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Transgenic Cytokines in COPD

慢性阻塞性肺病中的转基因细胞因子

基本信息

批准号：
7144991
负责人：
TAO ZHENG
金额：
$ 12.81万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-15 至 2007-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7144991
关键词：
Accounting Adult Alveolar Alveolus Animals Aspartic Endopeptidases Asthma Belief Biological Models Breeding CD8-Positive T-Lymphocytes Cathepsins Cells Chronic Obstructive Airway Disease Chronic Obstructive Asthma Cigarette smoke-induced emphysema Clara cell Cysteine Cysteine Proteinase Inhibitors Deterioration Development Endopeptidases Eosinophilia Equilibrium Gene Expression Generations Human Immunologics Individual Inflammation Inflammatory Inflammatory Response Integration Host Factors Interferon Type II Interferons Interleukin-13 Interleukin-13 Overexpression Knock-out Leukocyte Elastase Lung Lymphocyte Mediating Messenger RNA Metalloproteases Metaplasia Minority Mucous body substance Mus Mutation Nature Numbers Pathogenesis Pathologic Pathway interactions Patients Peptide Hydrolases Phenotype Physiological Play Predisposition Process Protease Inhibitor Protein C Inhibitor Protein Overexpression Proteins Pulmonary Emphysema Rate Research Design Respiratory physiology Role Sampling Serine Smoker System Testing Tetracycline Tetracyclines Thinking Tissues Trans-Activators Transgenes Transgenic Animals Transgenic Organisms Upper arm airway hyperresponsiveness alveolar destruction antileukoprotease base cigarette smoke-induced cigarette smoking cigarette smoking concept cytokine eosinophil granulocyte human SLPI protein injured airway interleukin-13 receptor lung development lung volume macrophage mature animal neutrophil null mutation post gamma-globulins promoter receptor respiratory response

项目摘要

DESCRIPTION (provided by applicant): Cigarette smoke (CS) is a major factor in the pathogenesis of COPD. However, only a minority of smokers get COPD and the rate of CS-induced pulmonary deterioration differs greatly amongst individuals. CS induced emphysema via altering protease/antiprotease balance in the lung. However, the mechanisms by which CS exerts its effects and the host factors that define individual susceptibility are poorly understood. Inflammation (macrophages, lymphocytes, eosinophils, neutrophils) is common in COPD. The importance of inflammation in generating COPD, the ability of inflammation to alter proteases and antiproteases and, the degree to which different types of inflammation can account for different presentations of patients with COPD have not been defined. We recently established an inducible overexpression (OE) transgenic system and used this system to overexpress IL-13 and/or gamma-interferon (IFN-gamma) in the adult murine lung. Individually both cytokines caused impressive emphysema. With IL-13 the emphysema occurred rapidly and was associated with mucus metaplasia and macrophage, lymphocyte and eosinophil rich inflammation. In the IFN-gamma mouse, the emphysema occurred slowly, was not associated with mucus metaplasia and was associated with macrophage and granulocyte rich inflammation. Mice expressing both IFN-gamma and IL-13 had a synergistic increase in emphysema. We hypothesize that: (1) IL-13 and IFN-gamma alone and in combination, activate important emphysema generating pathways in the lung; (2) effects of IL-13 and/or IFN-gamma are mediated by distinct and differentiable alterations in pulmonary protease / antiprotease balance and (3) IFN-gamma and IL-13 play an important role in the pathogenesis of CS-induced emphysema. To test this hypothesis we propose to: (1) Further define the phenotype and protease / antiprotease alterations in IL-13 OE and IFN-y OE mice and progeny of crosses of these animals. (2) Characterize the importance of IL-13 / IFN-gamma-induced alterations in protease / antiprotease balance in the generation of the emphysema seen in these animals. (3) Characterize the expression and roles of IL-13 and/or IFN-gamma in murine CS-induced emphysema.

描述（由申请人提供）：