Role of particle surface functionalization in inflammation

颗粒表面功能化在炎症中的作用

• 批准号: 10810001
• 负责人: Andrij Holian
• 金额: $ 5.4万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-05 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10810001
• 关键词: Aerosols; Affect; Alveolar Macrophages; Animal Model; Applied Research; Asbestos; Biological; Biological Models; CASP1 gene; Cell Membrane Permeability; Cell physiology; Cells; Characteristics; Charge; Chemistry; Cholesterol; Development; Disease; Dust; Engineering; Event; Exposure to; Goals; Health; IL18 gene; Immune; In Vitro; Industrialization; Inflammasome; Inflammation; Inflammatory; Inhalation; Injury; Interleukin-1 beta; Knockout Mice; Knowledge; Libraries; Lung diseases; Lysosomes; Macrophage; Mediating; Membrane; Mitochondria; Modeling; Nanosphere; Nanotechnology; Occupational; Outcome; Particle Size; Pathology; Pathway interactions; Peptide Hydrolases; Phagolysosome; Phagosomes; Pharmaceutical Preparations; Phenotype; Preparation; Process; Property; Pulmonary Fibrosis; Pulmonary Inflammation; Pulmonary Pathology; Research; Resolution; Role; Signal Transduction; Silicates; Silicon Dioxide; Surface; Surface Properties; Systemic disease; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; Uncertainty; Vesicle; Wettability; amphiphilicity; bafilomycin A; commercial application; cytokine; cytotoxicity; design; exposed human population; fundamental research; granite; hazard; in vivo; interest; large-conductance calcium-activated potassium channels; lysosome membrane; metal oxide; nanoengineering; nanomaterials; nanotoxicology; novel therapeutics; particle; particle exposure; paxilline; prevent; response; therapeutic development; therapeutically effective; titanium dioxide; water solubility

Lung and systemic diseases as a result of micron-sized particle exposures (e.g., silica, asbestos, and more recently, dusts from preparation of granite countertops) are a critical health problem in the US and around the world. Unfortunately, these diseases remain untreatable in part due to lack of information on the mechanisms of injury and inflammation. To date, extensive research that has failed to identify the key steps with potential for therapeutic intervention. Adding to the potential problems of the above particle exposures, there are growing concerns that the increased use of engineered nanomaterials (ENM) will add to the burden of lung and systemic diseases in humans exposed in environmental and occupational settings to these new materials. We know that the physicochemical characteristics of ENM play a role in toxicity and hazard potential. Therefore, there is a critical need to understand how specific physicochemical properties of ENM (e.g., surface chemistry, charge and wettability) affect cell function and in vivo inflammatory outcomes. Furthermore, although MeO ENM have been shown to cause inflammation, leading to lung fibrosis, the precise mechanisms of ENM-induced inflammation remain unclear. We have demonstrated that ENM cause phagolysosomal membrane permeability (LMP), leading to release of lysosomal proteases, which have been implicated in downstream effects such as NLRP3 inflammasome activation, and mitochondrial damage in alveolar macrophages, and significantly contribute to in vivo inflammation and pathology. However, the mechanisms responsible for LMP, which we proposed to be the key rate-limiting effect of ENM and silica toxicity, remain unknown. This uncertainty impedes the progress in the field of particle-induced inflammation and nanotoxicology and limits the ability to develop targeted treatments for adverse health effects. Our central hypothesis is that the relative biological activity of ENM and silica is dependent on specific surface properties that define particle-phagolysosome membrane interactions leading to LMP. Furthermore, we postulate that ENM and silica interact with the interior of the phagolysosomal membrane leading to K+ flux through the BK channel and membrane hyperpolarization causing LMP and initiate the inflammatory pathway described in our model. The following aims will test our central hypothesis and accomplish our goals: 1: Synthesize and characterize MeO ENM with specific physicochemical properties.; 2: Determine the mechanism of MeO-induced LMP leading to toxicity and NLRP3 inflammasome activation and the relationship between ENM surface properties and biological activity; and 3: Demonstrate that in vitro MeO ENM-induced LMP and macrophage responses define in vivo pathology following aerosol exposures to selected MeO ENM. It is anticipated that these studies will help elucidate the primary mechanism responsible for MeO ENM-mediated LMP, confirm the central role of LMP in macrophage response to ENM as well as in inflammation and pathology and test potential therapeutics.

由于暴露于微米级颗粒而导致的肺部和全身性疾病（例如，硅石、石棉等 最近，在美国和世界各地， 世界不幸的是，这些疾病仍然无法治疗，部分原因是缺乏关于这些疾病的机制的信息。 损伤和炎症。迄今为止，广泛的研究未能确定有可能实现这一目标的关键步骤。 治疗干预除了上述颗粒暴露的潜在问题外， 担心工程纳米材料（ENM）的使用增加将增加肺部和全身的负担， 在环境和职业环境中暴露于这些新材料的人类疾病。我们知道 环境纳米材料的物理化学特性在毒性和潜在危害方面发挥作用。因此有 迫切需要了解ENM的具体物理化学性质（例如，表面化学、电荷和 润湿性）影响细胞功能和体内炎症结果。此外，虽然MEO ENM已被 显示引起炎症，导致肺纤维化，ENM诱导炎症的确切机制 仍然不清楚。我们已经证明，ENM引起吞噬溶酶体膜通透性（LMP），导致 溶酶体蛋白酶的释放，这与下游效应有关，如NLRP 3 炎性小体活化和肺泡巨噬细胞中的线粒体损伤，并显著促进炎症反应。 体内炎症和病理学。然而，负责LMP的机制，我们建议是 ENM关键限速作用和二氧化硅毒性仍然未知。这种不确定性阻碍了 颗粒诱导的炎症和纳米毒理学领域，并限制了开发针对性治疗的能力， 对健康的不良影响。我们的中心假设是ENM和二氧化硅的相对生物活性是 依赖于限定颗粒-吞噬溶酶体膜相互作用的特定表面性质， 进出口股份此外，我们假设ENM和二氧化硅与吞噬溶酶体膜的内部相互作用 导致K+通量通过BK通道和膜超极化，引起LMP，并启动 在我们的模型中描述的炎症通路。以下目标将检验我们的中心假设，并实现 我们的目标：1：合成并表征具有特定理化性质的MeO ENM。2：确定 MeO诱导的LMP导致毒性和NLRP 3炎性小体激活的机制及其关系 ENM表面性质和生物活性之间的关系;以及3：证明体外MeO ENM诱导的 LMP和巨噬细胞反应定义了气溶胶暴露于选定的MeO ENM后的体内病理学。它 预计这些研究将有助于阐明负责MeO ENM介导的主要机制 LMP，证实了LMP在巨噬细胞对ENM的反应以及炎症和病理学中的中心作用 测试潜在的治疗方法