Epithelial chitinase and lung homeostasis

上皮几丁质酶和肺稳态

基本信息

批准号：
8946156
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/8946156
关键词：
Accounting Acetylglucosamine 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 In Situ Infiltration Inflammation Inflammatory Infiltrate Injury Insecta Interleukin-1 Interleukin-13 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 T-Lymphocyte TSLP gene Time Tissues Transgenic Mice Tumor Necrosis Factor-alpha 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 toll-like receptor 4

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.

描述（由申请人提供）：肺在一生中暴露于许多环境挑战，需要有关维持体内平衡的分泌部分的进一步信息我们培育了缺乏降解环境中广泛存在的环境多糖所必需的上皮酶的小鼠。多糖攻击后，这些小鼠会持续出现与第 2 组先天淋巴细胞 (ILC2) 和肺 γ-δ T 细胞激活相关的长期肺部炎症，这些细胞会释放细胞因子，包括IL-5 和 IL-13 以及 IL-17 分别产生包括中性粒细胞和嗜酸性粒细胞在内的炎症浸润，当上皮酶活性恢复时可以克服这种炎症浸润。出乎意料的是，这些基因敲除小鼠在 6 年内出现了自发性肺部炎症。 9个月，即使在无病原体的设施中维持，炎症也包括纤维化，最明显的是中气道周围，其特征是组织细胞结构增强和肺胶原蛋白增加。因此，这些小鼠提供了由于先天肺淋巴样细胞的激活和 IL-13 和 IL-7 的过度表达而导致的自发性肺纤维化模型，这两种细胞因子先前与我们建立的诱发器官和组织纤维化的模型有关。一些基因标记的报告小鼠追踪相关细胞和细胞因子，这将用于揭示这种纤维化表型的机制。该资助计划在三个具体目标中研究肺表型。 2. 确定肺 ILC2 细胞的作用，以确定这些细胞和 IL-13 是否发挥促进损伤或减轻损伤的作用。确定这些细胞和 IL-17 在表型中所起的作用。 3. 建立肺部处理不溶性环境多糖的机制。人类在支气管肺泡灌洗液中含有大量相同的酶，这表明该途径在肺中具有进化保守性。我们的研究可能与了解人类慢性纤维化综合征的修饰因素有关，例如特发性肺纤维化和慢性过敏性肺炎，以及慢性过敏性肺炎的条件。需要进一步的致病见解。