蛋白二硫键异构酶-内质网驻留蛋白57调节变应原诱导的气道炎症、纤维化和高反应性。
Protein disulfide isomerase-endoplasmic reticulum resident protein 57 regulates allergen-induced airways inflammation, fibrosis, and hyperresponsiveness.
作者信息
Hoffman Sidra M, Chapman David G, Lahue Karolyn G, Cahoon Jonathon M, Rattu Gurkiranjit K, Daphtary Nirav, Aliyeva Minara, Fortner Karen A, Erzurum Serpil C, Comhair Suzy A A, Woodruff Prescott G, Bhakta Nirav, Dixon Anne E, Irvin Charles G, Janssen-Heininger Yvonne M W, Poynter Matthew E, Anathy Vikas
机构信息
Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT.
Department of Medicine, University of Vermont College of Medicine, Burlington, VT; Woolcock Institute of Medical Research, Sydney Medical School, University of Sydney, Sydney, Australia.
出版信息
J Allergy Clin Immunol. 2016 Mar;137(3):822-32.e7. doi: 10.1016/j.jaci.2015.08.018. Epub 2015 Oct 4.
BACKGROUND
Evidence for association between asthma and the unfolded protein response is emerging. Endoplasmic reticulum resident protein 57 (ERp57) is an endoplasmic reticulum-localized redox chaperone involved in folding and secretion of glycoproteins. We have previously demonstrated that ERp57 is upregulated in allergen-challenged human and murine lung epithelial cells. However, the role of ERp57 in asthma pathophysiology is unknown.
OBJECTIVES
Here we sought to examine the contribution of airway epithelium-specific ERp57 in the pathogenesis of allergic asthma.
METHODS
We examined the expression of ERp57 in human asthmatic airway epithelium and used murine models of allergic asthma to evaluate the relevance of epithelium-specific ERp57.
RESULTS
Lung biopsy specimens from asthmatic and nonasthmatic patients revealed a predominant increase in ERp57 levels in epithelium of asthmatic patients. Deletion of ERp57 resulted in a significant decrease in inflammatory cell counts and airways resistance in a murine model of allergic asthma. Furthermore, we observed that disulfide bridges in eotaxin, epidermal growth factor, and periostin were also decreased in the lungs of house dust mite-challenged ERp57-deleted mice. Fibrotic markers, such as collagen and α smooth muscle actin, were also significantly decreased in the lungs of ERp57-deleted mice. Furthermore, adaptive immune responses were dispensable for house dust mite-induced endoplasmic reticulum stress and airways fibrosis.
CONCLUSIONS
Here we show that ERp57 levels are increased in the airway epithelium of asthmatic patients and in mice with allergic airways disease. The ERp57 level increase is associated with redox modification of proinflammatory, apoptotic, and fibrotic mediators and contributes to airways hyperresponsiveness. The strategies to inhibit ERp57 specifically within the airways epithelium might provide an opportunity to alleviate the allergic asthma phenotype.
背景
哮喘与未折叠蛋白反应之间关联的证据正在显现。内质网驻留蛋白57（ERp57）是一种定位于内质网的氧化还原伴侣，参与糖蛋白的折叠和分泌。我们之前已经证明，在变应原激发的人和小鼠肺上皮细胞中ERp57表达上调。然而，ERp57在哮喘病理生理学中的作用尚不清楚。
目的
在此，我们试图研究气道上皮特异性ERp57在过敏性哮喘发病机制中的作用。
方法
我们检测了人哮喘气道上皮中ERp57的表达，并使用过敏性哮喘小鼠模型评估上皮特异性ERp57的相关性。
结果
哮喘患者和非哮喘患者的肺活检标本显示，哮喘患者上皮中ERp57水平显著升高。在过敏性哮喘小鼠模型中，ERp57缺失导致炎症细胞计数和气道阻力显著降低。此外，我们观察到，在尘螨激发的ERp57缺失小鼠的肺中，嗜酸性粒细胞趋化蛋白、表皮生长因子和骨膜蛋白中的二硫键也减少。在ERp57缺失小鼠的肺中，纤维化标志物，如胶原蛋白和α平滑肌肌动蛋白也显著减少。此外，适应性免疫反应对于尘螨诱导的内质网应激和气道纤维化并非必需。
结论
在此我们表明，哮喘患者气道上皮和过敏性气道疾病小鼠中ERp57水平升高。ERp57水平升高与促炎、凋亡和纤维化介质的氧化还原修饰有关，并导致气道高反应性。在气道上皮内特异性抑制ERp57的策略可能为减轻过敏性哮喘表型提供机会。
Zotero 插件