Matrix Metalloproteinase-19 as a Mediator of Airway Fibrosis in Obese Allergic Asthma

基质金属蛋白酶-19 作为肥胖过敏性哮喘气道纤维化的调节剂

• 批准号: 10201483
• 负责人: Jennifer L. Ingram
• 金额: $ 20.13万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-24 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201483
• 关键词: Affect; Allergens; Allergic; Animal Model; Anti-Inflammatory Agents; Asthma; Autocrine Communication; Basement membrane; Biopsy; Bronchoalveolar Lavage Fluid; CRISPR/Cas technology; Cell physiology; Cells; Cellular Structures; Chronic; Chronic Disease; Clustered Regularly Interspaced Short Palindromic Repeats; Cryopreservation; Data; Deposition; Development; Enzymes; Epithelial; Epithelial Cells; Exhibits; Exposure to; Extracellular Matrix; Extrinsic asthma; Fibroblasts; Fibrosis; GLP-I receptor; Gastrectomy; Gene Expression; Goals; Growth Factor; Hormones; House Dust Mite Allergens; Human; Immune response; Impairment; Incidence; Individual; Inflammatory; Inflammatory Response; Insulin; Interleukin-13; Intervention; Knock-out; Knowledge; Leptin; Literature; Lung; Matrix Metalloproteinases; Measures; Mediating; Mediator of activation protein; Metabolic; Modeling; Mus; Obese Mice; Obesity; Operative Surgical Procedures; Paracrine Communication; Pathogenicity; Pathologic; Pathologic Processes; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Phenotype; Physiology; Play; Process; Production; Proteins; Proteomics; Pulmonary Fibrosis; Receptor Signaling; Research; Role; Serum; Severities; Signal Transduction; Structure; Structure of parenchyma of lung; Symptoms; System; Testing; Thinness; Tissues; adipokines; airway epithelium; airway inflammation; airway obstruction; airway remodeling; asthmatic; asthmatic patient; bariatric surgery; base; chemokine; cytokine; diet-induced obesity; experience; glucagon-like peptide 1; glucose metabolism; improved; in vivo; insulin secretion; matrix metalloproteinase 19; migration; mouse model; novel; obese patients; obesity treatment; patient population; peptide hormone; pulmonary function; response; screening; targeted treatment; therapeutic target; therapy development; wound healing

Nearly 40% of the asthma patient population is obese. These patients exhibit increased asthma symptoms and severity. Obesity is associated with inflammatory and metabolic changes that can contribute to asthma pathobiology. Specifically, increased levels of leptin, a pro-inflammatory adipokine, and decreased secretion of glucagon-like peptide 1 (GLP-1), a peptide hormone that regulates insulin production, may augment pathogenic processes in asthma by acting directly on airway structural cells. In allergic asthma, airway epithelial cells produce pro-fibrotic mediators that activate airway fibroblasts to secrete excess extracellular matrix (ECM). These processes contribute to airway remodeling, structural changes in asthma that can result in permanent airway obstruction. The mechanisms directing airway remodeling in obese asthma are poorly understood, but in allergic asthma, these processes are directed in part by the type 2 cytokine, interleukin-13 (IL-13). Matrix metalloproteinase-19 (MMP-19) is an allergen-activated protease produced by airway epithelial cells and fibroblasts that participates in normal processing of ECM. Our preliminary data suggest that GLP-1 stimulates, while IL-13 and leptin suppress, MMP-19 production by airway cells. Our hypothesis is that obesity- and allergen-induced suppression of MMP-19 production plays an important role in the development of airway fibrosis in allergic asthma. Furthermore, GLP-1 inhibits pro-fibrotic cellular functions and halts the progression of airway fibrosis in obese, allergic humans and mice by acting to enhance airway fibroblast and epithelial cell MMP-19 secretion. To test this hypothesis, we propose two Aims. In Aim 1, we will culture primary airway epithelial cells and fibroblasts from obese and lean allergic asthmatic and obese and lean non-asthmatic subjects. We will silence MMP19 expression in these cells using CRISPR-Cas9 and determine the role of MMP-19 in pro-fibrotic cellular functions in response to leptin, IL-13 and GLP-1 or a GLP-1 receptor antagonist. In Aim 2, diet-induced obese Mmp19-I- and Mmp19+I+ mice will be concurrently challenged with house dust mite allergen for 4 weeks before undergoing vertical sleeve gastrectomy to induce GLP-1 secretion. We will assess airway fibrosis in vivo and relate these findings to GLP-1, leptin and MMP-19 levels in lung tissue, serum and bronchoalveolar lavage fluid. We will evaluate ex vivo cultured mouse lung fibroblasts for MMP-19 and ECM production. In both aims, we will relate pathologic airway changes and ex vivo cellular responses to measures of airway physiology and lung function in order to predict airway remodeling. Successful completion of these Aims will not only increase our understanding of the mechanisms directing the pathobiology of obese allergic asthma, but also will test specific interventions to treat obese asthma patients.

近40%的哮喘患者是肥胖的。这些患者表现出哮喘加重 症状和严重程度。肥胖与炎症和代谢变化有关， 对哮喘的病理学有贡献。具体来说，瘦素水平的增加， 促炎性脂肪因子和胰高血糖素样肽1（GLP-1）分泌减少， 一种调节胰岛素产生激素，可能通过作用于 直接作用于气道结构细胞。在过敏性哮喘中， 促纤维化介质，其激活气道成纤维细胞以分泌过量的细胞外 矩阵（ECM）。这些过程有助于气道重塑，哮喘的结构变化， 会导致永久性气道阻塞肥胖患者气道重塑的机制 对哮喘知之甚少，但在过敏性哮喘中，这些过程部分是针对 2型细胞因子白细胞介素-13（IL-13）。基质金属蛋白酶-19（MMP-19）是 一种由气道上皮细胞和成纤维细胞产生的过敏原活化蛋白酶， 参与ECM的正常处理。我们的初步数据表明，GLP-1刺激，而 IL-13和瘦素抑制气道细胞产生MMP-19。我们的假设是，肥胖-和 过敏原诱导的MMP-19产生的抑制在过敏性鼻炎的发展中起重要作用。 过敏性哮喘的气道纤维化此外，GLP-1抑制促纤维化细胞功能， 在肥胖、过敏的人类和小鼠中，通过增强 气道成纤维细胞和上皮细胞分泌MMP-19。为了验证这一假设，我们提出了两个 目标。在目标1中，我们将培养原代气道上皮细胞和成纤维细胞从肥胖和瘦， 过敏性哮喘和肥胖和瘦的非哮喘受试者。我们将沉默MMP 19的表达， 这些细胞使用CRISPR-Cas9并确定MMP-19在促纤维化细胞功能中的作用 响应瘦素、IL-13和GLP-1或GLP-1受体拮抗剂。在目标2中，饮食诱导的肥胖 Mmp 19-I-和Mmp 19 +I+小鼠将同时用屋尘螨变应原攻击4 在进行垂直袖状胃切除术前10周，将大鼠皮下注射以诱导GLP-1分泌。我们将评估 并将这些发现与肺中GLP-1、瘦素和MMP-19水平相关 组织、血清和支气管肺泡灌洗液。我们将评估离体培养的小鼠肺 成纤维细胞用于MMP-19和ECM产生。在这两个目标中，我们将把病理性气道变化 以及对气道生理学和肺功能的测量的离体细胞反应， 预测气道重塑这些目标的成功实现不仅会增加我们的 了解肥胖过敏性哮喘的病理生物学机制， 测试特定的干预措施来治疗肥胖哮喘患者。

项目成果

Imbalanced Coagulation in the Airway of Type-2 High Asthma with Comorbid Obesity.

• DOI: 10.2147/jaa.s318017
• 发表时间: 2021
• 期刊: Journal of asthma and allergy
• 影响因子: 3.2
• 作者: Womble JT;McQuade VL;Ihrie MD;Ingram JL
• 通讯作者: Ingram JL