Epithelial chitinase and lung homeostasis

上皮几丁质酶和肺稳态

• 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
• 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

 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）：肺在整个生命过程中暴露于许多环境挑战，并且需要关于用于维持稳态的分泌部分的进一步信息。我们产生的小鼠缺乏降解环境中广泛存在的环境多糖所必需的上皮酶。在多糖攻击后，这些小鼠持续与第2组先天淋巴样细胞（ILC 2）和肺γ-δ T细胞的激活相关的长期肺部炎症，所述细胞释放细胞因子，分别包括IL-5和IL-13以及IL-17。由此产生的炎性浸润，包括中性粒细胞和嗜酸性粒细胞，导致肺损伤，当上皮酶活性恢复时可以克服。出乎意料的是，这些敲除小鼠在6-9个月内发生自发性肺部炎症，即使在无病原体的设施中也是如此。炎症包括纤维化，在中等气道周围最突出，其特征为组织细胞结构增强和肺胶原蛋白增加。因此，这些小鼠由于先天肺淋巴样细胞的活化和IL-13和IL-7的过表达而提供了肺纤维化的自发模型，IL-13和IL-7是先前在诱发的器官和组织纤维化的先前模型中涉及的两种细胞因子。我们已经产生了一些基因标记的报告小鼠，以跟踪相关的细胞和细胞因子，这将被用来解开这种纤维化表型的机制。该补助金建议在三个特定目标中研究肺表型。1.确定肺ILC 2细胞的作用，以确定这些细胞和IL-13是否发挥损伤促进或损伤减轻作用。2.为了确定肺γ-δ细胞在 确定这些细胞和IL-17在表型中的作用。3.建立肺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，这表明该途径在肺内稳态中的进化保守性。我们的研究可能与了解人类慢性纤维化综合征的修饰剂有关，如特发性肺纤维化和慢性过敏性肺炎，需要进一步了解发病机制。