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

项目总结 香烟烟雾激活补体级联导致远端肺不育的机制 慢性阻塞性肺疾病的损伤和进展尚不完全清楚。考虑到补体在治疗中的关键作用 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，而不是不加区别地抑制补体 对病原体的反应。在目标1中，我们提出了一种新的CS诱导肺损伤的机制， 聚焦于诱导补体沉积所必需的凝集素补体途径的成员 在肺中，2型肺泡上皮(AT2)细胞的增殖和向AT1细胞的分化减少， 导致肺气肿。在目标2中，我们将研究衰变加速因子(CD55)，一种补体 调节子是必需的，也是必需的，以防止凝集素补体在AT2上沉积，防止细胞 损伤和促进AT2的增殖/分化。在目标3中，我们提出了一种翻译方法来开发 一种包括补体蛋白及其调节因子的血浆补体活性分数，可以识别 高危吸烟者和早期COPD患者的肺气肿进展。我的建议针对的是临床 相关问题：利用AT2细胞膜CD55的表达和信号转导能否阻止 凝集素补体沉积和促进AT2增殖分化缓解肺气肿 发展。我们的体外和体内小鼠研究伴随着补体的测量 患有和不患有慢性阻塞性肺疾病的活动期吸烟者血浆中蛋白质和调节物水平和活性 COPD基因使用多重蛋白质组平台SomaScan。多个补体SomaScan蛋白 用于制定“补体活动评分”，以帮助预测肺气肿的进展。 该项目的完成将为靶向凝集素途径提供令人信服的实验证据 活化和保护AT2细胞膜CD55表达改善小鼠远端肺损伤 肺气肿模型和它可以作为人类COPD疾病的下一代生物标志物。我们的 在未来的研究中，新的补体活动评分可以识别有风险的吸烟者和早期COPD患者 药理临床试验。我们团队的互补专业知识，翻译方面的 建议，以及获得表型良好的人类样本增加了相关性和成功的机会 完成这一项目。

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.