Wang Tong, Yin Kai-sheng, Liu Kou-yin, Lu Guo-jun, Li Yu-hua, Chen Jun-di
Department of Respiratory Medicine, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
Chin Med J (Engl). 2008 Nov 20;121(22):2312-9.
Many studies have suggested that angiotensin II (Ang II) and its receptors may be involved in the development of asthma. However, the expression of angiotensin II receptors (AGTR) is not clear in the lung tissue of chronic asthmatics. This study was designed to determine the relationship between airway remodeling, dysfunction and the expression of AGTRs in a rat model of asthma.
Rats were sensitized with ovalbumin (OVA) for 2 weeks. Sixty minutes before an inhalation challenge, the rats were pretreated either with valsartan (15, 30, 50 mg x kg(-1) x d(-1)) or saline intragastrically. Then the rats received an OVA challenge for 30 alternative days. Acetylcholine (Ach)-induced bronchoconstriction was measured after the final antigen challenge. White cell counts in bronchoalveolar lavage fluid (BALF) and morphological changes in the airways were then assessed. The levels of transforming growth factor-beta 1 (TGF-beta(1)) and platelet-derived growth factor (PDGF) in BALF were detected by ELISA. The levels of AGTR1 and AGTR2 mRNA and protein in lung tissues were measured by RT-PCR and Western blotting.
AGTR1 mRNA and protein levels in repeatedly OVA-challenged rats were significantly increased as compared with negative controls. The AGTR1 mRNA expression versus white cell counts of BALF and airway wall thickness (mainly in small airways) in lungs of chronic antigen-exposed rats were positively correlated. Valsartan decreased the level of AGTR1 in repeatedly OVA-challenged rats. However, AGTR2 mRNA and protein levels in the OVA-challenged rats and high-dose valsartan-treated rats (50 mg x kg(-1) x d(-1)) were also increased. Valsartan significantly decreased inflammatory cell accumulation and attenuated Ach-evoked bronchoconstriction in repeatedly antigen-challenged rats. Valsartan also decreased allergen-induced structural changes in rat airway (including total airway wall thickness and smooth muscle area) and the levels of TGF-beta(1) and PDGF in BALF.
AGTR1 expression is potentially associated with airway remodeling and dysfunction in asthma. Ang II and AGTR1 may participate in airway inflammation and airway remodeling of chronic antigen-exposed rats. Valsartan, a AGTR1 antagonist, could inhibit AGTR1 expression and partially inhibits structural airway changes as well as airway inflammation in chronic OVA-exposed rats.
许多研究表明，血管紧张素II（Ang II）及其受体可能参与哮喘的发病过程。然而，慢性哮喘患者肺组织中血管紧张素II受体（AGTR）的表达尚不清楚。本研究旨在确定哮喘大鼠模型中气道重塑、功能障碍与AGTRs表达之间的关系。
用卵清蛋白（OVA）致敏大鼠2周。在吸入激发前60分钟，大鼠分别经缬沙坦（15、30、50mg·kg⁻¹·d⁻¹）或生理盐水灌胃预处理。然后大鼠接受OVA激发30天。在末次抗原激发后测量乙酰胆碱（Ach）诱导的支气管收缩。随后评估支气管肺泡灌洗液（BALF）中的白细胞计数和气道的形态学变化。通过ELISA检测BALF中转化生长因子-β1（TGF-β1）和血小板衍生生长因子（PDGF）的水平。通过RT-PCR和Western印迹法测量肺组织中AGTR1和AGTR2 mRNA及蛋白水平。
与阴性对照组相比，反复接受OVA激发的大鼠中AGTR1 mRNA和蛋白水平显著升高。慢性抗原暴露大鼠肺中AGTR1 mRNA表达与BALF白细胞计数及气道壁厚度（主要在小气道）呈正相关。缬沙坦降低了反复接受OVA激发大鼠中AGTR1的水平。然而，OVA激发大鼠和高剂量缬沙坦治疗大鼠（50mg·kg⁻¹·d⁻¹）中AGTR2 mRNA和蛋白水平也升高。缬沙坦显著减少反复抗原激发大鼠中的炎性细胞积聚并减轻Ach诱发的支气管收缩。缬沙坦还减少了变应原诱导的大鼠气道结构变化（包括气道壁总厚度和平滑肌面积）以及BALF中TGF-β1和PDGF的水平。
AGTR1表达可能与哮喘中的气道重塑和功能障碍相关。Ang II和AGTR1可能参与慢性抗原暴露大鼠的气道炎症和气道重塑。缬沙坦，一种AGTR1拮抗剂，可抑制AGTR1表达并部分抑制慢性OVA暴露大鼠的气道结构变化以及气道炎症。
