Autophagy Activation in Asthma Airways Remodeling
Autophagy Activation in Asthma Airways Remodeling
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DOI：
10.1165/rcmb.2018-0169oc
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发表时间：
2019-05-01
影响因子：
6.4
通讯作者：
Sharma, Pawan
中科院分区：
文献类型：
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作者：
McAlinden, Kielan D.;Deshpande, Deepak A.;Sharma, Pawan
目前的哮喘治疗方法未能针对与哮喘严重程度相关的气道重塑，从而推动疾病进展，最终导致肺功能丧失。巨自噬(下称“自噬”)是所有真核细胞中一种基本的细胞循环机制；新的证据表明，它在哮喘中处于失调状态。我们研究了自噬和气道重塑之间的相互关系，并评估了一种已知的自噬抑制剂在哮喘小鼠模型中的临床前疗效。对哮喘和非哮喘肺组织进行组织学评估，并对关键的自噬标记进行免疫组织化学染色。用ImageJ软件对上皮和气道平滑肌束的阳性染色面积百分比进行定量。此外，在预防(3wk)和治疗(5wk)的过敏性哮喘小鼠模型中，对自噬抑制剂氯喹进行了鼻腔内试验。与非哮喘对照组相比，人类哮喘组织表现出更严重的组织炎症和明显的气道重塑特征，表现为上皮增厚(P<；0.001)和网状基底膜(P<；0.0001)，固有层厚度(P<；0.005)增加，气道平滑肌束增加(P<；0.001)，柏林-1(P<；0.01)和ATG5(自噬相关基因5)表达增加(P<；0.05)，p62表达降低(P<；0.05)。柏林-1在哮喘上皮和纤毛细胞中的表达显著升高(P<；0.05)，提示纤毛吞噬在哮喘中可能起作用。小鼠哮喘模型显示了自噬抑制剂氯喹的有效临床前疗效(减少了过敏性哮喘的关键特征：呼吸道炎症、气道高反应性和气道重塑)。我们的数据显示哮喘中结构细胞中的自噬依赖于细胞环境和选择性地激活。此外，该途径可有效靶向改善哮喘患者的气道重塑。
Current asthma therapies fail to target airway remodeling that correlates with asthma severity driving disease progression that ultimately leads to loss of lung function. Macroautophagy (hereinafter "autophagy") is a fundamental cell-recycling mechanism in all eukaryotic cells; emerging evidence suggests that it is dysregulated in asthma. We investigated the interrelationship between autophagy and airway remodeling and assessed preclinical efficacy of a known autophagy inhibitor in murine models of asthma. Human asthmatic and nonasthmatic lung tissues were histologically evaluated and were unmunostained for key autophagy markers. The percentage area of positive staining was quantified in the epithelium and airway smooth muscle bundles using ImageJ software. Furthermore, the autophagy inhibitor chloroquine was tested intranasally in prophylactic (3 wk) and treatment (5 wk) models of allergic asthma in mice. Human asthmatic tissues showed greater tissue inflammation and demonstrated hallmark features of airway remodeling, displaying thickened epithelium (P < 0.001) and reticular basement membrane (P < 0.0001), greater lamina propria depth (P < 0.005), and increased airway smooth muscle bundles (P < 0.001) with higher expression of Berlin-1 (P < 0.01) and ATG5 (autophagy-related gene 5) (P < 0.05) together with reduced p62 (P < 0.05) compared with nonasthmatic control tissues. Berlin-1 expression was significantly higher in asthmatic epithelium and ciliated cells (P < 0.05), suggesting a potential role of ciliophagy in asthma. Murine asthma models demonstrated effective preclinical efficacy (reduced key features of allergic asthma: airway inflammation, airway hyperresponsiveness, and airway remodeling) of the autophagy inhibitor chloroquine. Our data demonstrate cell context-dependent and selective activation of autophagy in structural cells in asthma. Furthermore, this pathway can be effectively targeted to ameliorate airway remodeling in asthma.