Development of PolyAspirin Particles for Therapeutic Intervention in ALI/ARDS via the Passive Restraint of Neutrophil Function

开发聚阿司匹林颗粒，通过被动抑制中性粒细胞功能来治疗 ALI/ARDS

• 批准号: 9897158
• 负责人: Omolola Eniola-Adefeso
• 金额: $ 46.65万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9897158
• 关键词: Acute Lung Injury; Adhesions; Adult Respiratory Distress Syndrome; Affect; Alpha Particles; Alveolar capillary destruction; Anti-Inflammatory Agents; Antibodies; Aspirin; Bacteria; Bacterial Infections; Binding; Biodistribution; Blood; Blood Circulation; Blood Vessels; Blood capillaries; Carbon Dioxide; Caring; Cell Adhesion Molecules; Cell Count; Characteristics; Clinical; Colony-forming units; Complex; Development; Disease; Disease model; Edema; Endothelium; Ensure; Epithelial; Epithelium; Evaluation; Event; Excision; Future; Goals; Gram-Negative Aerobic Bacteria; Histologic; Human; Immunologics; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Intercellular adhesion molecule 1; Intervention; Intravenous; Knowledge; Lead; Leukocytes; Liquid substance; Liver; Lung; Measurement; Measures; Mechanical Ventilators; Mesentery; Modeling; Mus; Particle Size; Pathologic; Pathology; Patients; Permeability; Pharmaceutical Preparations; Pharmacology; Poly A; Polymers; Pseudomonas; Pseudomonas aeruginosa; Resolution; Respiratory physiology; Route; Salicylic Acids; Severity of illness; Signal Transduction; Signaling Molecule; Surface; System; Therapeutic; Therapeutic Intervention; Tissues; Toxic effect; Work; base; biomaterial compatibility; clinically relevant; cytokine; design; effective therapy; healing; human disease; in vitro Assay; in vivo; innovation; intravital microscopy; lung injury; microscopic imaging; migration; mortality; neutrophil; novel; particle; perpetrators; prevent; protective effect; response; restraint; stem; success; treatment strategy; venule

ABSTRACT The central goal of this work is to develop intravenously (IV)-injected Poly-Aspirin (Poly-A) particles as passive restraints of neutrophil function for therapeutic intervention in Acute Lung Injury (ALI). ALI is a rapidly progressing inflammatory disease characterized by the disruption of the lung endothelial and epithelial barriers, leading to accumulation of fluids in the lung airway and hence impaired lung function. ALI together with acute respiratory distress syndrome (ARDS), a more severe form of ALI, affects ~200,000 patients per year in the US currently, with a mortality rate of ~40-60%. To date, there is no one pharmacological strategy effective towards reducing the mortality in ALI/ARDS, likely due to the numerous and complex set of pathological events that can lead to this disease. Thus, the primary treatment for this disease is the use of a mechanical ventilator for blood oxygenation and CO2 removal to allow the damaged lung to heal, but this can lead to further damage to the lung if not employed with care. Neutrophils have been identified as the primary perpetrator of inflammation in ALI/ARDS, where their excessive migration into the lungs contributes to the destruction of the alveolar-capillary barrier that leads to edema in the lungs. Indeed, disease severity correlates with the concentration of neutrophils in the lung airways. Thus, halting the destructive potential of unwanted neutrophil accumulation has been a principal focus for the development of ALI/ARDS treatment. However, prior attempts at developing drugs that block neutrophil signaling/adhesion molecules have met with limited success due to the numerous redundancies in the inflammatory response cascade. Here, we propose to rationally design vascular-targeted particles (VTPs) that physically interact with neutrophils to passively and rapidly block neutrophil accumulation into inflamed tissue in ALI/ARDS. Our main hypothesis is that VTPs interact with neutrophils in the bloodstream, via physical interaction and competition for vascular binding space, to alter neutrophil adhesion to the vessel wall, which critically impacts their migration into the diseased tissue. In this proposal, we harness these blocking interactions to develop a biodegradable, biocompatible VTPs as an effective treatment for ALI/ARDS through three Aims. First, we will fabricate a PolyAspirin-based VTP system and evaluate the impact of their particle size and surface characteristics on their ability to specifically block neutrophil adhesion to the vessel wall in vitro. Second, we will visualize, via intravital microscopy imaging, the adhesion of the PolyAspirin-based VTPs to the blood vessel wall and their blocking of neutrophil adhesion in vivo in inflamed mesentery tissue in mice. Thirdly, we will evaluate the therapeutic functionality of PolyAspirin particles in mice with bacteria-induced ALI/ARDS, representing a realistic model of the human disease. Overall, the knowledge gained from these Aims is expected to drive the future development of novel particle-based anti-inflammatory therapeutics in the treatment of ALI/ARDS. The proposed direct action of VTPs on neutrophils, rather than blocking of adhesion or signaling molecules, will ensure that the proposed system can function irrespective of the primary cause of ALI/ARDS.

抽象的 这项工作的核心目标是静脉内（IV）注射的多峰蛋白（poly-A）颗粒作为 急性肺损伤（ALI）治疗干预的中性粒细胞功能的被动约束。阿里迅速 炎症性疾病的发展为特征，其特征是肺部内皮和上皮屏障的中断， 导致肺气道中的液体积累，从而降低肺功能。阿里和急性 呼吸窘迫综合征（ARDS）是一种更严重的ALI形式，在美国每年影响约20万名患者 目前，死亡率约为40-60％。迄今为止，还没有一种有效的药理策略 降低ALI/ARD的死亡率，这可能是由于许多可以 导致这种疾病。因此，这种疾病的主要治疗方法是使用机械呼吸机进行血液 氧合和二氧化碳去除以允许受损的肺愈合，但这可能导致肺部进一步损害 如果不小心。中性粒细胞已被确定为炎症的主要犯罪者 ALI/ARDS，其过度迁移到肺部有助于破坏肺泡毛细管 导致肺水肿的障碍。实际上，疾病的严重程度与中性粒细胞的浓度相关 在肺气道中。因此，停止不必要的嗜中性粒细胞积累的破坏性潜力一直是 发展ALI/ARDS治疗的主要重点。但是，事先尝试开发药物 由于众多的冗余，中性粒细胞信号传导/粘附分子取得了有限的成功 在炎症反应级联中。在这里，我们建议合理设计血管靶向的颗粒（VTP） 从物理上与中性粒细胞相互作用，可被动，快速地阻塞中性粒细胞积累到发炎的组织 在ali/ards中。我们的主要假设是VTP通过物理与血液中的中性粒细胞相互作用 血管结合空间的相互作用和竞争，以改变对血管壁的嗜中性粒细胞的粘附 批判性地影响了他们迁移到患病组织中。在此提案中，我们利用这些阻止互动 通过三个目标开发可生物降解的可生物相容性VTP作为ALI/ARD的有效治疗方法。 首先，我们将制造一个基于多重肌蛋白的VTP系统，并评估其粒径和表面的影响 其特异性阻断中性粒细胞粘附到容器壁的能力的特征。第二，我们会的 通过插入显微镜成像可视化，基于多重马毒蛋白的VTP的粘附于血管壁 以及它们在小鼠中发炎的肠系膜组织中体内中性粒细胞粘附的阻塞。第三，我们将评估 用细菌诱导的ALI/ARD的小鼠中多重肌蛋白颗粒的治疗功能，代表A 人类疾病的现实模型。总体而言，从这些目标中获得的知识有望推动 新型基于粒子的抗炎治疗剂在ALI/ARDS治疗中的未来发展。这 VTP对中性粒细胞的直接作用，而不是阻止粘附或信号分子的直接作用，将会 确保所提出的系统可以发挥作用，而不论ALI/ARDS的主要原因。