Epithelial chitinase and lung homeostasis

上皮几丁质酶和肺稳态

• 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
• 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

 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)：肺在一生中暴露在许多环境挑战中，需要进一步了解有助于维持体内平衡的分泌部分。我们培育的小鼠缺乏一种上皮酶，这种酶是降解环境中普遍存在的环境多糖所必需的。在多糖攻击后，这些小鼠持续的肺部炎症与第二组固有淋巴样细胞(ILC2s)和肺伽马-德尔塔T细胞的激活有关，后者分别释放细胞因子，包括IL-5、IL-13和IL-17。由此产生的炎性浸润物包括中性粒细胞和嗜酸性粒细胞，会导致肺损伤，当上皮酶活性恢复时，这种损伤可以克服。出乎意料的是，这些基因敲除的小鼠在6-9个月内出现了自发性肺部炎症，即使在无病原体的设施中也是如此。炎症包括纤维化，最突出的是中气道周围，其特征是组织细胞增加和肺胶原蛋白增加。因此，这些小鼠提供了一种自发的肺纤维化模型，这是由于先天肺淋巴样细胞的激活和IL-13和IL-7的过度表达，这两种细胞因子以前在引发器官和组织纤维化的模型中被认为是相关的。我们已经产生了一些带有遗传标记的报告小鼠来跟踪相关的细胞和细胞因子，这些细胞和细胞因子将被用来揭开这种纤维化表型的机制。该基金建议从三个具体目标来研究肺表型。1.建立肺ILC2细胞的作用，以确定这些细胞和IL-13是起促进损伤还是减轻损伤的作用。2.确定肺伽马-三角洲细胞在 确定这些细胞和IL-17在表型中所起的作用。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，这表明这条肺内稳态的途径在进化上是保守的。我们的研究可能与了解人类慢性纤维化综合征的修饰物有关，如特发性肺纤维化和慢性过敏性肺炎，这些情况需要进一步的病理认识。