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（例如二氧化硅、石棉等）而导致的肺部和全身疾病 最近，花岗岩台面制备过程中产生的灰尘）在美国和其他地区是一个严重的健康问题 世界。不幸的是，这些疾病仍然无法治疗，部分原因是缺乏有关其机制的信息。 受伤和炎症。迄今为止，广泛的研究未能确定具有潜力的关键步骤 治疗干预。除了上述颗粒暴露的潜在问题之外，还有越来越多的问题 人们担心工程纳米材料（ENM）的使用增加会增加肺部和全身的负担 在环境和职业环境中接触这些新材料的人类疾病。我们知道 ENM 的物理化学特性在毒性和潜在危险中发挥着作用。因此，有一个 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 被证明会引起炎症，导致肺纤维化，ENM 诱导炎症的精确机制 仍不清楚。我们已经证明 ENM 会导致吞噬溶酶体膜通透性 (LMP)，从而导致 溶酶体蛋白酶的释放，这与 NLRP3 等下游效应有关 炎症小体激活和肺泡巨噬细胞线粒体损伤，并显着促进 体内炎症和病理学。然而，负责 LMP 的机制，我们建议将其作为 ENM 和二氧化硅毒性的关键限速作用仍然未知。这种不确定性阻碍了进展 粒子引起的炎症和纳米毒理学领域，并限制了开发靶向治疗的能力 不利的健康影响。我们的中心假设是 ENM 和二氧化硅的相对生物活性是 取决于定义颗粒-吞噬溶酶体膜相互作用的特定表面特性，从而导致 末次月经。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，导致 LMP 并启动 我们的模型中描述的炎症途径。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LMP毒性与NLRP3炎症小体激活的机制及其关系 ENM 表面特性与生物活性之间的关系； 3：证明体外 MeO ENM 诱导 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 MeO ENM 介导的主要机制 LMP，证实 LMP 在巨噬细胞对 ENM 的反应以及炎症和病理学中的核心作用 并测试潜在的治疗方法。