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。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，这些细胞分别释放细胞因子，包括 IL-5 和 IL-13 以及 IL-17。由此产生的炎症浸润（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，这种损伤可以得到克服。出乎意料的是，这些基因敲除小鼠在 6-9 个月内出现自发性肺部炎症，即使是在无病原体的环境中饲养也是如此。炎症包括纤维化，在中气道周围最为突出，其特征是组织细胞结构增强和肺胶原蛋白增加。因此，这些小鼠提供了一个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 的过度表达所致，这两种细胞因子先前与诱发器官和组织纤维化的模型有关。我们已经培育了许多带有基因标记的报告小鼠来追踪相关细胞和细胞因子，这将用于揭示这种纤维化表型背后的机制。该赠款提议研究三个具体目标的肺表型。 1. 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。 2. 确定肺 γ-δ 细胞在 确定这些细胞和 IL-17 在表型中发挥的作用。 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，这表明这种肺稳态途径的进化保守性。我们的研究可能与了解人类慢性纤维化综合征的修饰因素相关，例如特发性肺纤维化和慢性过敏性肺炎，这些疾病需要进一步的发病机制了解。