Shared Mechanisms of Pulmonary Lymphocyte Activation by Bacteria and Toxicants

细菌和毒物激活肺淋巴细胞的共同机制

• 批准号: 7163144
• 负责人: Michael Borchers
• 金额: $ 50.45万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7163144
• 关键词: Pseudomonas aeruginosa; acrolein; air pollution; bacteria; biological signal transduction; cell cell interaction; chronic obstructive pulmonary disease; cytotoxic T lymphocyte; environmental exposure; genetic models; genetically modified animals; hazardous substances; host organism interaction; immunologic receptors; immunopathology; laboratory mouse; leukocyte activation /transformation; lung alveolus; lymphocyte; model design /development; natural killer cells; pathologic process; physiologic stressor; receptor expression; respiratory epithelium; respiratory infections

DESCRIPTION (provided by applicant): Environmental exposure to fundamentally diverse agonists such as bacteria and air pollutants can signal through shared mechanisms to activate the innate immune system. Although the roles of pulmonary lymphocytes in response to bacterial infection are well established, the roles of pulmonary lymphocytes in response to air pollutants are unclear. We propose to explore the paradigm that the same lymphocyte effector functions necessary to protect the lung from pathogens can lead to chronic pulmonary disease when stimulated by persistent exposure to environmental toxicants. To understand shared roles and mechanisms of lymphocyte activation following bacterial infection and toxicant exposure, we will study epithelial cell lymphocyte interactions in response to the common bacteria Pseudomonas aeruginosa (PA) and the ubiquitous air pollutant, acrolein. PA is a well-characterized gram-negative bacterium that constitutes a major cause of nosocomial infections. Acrolein is a hazardous air pollutant found in tobacco smoke, photochemical smog and diesel exhaust. We have examined specific mediators involved in the signaling of epithelial cell stress to the pulmonary immune system and identified NKG2D receptor activation as a potential mechanistic link between epithelial cell stress and lymphocyte activation. The central hypothesis of this application is that chronic acrolein exposure induces NKG2D ligand expression on pulmonary epithelial cells, activates cytotoxic lymphocytes that contribute to the development of Chronic Obstructive Pulmonary Disease (COPD). The Specific Aims are to (i) determine the role of NKG2D receptor activation in the clearance of pulmonary PA infection, (ii) determine the role of NKG2D receptor activation in the development of acrolein-induced airspace enlargement, and (iii) define the consequences of conditional NKG2D ligand expression on pulmonary epithelial cells. These shared mechanisms represent potential disease points that may shift the immune response from protective to pathological. Further, the development of the novel conditional NKG2D ligand-expressing transgenic mouse model will allow us to dissect the mechanisms of epithelial cell-lymphocyte interactions in emphysema. The successful completion of these studies will provide a better understanding of the pathways and mechanisms of immune system activation in response to environmental exposures that contribute to the pathophysiology of chronic airway diseases.

描述（由申请人提供）： 环境暴露于从根本上多样化的激动剂，例如细菌和空气污染物，可以通过共同的机制发出信号，以激活先天的免疫系统。尽管肺淋巴细胞对细菌感染的作用尚不清楚，但肺淋巴细胞对空气污染物的作用尚不清楚。我们建议探索这样的范例，即保护肺部免受病原体所必需的相同淋巴细胞效应子功能可能导致慢性肺部疾病，而持续暴露于环境毒物中。为了了解细菌感染和毒性暴露后淋巴细胞激活的共同作用和机制，我们将研究上皮细胞淋巴细胞相互作用，以响应普通细菌铜绿假单胞菌（PA）（PA）和无处不在的空气污染物Acroleoin，Acroleoin，Acrolein。 PA是一种良好的革兰氏阴性细菌，构成了医院感染的主要原因。丙烯醛是在烟草烟雾，光化学烟雾和柴油排气中发现的危险空气污染物。我们已经检查了涉及上皮细胞应激对肺免疫系统信号传导的特定介体，并将NKG2D受体激活确定为上皮细胞应激与淋巴细胞激活之间的潜在机械联系。该应用的中心假设是，慢性丙烯醛暴露在肺上皮细胞上诱导NKG2D配体表达，激活细胞毒性淋巴细胞，从而有助于慢性阻塞性肺疾病（COPD）的发展。具体目的是（i）确定NKG2D受体激活在清除肺PA感染中的作用，（ii）确定NKG2D受体激活在丙烯醛诱导的空域增大的发展中的作用，（III）定义了条件NKGG2D ligand ligand tiganter octiatal inkg2d ligand cormonal colmonial climonial spithithial spittillial spittillial spithithiralial spithithitelial lignial lignial。这些共同的机制代表了潜在的疾病点，可能会将免疫反应从保护性转移到病理。此外，新型条件NKG2D配体表达转基因小鼠模型的发展将使我们能够剖析肺气肿中上皮细胞 - 淋巴细胞相互作用的机理。这些研究的成功完成将更好地理解免疫系统激活的途径和机制，以响应有助于慢性气道疾病的病理生理学的环境暴露。