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Epithelial chitinase and lung homeostasis

上皮几丁质酶和肺稳态

基本信息

批准号：
9262267
负责人：
Richard M Locksley
金额：
$ 39.63万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9262267
关键词：
Affect Alleles Allergic Allergic inflammation Antigens Appearance Arthropods Aspergillus Aspirate substance Attenuated Bacteria Binding Breathing Bronchoalveolar Lavage Carbohydrates Cells Cellularity Cellulose Chitin Chitin Synthase Chitinase Chronic Collagen D Cells Dictyoptera Disease Environment Enzymes Eosinophilia Epithelial Epithelium Exposure to Extrinsic allergic alveolitis Fibrosis Grant Hamman-Rich syndrome Homeostasis Host Defense House Dust House mice Human Image Immunity Impairment In Situ Infiltration Inflammation Inflammatory Infiltrate Injury Insecta Interleukin-1 Interleukin-13 Interleukin-13 Overexpression Interleukin-17 Interleukin-5 Interleukin-7 Invertebrates Knockout Mice Lectin Life Lung Lung Inflammation Lung diseases Lymphocyte Lymphoid Cell Mediating Modeling Morphogenesis Mus Nutrient Organ Organism Pathway interactions Phenotype Plants Play Polymers Polysaccharides Process Production Pulmonary Fibrosis Pyroglyphidae Reporter Resistance Resolution Respiratory physiology Role Signal Transduction Stomach Structure of respiratory bronchiole Syndrome TLR4 gene TNF gene TSLP gene Time Tissues Transgenic Mice Vertebrates acidic mammalian chitinase asthmatic patient attenuation base cytokine eosinophil fungus gene replacement genetic linkage insight interleukin-23 lung injury macrophage neutrophil novel therapeutics particle pathogen public health relevance response γδ T cells

项目摘要

DESCRIPTION (provided by applicant): The lung is exposed to many environmental challenges throughout life, and further information is needed about secreted moieties that serve to sustain homeostasis. We generated mice that lack an epithelial enzyme necessary to degrade environmental polysaccharides widely prevalent in the environment. After polysaccharide challenge, these mice sustain prolonged lung inflammation associated with activation of Group 2 innate lymphoid cells (ILC2s) and lung gamma-delta T cells that release cytokines, including IL-5 and IL-13, and IL-17, respectively. The resultant inflammatory infiltrate including neutrophils and eosinophils, cause lung damage that can be overcome when epithelial enzymatic activity is restored. Unexpectedly, these knockout mice developed spontaneous lung inflammation over 6-9 months, even when maintained in a pathogen-free facility. Inflammation included fibrosis, most prominent around medium airways, and was characterized by enhanced tissue cellularity and increased lung collagen. As such, these mice provide a spontaneous model for pulmonary fibrosis due to activation of innate lung lymphoid cells and over-expression of IL-13 and IL-7, two cytokines previously implicated in prior models of provoked organ and tissue fibrosis. We have generated a number of genetically marked reporter mice to follow the relevant cells and cytokines, which will be used to unravel the mechanisms underlying this fibrosing phenotype. The grant proposes to study the lung phenotype in three Specific Aims. 1. To establish the role for lung ILC2 cells to determine whether these cells and IL-13 play an injury-promoting or injury-attenuating role. 2. To establish the role for lung gamma-delta cells to determine the role these cells and IL-17 play in the phenotype. 3. To establish the mechanism by which the lung disposes of insoluble environmental polysaccharides. Humans contain the same enzyme in robust amounts in bronchoalveolar lavage, suggesting evolutionary conservation of this pathway for lung homeostasis. Our studies may have relevance to understanding modifiers of chronic fibrosing syndromes of humans, such as idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis, conditions for which further pathogenetic insights are needed.