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）：