Suppression of SPARC Ameliorates Ovalbumin-induced Airway Remodeling via TGFβ1/Smad2 in Chronic Asthma.

IF 4.1 2区医学 Q2 ALLERGY Allergy, Asthma & Immunology Research Pub Date : 2024-01-01 DOI:10.4168/aair.2024.16.1.91

Yun Pan, Dong Zhang, Jintao Zhang, Xiaofei Liu, Jiawei Xu, Rong Zeng, Wenjing Cui, Tian Liu, Junfei Wang, Liang Dong

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Abstract

Purpose: Airway remodeling is a critical feature of asthma. Secreted protein acidic and rich in cysteine (SPARC), which plays a cardinal role in regulating cell-matrix interactions, has been implicated in various fibrotic diseases. However, the effect of SPARC in asthma remains unknown.

Methods: We studied the expression of SPARC in human bronchial epithelial cells and serum of asthmatics as well as in the lung tissues of chronic asthma mice. The role of SPARC was examined by using a Lentivirus-mediated SPARC knockdown method in the ovalbumin (OVA)-induced asthma mice. The biological processes regulated by SPARC were identified using RNA sequencing. The function of SPARC in the remodeling process induced by transforming growth factor β1 (TGFβ1) was conducted by using SPARC small interfering RNA (siRNA) or recombinant human SPARC protein in 16HBE cells.

Results: We observed that SPARC was up-regulated in human bronchial epithelia of asthmatics and the asthmatic mice. The levels of serum SPARC in asthmatics were also elevated and negatively correlated with the forced expiratory volume in one second (FEV1) to forced vital capacity ratio (FVC) (r = -0.485, P < 0.01) and FEV1 (%predicted) (r = -0.425, P = 0.001). In the chronic asthmatic mice, Lentivirus-mediated SPARC knockdown significantly decreased airway remodeling and airway hyper-responsiveness. According to gene set enrichment analysis, negatively enriched pathways found in the OVA + short hairpin-SPARC group included ECM organization and collagen formation. In the lung function studies, knockdown of SPARC by siRNA reduced the expression of remodeling-associated biomarkers, cell migration, and contraction by blocking the TGFβ1/Smad2 pathway. Addition of human recombinant SPARC protein promoted the TGFβ1-induced remodeling process, cell migration, and contraction in 16HBE cells via the TGFβ1/Smad2 pathway.

Conclusions: Our studies provided evidence for the involvement of SPARC in the airway remodeling of asthma via the TGFβ1/Smad2 pathway.

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抑制 SPARC 可通过 TGFβ1/Smad2 改善慢性哮喘患者卵清蛋白诱导的气道重塑

目的：气道重塑是哮喘的一个重要特征。富含半胱氨酸的酸性分泌蛋白（SPARC）在调节细胞与基质之间的相互作用中发挥着重要作用，与多种纤维化疾病有关。然而，SPARC对哮喘的影响仍是未知数：我们研究了 SPARC 在人类支气管上皮细胞、哮喘患者血清以及慢性哮喘小鼠肺组织中的表达。在卵清蛋白（OVA）诱导的哮喘小鼠中采用慢病毒介导的 SPARC 基因敲除法研究了 SPARC 的作用。通过RNA测序确定了SPARC调控的生物学过程。利用SPARC小干扰RNA（siRNA）或重组人SPARC蛋白在16HBE细胞中研究了SPARC在转化生长因子β1（TGFβ1）诱导的重塑过程中的功能：结果：我们观察到 SPARC 在哮喘患者和哮喘小鼠的支气管上皮细胞中上调。哮喘患者血清中 SPARC 的水平也升高，并与一秒钟用力呼气容积（FEV1）与用力呼吸容量比值（FVC）（r = -0.485，P < 0.01）和 FEV1（预测百分比）（r = -0.425，P = 0.001）呈负相关。在慢性哮喘小鼠中，慢病毒介导的 SPARC 基因敲除显著减少了气道重塑和气道高反应性。根据基因组富集分析，在 OVA + 短发夹-SPARC 组中发现的负富集通路包括 ECM 组织和胶原形成。在肺功能研究中，通过 siRNA 敲除 SPARC 可阻断 TGFβ1/Smad2 通路，从而减少重塑相关生物标志物、细胞迁移和收缩的表达。加入人重组 SPARC 蛋白可通过 TGFβ1/Smad2 通路促进 TGFβ1 诱导的 16HBE 细胞重塑过程、细胞迁移和收缩：我们的研究为SPARC通过TGFβ1/Smad2途径参与哮喘的气道重塑提供了证据。

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来源期刊

Allergy, Asthma & Immunology Research ALLERGY-IMMUNOLOGY

CiteScore

6.10

自引率

6.80%

发文量

审稿时长

>12 weeks

期刊介绍： The journal features cutting-edge original research, brief communications, and state-of-the-art reviews in the specialties of allergy, asthma, and immunology, including clinical and experimental studies and instructive case reports. Contemporary reviews summarize information on topics for researchers and physicians in the fields of allergy and immunology. As of January 2017, AAIR do not accept case reports. However, if it is a clinically important case, authors can submit it in the form of letter to the Editor. Editorials and letters to the Editor explore controversial issues and encourage further discussion among physicians dealing with allergy, immunology, pediatric respirology, and related medical fields. AAIR also features topics in practice and management and recent advances in equipment and techniques for clinicians concerned with clinical manifestations of allergies and pediatric respiratory diseases.