Decay accelerating factor (CD55) protects against lectin pathway-mediated AT2 cell dysfunction in cigarette smoke-induced emphysema

衰变加速因子 (CD55) 可防止香烟烟雾引起的肺气肿中凝集素途径介导的 AT2 细胞功能障碍

• 批准号: 10737359
• 负责人: Karina Serban
• 金额: $ 76.04万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2023-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10737359
• 关键词: Address; Alveolar; Alveolar Cell; Alveolus; Automobile Driving; Binding; Biological Markers; Blood capillaries; Bone Marrow; Brain; CD55 Antigens; Cell Death; Cell Differentiation process; Cell Proliferation; Cell Survival; Cell membrane; Cells; Chimera organism; Chronic Obstructive Pulmonary Disease; Cigarette smoke-induced emphysema; Clinical; Clinical Trials; Complement; Complement Activation; Complement Membrane Attack Complex; Complex; Data; Deposition; Development; Disease; Distal; Dropout; Enrollment; Ensure; Epithelial Cell Proliferation; Epithelial Cells; Foundations; Functional disorder; Hematopoietic; Homeostasis; Host Defense; Human; Impairment; Individual; Inflammation; Injury; Lectin; Lung; MASP2 gene; Mannose Binding Lectin; Measurement; Measures; Mediating; Membrane; Mus; Organ; Organoids; Orphan; Pathogenesis; Pathway interactions; Patients; Phenotype; Plasma; Pre-Eclampsia; Proliferating; Proteins; Proteomics; Pulmonary Emphysema; Receptor Activation; Receptor Protein-Tyrosine Kinases; Regression Analysis; Risk; Role; Serine Protease; Signal Transduction; Smoker; Specimen; Sterility; Technology; Testing; Tissues; Vasculitis; alveolar epithelium; antimicrobial; cell injury; cigarette smoke; cigarette smoke-induced; cigarette smoke-induced lung injury; cigarette smoking; clinically relevant; cohort; complement pathway; epithelial injury; exposure to cigarette smoke; immune activation; improved; in vivo; injured; kidney cell; loss of function; lung injury; member; mouse model; next generation; novel; pathogen; pharmacologic; preservation; prevent; proliferation potential; receptor; response; risk stratification; therapeutic target; translational approach

Project summary The mechanisms by which cigarette smoke (CS) activates the complement cascade to cause distal lung sterile injury and progression to COPD are not completely understood. Considering the critical role of complement in pathogen-induced inflammation, selective inhibition of the lectin complement pathway may result in decreased CS-induced emphysema-like airspace enlargement without an indiscriminate inhibition of complement’s response to pathogens. In Aim 1 we propose to investigate a novel mechanism of CS-induced lung injury, focusing on members of the lectin complement pathway that are necessary to induce complement deposition in the lung, decreased type-2 alveolar epithelial (AT2) cell proliferation and differentiation into AT1 cells, resulting in emphysema. In Aim 2 we will investigate whether decay accelerating factor (CD55), a complement regulator is necessary and required to protect against lectin complement deposition on AT2, preventing cell injury and improving AT2 proliferation / differentiation. In Aim 3 we propose a translational approach to develop a plasma complement activity score encompassing complement proteins and their regulators that could identify emphysema progression in smokers at risk and early COPD individuals. My proposal addresses the clinically relevant question whether harnessing membrane CD55 expression and signaling in AT2 cells can prevent lectin complement deposition and improve AT2 proliferation and differentiation mitigating emphysema development. Our ex-vivo and in-vivo murine studies are accompanied by measurements of complement proteins and regulators levels and activity in plasma from active smokers with and without COPD enrolled in COPDGene using a multiplex proteomic platform, SomaScan. Multiple complement SomaScan proteins are used to develop a “complement activity score” to help predict emphysema progression. Completion of this project will provide compelling experimental evidences that targeting lectin pathway activation and preserving membrane CD55 expression on AT2 cells ameliorates distal lung injury in murine models of emphysema and it can be harnessed as next generation biomarkers in human COPD disease. Our newly complement activity score could identify smokers at risk and early COPD subjects in future research and pharmacological clinical trials. The complementary expertise of our team, the translational aspect of the proposal, and access to well-phenotyped human specimens increase the relevance and chance of successful completion of this project.

项目摘要 香烟烟雾（CS）激活补体级联反应导致远端肺不育的机制 损伤和进展为COPD还不完全清楚。考虑到补体在 病原体诱导的炎症，选择性抑制凝集素补体途径可能导致减少 CS诱导的肺气肿样空域扩大，而无补体的不加选择的抑制 对病原体的反应。在目的1中，我们提出研究CS诱导的肺损伤的新机制， 集中于诱导补体沉积所必需的凝集素补体途径的成员 在肺中，降低2型肺泡上皮（AT 2）细胞增殖和分化成AT 1细胞， 导致肺气肿。在目标2中，我们将研究是否衰变加速因子（CD 55），一种补体， 调节子是必需的，并且是防止凝集素补体沉积在AT 2上，防止细胞增殖的必需的。 损伤和促进AT 2增殖/分化。在目标3中，我们提出了一种翻译方法来开发 包括补体蛋白及其调节因子的血浆补体活性评分， 吸烟者和早期COPD患者的肺气肿进展。我的建议是针对临床上 利用AT 2细胞中的膜CD 55表达和信号传导是否可以预防 凝集素补体沉积和促进AT 2增殖和分化减轻肺气肿 发展我们的离体和体内小鼠研究伴随着补体的测量。 来自入选研究的患有和不患有COPD的活跃吸烟者的血浆中的蛋白质和调节剂水平和活性 COPDGene使用多路蛋白质组学平台SomaScan。多种补体SomaScan蛋白是 用于开发“补体活性评分”，以帮助预测肺气肿的进展。 本项目的完成将为靶向外源凝集素途径提供有力的实验证据 活化和保留AT 2细胞膜CD 55表达改善小鼠远端肺损伤 肺气肿模型，并且它可以作为人类COPD疾病的下一代生物标志物。我们 在未来的研究中，新的补体活性评分可以识别高危吸烟者和早期COPD受试者， 药理学临床试验。我们团队的互补专业知识， 建议，并获得良好的表型人类标本增加的相关性和成功的机会， 完成这个项目。