERs] <20 microg/min) and 8 had microalbuminuria (at least 2 AERs 20-200 microg/min). Overnight urinary TGF-beta1 and alpha1-microglobulin levels were measured and the results expressed as the ratio to urinary creatinine concentration. RESULTS: Data are medians (range). Diabetic patients had higher urinary TGF-beta1 levels than those of control subjects: 0.9 ng/mg (0.05-122.3) vs. 0.3 ng/mg (0.05-2.2) creatinine, respectively (P = 0.003). Urinary TGF-beta1 levels correlated with urinary glucose (r = 0.2, P = 0.03) and alpha1-microglobulin (r = 0.2, P = 0.02) levels, but not with HbA1c, AER, age, or duration of diabetes. In 43 patients with urinary TGF-beta1 above the control levels, urinary TGF-beta1 levels correlated with urinary glucose (r = 0.6, P < 0.001) and alpha1-microglobulin (r = 0.6, P < 0.001) levels. Diabetic patients had higher urinary alpha1-microglobulin levels than those of control subjects: 4.8 microg/mg (0.6-48.8) vs. 2.7 microg/mg (0.8-11.6) creatinine, respectively (P < 0.001). Alpha1-microglobulin levels correlated with AER (r = 0.2, P = 0.02), HbA1c (r = 0.3, P = 0.001), urinary glucose (r = 0.5, P < 0.001), and urinary TGF-beta1 levels. CONCLUSIONS: An early rise in urinary TGF-beta1 levels was observed in young type 1 diabetic patients. Urinary TGF-beta1 is associated with 2 interrelated tubular markers, alpha1-microglobulin and urinary glucose.