Targeted HAS2 Expression Lessens Airway Responsiveness in Chronic Murine Allergic Airway Disease.
Targeted HAS2 Expression Lessens Airway Responsiveness in Chronic Murine Allergic Airway Disease.
复制标题
靶向 HAS2 表达可降低慢性小鼠过敏性气道疾病的气道反应性。
DOI：
10.1165/rcmb.2017-0095oc
复制
发表时间：
2017
影响因子：
6.4
通讯作者：
Ingram,JenniferL
中科院分区：
文献类型：
--
作者：
Walker,JuliaKL;Theriot,BarbaraS;Ghio,Michael;Trempus,CarolS;Wong,JordanE;McQuade,VictoriaL;Liang,Jiurong;Jiang,Dianhua;Noble,PaulW;Garantziotis,Stavros;Kraft,Monica;Ingram,JenniferL
透明质酸 (HA) 是细胞外基质的主要成分，由气道结构细胞分泌。过敏性哮喘中的气道成纤维细胞分泌的 HA 水平升高，与 HA 合酶 2 (HAS2) 表达增加相关。因此，我们假设HA在气道壁中的积累可能有助于过敏性气道疾病的气道重塑和高反应性。为了验证这一假设，我们制备了α-平滑肌肌动蛋白（α-SMA）启动子驱动HAS2表达的转基因小鼠。雄性和雌性混合 α-SMA-HAS2 小鼠（HAS2+小鼠，n= 16；HAS2−小鼠，n= 13）通过腹腔注射致敏，然后用雾化卵清蛋白（OVA）长期攻击 6 周。为了测试气道反应性，增加静脉注射乙酰甲胆碱的剂量，并使用强制振荡技术测量气道阻力。分析支气管肺泡灌洗液、血清和全肺匀浆中的 HA、细胞因子和细胞类型。使用 HA 结合蛋白 (HABP) 和 α-SMA 特异性抗体以及 Masson 三色染色剂对肺切片进行染色。肺组织染色表明，与 α-SMA–HAS2− 小鼠相比，OVA 攻击的 α-SMA–HAS2+ 小鼠支气管周围 HA、α-SMA 和胶原蛋白沉积显着增加。出乎意料的是，与接受类似治疗的 α-SMA-HAS2− 小鼠相比，OVA 攻击的 α-SMA–HAS2+ 小鼠表现出气道对乙酰甲胆碱的反应性显着降低。 OVA 攻击的 α-SMA–HAS2+ 小鼠和 α-SMA–HAS2− 小鼠之间支气管肺泡灌洗液中炎症细胞类型的总数没有显着差异。我们得出的结论是，肌成纤维细胞和平滑肌细胞中过度表达HAS2的过敏原小鼠会出现气道纤维化增加，从而减轻气道对支气管收缩剂的高反应性。
Hyaluronan (HA), a major component of the extracellular matrix, is secreted by airway structural cells. Airway fibroblasts in allergic asthma secrete elevated levels of HA in association with increased HA synthase 2 (HAS2) expression. Thus, we hypothesized that HA accumulation in the airway wall may contribute to airway remodeling and hyperresponsiveness in allergic airways disease. To examine this hypothesis, transgenic mice in which the α-smooth muscle actin (α-SMA) promoter drivesHAS2expression were generated. Mixed male and female α-SMA–HAS2mice (HAS2+mice,n= 16;HAS2−mice,n= 13) were sensitized via intraperitoneal injection and then chronically challenged with aerosolized ovalbumin (OVA) for 6 weeks. To test airway responsiveness, increasing doses of methacholine were delivered intravenously and airway resistance was measured using the forced oscillation technique. HA, cytokines, and cell types were analyzed in bronchoalveolar lavage fluid, serum, and whole lung homogenates. Lung sections were stained using antibodies specific for HA-binding protein (HABP) and α-SMA, as well as Masson’s trichrome stain. Staining of lung tissue demonstrated significantly increased peribronchial HA, α-SMA, and collagen deposition in OVA-challenged α-SMA–HAS2+mice compared with α-SMA–HAS2−mice. Unexpectedly, OVA-challenged α-SMA–HAS2+mice displayed significantly reduced airway responsiveness to methacholine compared with similarly treated α-SMA–HAS2−mice. The total numbers of inflammatory cell types in the bronchoalveolar lavage fluid did not differ significantly between OVA-challenged α-SMA–HAS2+mice and α-SMA–HAS2−mice. We conclude that allergen-challenged mice that overexpressHAS2in myofibroblasts and smooth muscle cells develop increased airway fibrosis, which lessens airway hyperresponsiveness to bronchoconstrictors.