Integrin alphavbeta8 Inhibits Airway Epithelial Cell Growth

整合素 alphavbeta8 抑制气道上皮细胞生长

• 批准号: 7392377
• 负责人: Stephen L Nishimura
• 金额: $ 34.68万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7392377
• 关键词: Accounting; Air; Alveolar wall; Cell Culture System; Cell Proliferation; Cells; Chronic; Chronic Obstructive Airway Disease; Coculture Techniques; Complex; Data; Disease; Disease Progression; Dominant-Negative Mutation; EMSA; End Point; Epithelial; Epithelial Cells; Equilibrium; Event; Failure; Fibroblasts; Gene Silencing; Goals; Histone Acetylation; Histone Deacetylase; Human; Immune; Inflammatory; Integrins; Interleukin-16; Investigation; Lead; Liquid substance; Lung; MAPK14 gene; MMP14 gene; Mediating; Mesenchymal; Modeling; Obstruction; Oxidative Stress; Oxidative Stress Pathway; Pathologic; Pathway interactions; Pattern; Play; Process; Protein Isoforms; Protein Overexpression; Publishing; Regulation; Role; Sampling; Severities; Signal Transduction; Standards of Weights and Measures; Stress; System; Testing; Therapeutic; Therapy Clinical Trials; Tissue Therapy; Tissues; Tobacco smoke; Transcriptional Regulation; Work; airway epithelium; airway obstruction; airway remodeling; autocrine; cell growth; cell type; chromatin immunoprecipitation; cytokine; human MMP14 protein; human tissue; improved; in vitro Model; injured airway; integrin alphavbeta8; lung development; migration; paracrine; programs; promoter; pulmonary function decline; response; response to injury; small airways disease; spatiotemporal; therapeutic target; transcription factor; two-dimensional

DESCRIPTION (provided by applicant): Failure of therapeutic trials for Chronic Obstructive Lung Disease (COPD) reflects our poor mechanistic understanding of the disease. The long term goal of this project is to improve the mechanistic understanding of COPD. The two major pathologic features of COPD that contribute to airway obstruction are loss of alveolar walls and wall thickening of small airways (<2mm). Small airway changes progress with increasing severity of COPD and therefore represent a therapeutic target to stabilize or potentially reverse airway obstruction. Recent investigation suggests that TGF¿ is likely to play a major mechanistic role in wall thickening in COPD by regulating the balanced autocrine and paracrine interactions between airway epithelial and mesenchymal cell types, collectively known as the epithelial-mesenchymal trophic unit (EMTU). These autocrine and paracrine interactions dictate cellular differentiation during lung development. Imbalances in these interactions could result from chronic airway injury (e.g. tobacco smoke) and lead to airway remodeling. TGF¿ isoforms are expressed by all cell types within the EMTU, but almost entirely in an inactive form. Hence, activation of TGF¿ is a major point of regulation of TGF¿ function. We have recently developed one of the first in vitro models of the human EMTU (Araya, et al, Am. J. Path, 2006) and have used it to determine that the integrin av¿8 plays a major role in TGF¿ activation, and subsequent autocrine and paracrine interactions between airway epithelial cells and fibroblasts. Using human COPD samples, we demonstrate increased ¿8 expression in both the airway epithelium and small airway fibroblasts, which significantly correlates with declining pulmonary function and airway wall thickening. These findings have led us to our overall hypothesis: Increased av¿8-dependent activation of TGF¿ in COPD airway epithelial cells and fibroblasts leads to inappropriate reactivation of morphogenic programs within the EMTU, which leads to airway remodeling. Using physiologically relevant primary human airway epithelial and fibroblast cell culture systems, we will: 1) determine the mechanism of increased (38 expression in COPD by airway epithelial cells and fibroblasts; 2) determine mechanism of increased av¿8-mediated activation of TGF¿ in COPD; 3) determine the functional consequence of increased av¿8-mediated activation of TGF¿ in autocrine and paracrine interactions between airway epithelial and fibroblast cell types. TGF¿ is one of the most fibrogenic cytokines known, but because of its normal homeostatic role in virtually all tissues, therapies targeted at global TGF¿ neutralization will also have undesired systemic effects. The TGF¿ activating integrin, av¿8, is upregulated in COPD but has a highly restricted pattern of expression in normal human tissues making it a possible therapeutic target to specifically inhibit TGF¿ in COPD. This proposal is the first step in testing the therapeutic potential of inhibiting av¿8 function in COPD.

描述(由申请人提供)：慢性阻塞性肺疾病(COPD)治疗试验的失败反映了我们对该疾病机制的了解不足。该项目的长期目标是提高对慢性阻塞性肺疾病的机制认识。导致呼吸道阻塞的两个主要病理特征是肺泡壁丢失和小气道壁增厚(1 mm；2 mm)。小气道改变随着COPD严重程度的增加而进展，因此是稳定或潜在逆转气道阻塞的治疗靶点。最近的研究表明，转化生长因子β可能通过调节呼吸道上皮细胞和间充质细胞之间平衡的自分泌和旁分泌相互作用，在COPD的管壁增厚中发挥重要的机制作用，统称为上皮-间充质营养单位(EMTU)。这些自分泌和旁分泌的相互作用决定了肺发育过程中的细胞分化。这些相互作用的失衡可能是慢性呼吸道损伤(如烟草烟雾)造成的，并导致气道重塑。转化生长因子？亚型在EMTU内的所有细胞类型中都有表达，但几乎全部以非活性形式表达。因此，转化生长因子的激活是转化生长因子功能调节的重要环节。我们最近开发了第一批人类EMTU的体外模型之一(Araya等，AmJ.Path，2006)，并利用它来确定整合素av？8在转化生长因子β的激活以及随后的呼吸道上皮细胞和成纤维细胞之间的自分泌和旁分泌相互作用中发挥主要作用。使用人类COPD样本，我们发现8在呼吸道上皮细胞和小气道成纤维细胞中的表达增加，这与肺功能下降和气道壁增厚显著相关。这些发现使我们得出了我们的总体假设：COPD气道上皮细胞和成纤维细胞中依赖av？8的转化生长因子的激活增加，导致EMTU内的形态发生程序不适当地重新激活，从而导致气道重塑。利用生理相关的原代人呼吸道上皮细胞和成纤维细胞培养系统，我们将：1)确定COPD中气道上皮细胞和成纤维细胞表达增加的机制；2)确定在COPD中av？8介导的转化生长因子β的激活增加的机制；3)确定av？8介导的转化生长因子β在呼吸道上皮细胞和成纤维细胞类型之间的自分泌和旁分泌相互作用中的功能后果。转化生长因子是已知的最具纤维化作用的细胞因子之一，但由于其在几乎所有组织中的正常稳态作用，针对全局转化生长因子的中和治疗也会产生不良的全身效应。转化生长因子活化的整合素av？8在COPD中表达上调，但在正常人组织中的表达模式高度受限，这使得它可能成为特异性抑制COPD中转化生长因子β的治疗靶点。这项建议是测试抑制慢性阻塞性肺疾病av？8功能的治疗潜力的第一步。