Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada.
Am J Respir Cell Mol Biol. 2012 Jan;46(1):96-105. doi: 10.1165/rcmb.2011-0014OC.
Increased proteoglycan (PG) deposition is a feature of airway remodeling in asthma. Glycosaminoglycans (GAGs) mediate many of the biological and mechanical properties of PGs by providing docking sites through their carbohydrate chains to bioactive ligands; therefore, it is imperative to define structural and metabolic changes of GAGs in asthma. Using a Brown Norway (BN) ovalbumin (OVA)-sensitized and -challenged rat model to induce airway remodeling, we found excessive deposition of chondroitin/dermatan (CS/DS)-, heparan (HS), and keratan (KS) sulfate GAGs in the airways and bronchoalveolar lavage cells of OVA-challenged rats. Disaccharide composition of CS/DS of OVA-challenged rats was significantly different compared with saline-treated (SAL) control rats, with increased levels of 0-, 6-, and 4-sulfated disaccharides. Increases in the amount and a change in the proportion of CS/DS versus HS GAGs were noted in OVA-challenged rats. The higher content and sulfation of CS/DS disaccharides was reflected by the increased expression of xylosyltransferase-I, β1,3-glucuronosyltransferase-I, chondroitin-4, and chondroitin-6 sulfotransferase genes and protein expression of xylosyltransferase-I and β1,3-glucuronosyltransferase-I in OVA-challenged rats. Genes encoding the core proteins of the CS/DS and KS-containing PGs, such as versican, biglycan, decorin, and lumican, were overexpressed in OVA-challenged rats. Our results suggest that GAG biosynthetic enzymes may be involved in the altered expression of GAGs in the airways and are potential targets for inhibiting excess PG-GAG deposition and the airway remodeling process in asthma.
气道重塑是哮喘的一个特征，其中包括蛋白聚糖（PG）的沉积增加。糖胺聚糖（GAG）通过其碳水化合物链为生物活性配体提供结合位点，从而介导 PG 的许多生物学和机械特性；因此，定义哮喘中 GAG 的结构和代谢变化至关重要。我们使用 Brown Norway (BN) 卵清蛋白 (OVA) 致敏和激发大鼠模型来诱导气道重塑，发现 OVA 激发的大鼠气道和支气管肺泡灌洗液中存在过多的软骨素/硫酸皮肤素（CS/DS）、硫酸乙酰肝素（HS）和硫酸角质素（KS）GAG 沉积。与盐水处理（SAL）对照大鼠相比，OVA 激发大鼠的 CS/DS 二糖组成明显不同，0-、6-和 4-硫酸化二糖水平升高。OVA 激发大鼠 CS/DS 与 HS GAG 的量增加和比例变化。CS/DS 二糖含量增加和硫酸化程度增加反映了木糖基转移酶-I、β1,3-葡糖醛酸基转移酶-I、软骨素-4 和软骨素-6 硫酸转移酶基因的表达增加，以及 OVA 激发大鼠中木糖基转移酶-I 和β1,3-葡糖醛酸基转移酶-I 的蛋白表达增加。CS/DS 和 KS 含 PG 的核心蛋白编码基因，如 versican、biglycan、decorin 和 lumican，在 OVA 激发的大鼠中过度表达。我们的结果表明，GAG 生物合成酶可能参与气道中 GAG 的改变表达，是抑制过度 PG-GAG 沉积和哮喘气道重塑过程的潜在靶点。
