Role of Surfactant Protein-C Mutation and Ozone Exposure in the Exacerbation of Pulmonary Fibrosis

表面活性剂蛋白 C 突变和臭氧暴露在肺纤维化恶化中的作用

• 批准号: 10331034
• 负责人: ALESSANDRO VENOSA
• 金额: $ 38.01万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10331034
• 关键词: Acute; Air Pollutants; Bleomycin; Cells; Cessation of life; Chemical Injury; Clinical; Data; Degenerative Disorder; Dependence; Diagnosis; Disease; Ectopic Expression; Environmental Exposure; Environmental Risk Factor; Epidemiology; Epithelial; Epithelial Cells; Fibrosis; Flow Cytometry; Future; Genes; Genetic; Genetic Transcription; Heterogeneity; Histologic; Histology; Human; Inflammation; Inflammatory; Inflammatory Response; Inhalation; Injury; Lesion; Life Expectancy; Link; Lung; Lung Transplantation; Lung diseases; Mediator of activation protein; Methods; Modeling; Mutant Strains Mice; Mutation; Myeloid Cell Activation; Myeloid Cells; Oxidative Stress; Ozone; Pathogenesis; Patients; Peripheral; Pharmacology; Phenotype; Population; Pre-Clinical Model; Property; Publishing; Pulmonary Fibrosis; Pulmonary Inflammation; Pulmonary Surfactant-Associated Protein C; Role; Severities; Signal Transduction; Solid; System; Testing; Time; Tissues; Toxic Environmental Substances; Toxic effect; Vulnerable Populations; Work; chemokine receptor; clinically relevant; cytokine; effective therapy; fibrogenesis; fibrotic lung; fractalkine receptor; improved; information model; injured; lung health; macrophage; monocyte; mouse model; mutant; novel; ozone exposure; recruit; response; single-cell RNA sequencing; transcriptome sequencing; ventilation

Project Summary/Abstract: Pulmonary fibrosis (PF) is a rare degenerative disease characterized by progressive lung stiffening, resulting in death within 3-5 years of diagnosis. Compelling clinical evidence show that mutations of the epithelial cell- specific gene encoding surfactant protein-C (SP-C), are linked to a particularly extreme lung phenotype. Progression of PF in humans is often punctuated by inflammatory bursts, clinically termed “acute exacerbations”, that drastically accelerate the disease and reduce life expectancy. In accord with this notion, monocyte mobilization and the persistence of monocyte-derived macrophages in the lung are strong predictors of PF severity. Several environmental factors have been proposed to promote and accelerate acute inflammatory exacerbations of PF; however, the exact mechanisms have not been interrogated. The ubiquitous air pollutant ozone (O3) represents a major, and unavoidable, environmental contributor to pulmonary disease through oxidative stress and monocyte/macrophage rich inflammation. To closely mimic causes of human PF, we developed a novel mouse model that develops spontaneous lesions over time, as a result of inducible ectopic expression of the most common PF-linked SP-C mutation (SP-CI73T). This preclinical model provides a unique platform to decipher mechanisms of PF progression and specifically the roles of acute exacerbations (induced by O3), infiltrating monocytes, and monocyte-derived macrophages in promoting PF. Our published work showed that SP-C mutation is accompanied by a dynamic monocyte/macrophage inflammatory response, initiated by the epithelium. Preliminary evidence confirm that O3 exposure amplifies inflammatory cell influx and pro- inflammatory signaling in SP-C mutant mice, worsening PF. Assessment of the proposed paradigm will provide fundamental data to define the responses of the healthy, acutely inflamed, and fully fibrotic lung to environmental exposure. Our hypothesis is that O3-induced acute exacerbation of PF driven by SP-C mutation enhances the recruitment and activation of inflammatory monocytes, triggering a monocyte-derived macrophage pro-fibrotic response. Our Specific Aims are to: 1) Define monocyte dynamics following O3-induced pulmonary inflammation and PF. 2) Investigate the role of monocyte-derived macrophages and O3-induced exacerbation of PF; and 3) : Establish the role of monocyte subpopulations in the PF phenotype.

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