Mechanisms of Airway Epithelial Injury and Response

气道上皮损伤和反应的机制

基本信息

批准号：
10021691
负责人：
Jenora Waterman
金额：
$ 36万
依托单位：
NORTH CAROLINA AGRI & TECH ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-23 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10021691
关键词：
Affect Agricultural Development Agricultural Workers Agriculture American Animal Model Animals Applications Grants Behavior Bronchoalveolar Lavage Ca(2+)-Calmodulin Dependent Protein Kinase Cause of Death Cell Differentiation process Characteristics Chemicals Chronic Chronic Bronchitis Chronic Obstructive Airway Disease Data Death Rate Development Down-Regulation Dust Early Diagnosis Eicosanoids Endotoxins Environment Epidermal Growth Factor Receptor Epithelial Epithelial Cells Epithelium Exposure to Family suidae Fibrosis Future General Population Goblet Cells Hyperplasia Immunologics Impairment In Vitro Inflammation Inflammation Mediators Inflammatory Response Inhalation Injury Innate Immune Response Interleukin-8 Knowledge Lead Lesion Leukocytes Livestock Longitudinal Studies Lung Lung diseases Measures Mediating Modeling Molecular Morphology Mucins Mucous body substance Mucus-Secreting Cell NF-kappa B Occupational Occupational Exposure Oxidants Oxidative Stress Oxidative Stress Pathway Pathogenesis Pathology Pathway interactions Phagocytes Pharmacologic Substance Phenotype Phosphoric Monoester Hydrolases Phosphotransferases Physiological Pollution Population Prevalence Prevention Production Prostaglandins Protein Tyrosine Kinase Proteomics Pulmonary Fibrosis Reporting Research Risk Factors Role Signal Pathway Signal Transduction Slice Smooth Muscle Source Structure of parenchyma of lung TNF gene Time Tissues Tracheobronchial United States airway epithelium airway inflammation base calmodulin-dependent protein kinase II cigarette smoking cyclooxygenase 2 cytokine epithelial injury farmer inflammatory lung disease inhibitor/antagonist innovation lung development metropolitan modifiable risk mucin hypersecretion mucus hypersecretion muscle hypertrophy new therapeutic target novel novel therapeutics particle pathogen response response to injury rural area

项目摘要

ABSTRACT Cigarette smoking is the leading cause of chronic obstructive pulmonary disease (COPD); however, other exposures, such as occupational exposure to indoor pollution accounts for 20-25% of COPD cases in the United States. Exposure to organic dusts within swine confinement facilities (SCF) is a significant modifiable risk factor for lung disease in SCF workers. Numerous reports recognize the association between repetitive SCF organic dust exposure and development of a broad spectrum of chronic inflammatory lung diseases including chronic bronchitis (CB) – one of two major forms of COPD. However, the cellular and molecular mechanisms governing development of agriculture-related CB remain unclear. Challenges in the field of agriculture-related lung disease research include the difficulty in recreating SCF exposure conditions and the lack of physiologically relevant animal models to study `real world' exposures. Our preliminary data show that SCF pigs are a model for early airway epithelium injury and response, as evidenced by phenotypic lesions characteristic of CB including increased levels of the secreted airway mucins, airways contain goblet cell hyperplasia, inflammation, and evidence of smooth muscle hypertrophy compared to non-SCF (pasture) pigs. In this proposal, we will investigate mechanisms of airway epithelial injury and response to SCF organic dust by comparing the behavior of lung tissue from SCF and non-SCF pigs. To identify sources of inflammatory mediators, responses of lung leukocytes, lung slices and porcine tracheobronchial epithelial (PTBE) cells from SCF and non-SCF to endotoxin will be compared (Aim 1). The calcium/calmodulin-dependent protein kinase II (CaMKII), a kinase regulated by oxidative stress and implicated in pulmonary fibrosis, is more abundant in airway epithelial tissue of SCF pigs compared to non-SCF pigs. Therefore, studies using various inhibitors will be conducted to determine the role of CaMKII and oxidative stress in activation of airway inflammation pathways, including nuclear factor kappa B, using PTBE cells from SCF pigs (Aim 2). Given the observance of goblet cell hyperplasia in the airway epithelia of SCF pigs, we will utilize comprehensive proteomics approaches to identify molecular pathways associated with goblet cell hyperplasia in porcine models (Aim 3). Utilizing global and targeted proteomics approaches, pathways governing initiation and progression of goblet cell hyperplasia and mucus secretion will be identified. Knowledge of molecular pathways that regulate goblet cell hyperplasia will serve as potential targets for development of novel therapeutic strategies to treat CB affecting agricultural workers and the general population.

抽象的然而，吸烟是慢性阻塞性肺病 (COPD) 的主要原因；慢性阻塞性肺病 (COPD) 病例中 20-25% 是由于职业性接触室内污染造成的美国，猪圈养设施 (SCF) 内接触有机粉尘是一个重要的可改变因素。许多报告认识到重复性工作之间存在关联。 SCF 有机粉尘暴露与多种慢性炎症性肺病的发生包括慢性支气管炎（CB）——慢性阻塞性肺病的两种主要形式之一，但是，细胞和分子。农业相关CB发展的管理机制仍不明确。与农业相关的肺部疾病研究包括重建 SCF 暴露条件的困难以及我们的初步数据表明，缺乏生理相关的动物模型来研究“现实世界”的暴露。 SCF 猪是早期气道上皮损伤和反应的模型，如表型病变所证明 CB 的特征包括分泌性气道粘蛋白水平增加，气道含有杯状细胞与非 SCF（放牧）猪相比，有增生、炎症和平滑肌肥大的证据。在本提案中，我们将研究气道上皮损伤的机制以及对 SCF 有机粉尘的反应通过比较 SCF 和非 SCF 猪的肺组织行为来确定炎症来源。介质、肺白细胞、肺切片和猪气管支气管上皮 (PTBE) 细胞的反应将比较 SCF 和非 SCF 与内毒素的关系（目标 1）钙/钙调蛋白依赖性蛋白激酶 II。 (CaMKII) 是一种受氧化应激调节并与肺纤维化有关的激酶，在 SCF 猪与非 SCF 猪的气道上皮组织的比较因此，使用各种抑制剂的研究将进行。进行以确定 CaMKII 和氧化应激在气道炎症激活中的作用途径，包括核因子 kappa B，使用来自 SCF 猪的 PTBE 细胞（目标 2）。 SCF猪气道上皮杯状细胞增生，我们将利用综合蛋白质组学确定与猪模型中杯状细胞增生相关的分子途径的方法（目标 3）。利用全局和有针对性的蛋白质组学方法、杯状结构起始和进展的途径将识别细胞增生和粘液分泌的分子途径的知识。细胞增生将作为开发新的治疗策略来治疗 CB 的潜在目标影响农业工人和普通民众。