Cholesterol crystal-mediated inflammation in alveolar macrophages: an emerging role inidiopathic lung fibrosis?

胆固醇晶体介导的肺泡巨噬细胞炎症：在特发性肺纤维化中的新兴作用？

• 批准号: 462596862
• 负责人: Dr. Sonia Giambelluca, Ph.D.
• 金额: --
• 依托单位: Institut für Funktionelle Anatomie
• 依托单位国家: 德国
• 项目类别: WBP Position
• 财政年份: 2021
• 资助国家: 德国
• 起止时间: 2020-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/462596862?language=en
• 关键词: Cholesterol; crystal; mediated; inflammation; alveolar

Idiopathic Pulmonary Fibrosis (IPF) is a chronic lung disease characterized by progressive scarring of the lung, eventually causing respiratory failure and death. It currently affects 80,000-111,000 people in Europe and has no cure yet. Alveolar macrophages (AMs) are important immune cells involved in the defense against microorganisms. Moreover, they are partially responsible of lung lipid recycling, even though the specific mechanism is still not known. Thus, altered activity of AMs may lead to lipid accumulation. Among lipids, cholesterol seems to play a key role, since animal models of IPF show accumulation of cholesterol in macrophages. Moreover, accumulation of structures similar to cholesterol crystals (CCs), have been observed in mouse lungs from different lung disease models. We hypothesize that altered cholesterol metabolism leads to formation of CCs in AMs, contributing to lung fibrosis. The main goal of present study is to detect altered lipid metabolic mechanisms in AMs and to clarify the mechanisms leading to CC formation/accumulation in AMs and their involvement in lung fibrosis. To this purpose, the project specifically aims to: characterize the molecular mechanism of CC formation in AMs and potential activation of inflammatory processes in AM-like cell cultures; validate the results in an animal model of lung fibrosis; detect altered lung lipid metabolic mechanisms involved in human IPF lung samples. The research will focus on an interdisciplinary approach including experiments in cells and in human samples by means of cutting-edge technologies, such as electron microscopy to detect changes in AM morphology and the ability of AMs to produce and/or uptake CCs, and mass spectrometry to elucidate altered lipid levels in IPF patients. Given the urgency of an effective therapy for IPF, the growing interest of the medical community on the role of lipid metabolism in the development of lung fibrosis, and the innovative approach proposed here, the project could provide new insights into the development of therapeutic targets and diagnostic tools. The applicant has expertise in lipid analyses of lung samples that will help in identifying altered mechanism. The proposed project will help her to develop further her laboratory competences, along with her professional growth through the collaboration with colleagues from different backgrounds, thus enabling the applicant to independently lead her own research projects in the field of lung physiology in the future.

特发性肺纤维化(IPF)是一种慢性肺部疾病，其特征是肺部逐渐形成疤痕，最终导致呼吸衰竭和死亡。目前，它影响着欧洲的8万至11.1万人，目前还没有治愈的方法。肺泡巨噬细胞(Am)是参与防御微生物的重要免疫细胞。此外，尽管具体机制尚不清楚，但它们对肺脂循环负有部分责任。因此，AM活性的改变可能导致脂质堆积。在脂质中，胆固醇似乎起着关键作用，因为IPF的动物模型显示胆固醇在巨噬细胞中积累。此外，在不同肺部疾病模型的小鼠肺中观察到类似胆固醇晶体(CCS)的结构积累。我们假设胆固醇代谢改变导致AM中CCS的形成，从而导致肺纤维化。本研究的主要目的是检测肺泡巨噬细胞脂质代谢改变的机制，阐明肺泡巨噬细胞CC形成/积聚的机制及其参与肺纤维化的机制。为此，该项目的具体目标是：表征AM中CC形成的分子机制和AM样细胞培养中炎症过程的潜在激活；在肺纤维化动物模型中验证结果；检测人类IPF肺样本中涉及的改变的肺脂代谢机制。这项研究将集中于一种跨学科的方法，包括通过尖端技术在细胞和人体样本中进行实验，例如电子显微镜来检测AM形态的变化以及AM产生和/或摄取CCS的能力，以及质谱仪来阐明IPF患者血脂水平的变化。鉴于 对特发性肺纤维化有效治疗的迫切性，以及医学界对脂代谢在肺纤维化发展中的作用日益增长的兴趣，以及这里提出的创新方法，该项目可以为治疗靶点和诊断工具的开发提供新的见解。申请者在肺部样本的脂肪分析方面具有专业知识，这将有助于识别改变的机制。建议的项目将帮助她通过与不同背景的同事合作，进一步发展她的实验室能力，以及她的专业成长，从而使申请者能够在未来独立领导自己在肺生理学领域的研究项目。