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: 10356854
• 负责人: Omolola Eniola-Adefeso
• 金额: $ 34.3万
• 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/10356854
• 关键词: Acute Lung Injury; Acute Respiratory Distress Syndrome; Adhesions; 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; 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; 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; pulmonary function; rational design; 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 这项工作的中心目标是开发静脉 (IV) 注射聚阿司匹林 (Poly-A) 颗粒作为 被动抑制中性粒细胞功能以治疗急性肺损伤（ALI）。 ALI 是一个快速 以肺内皮和上皮屏障破坏为特征的进行性炎症性疾病， 导致肺气道积液，从而损害肺功能。 ALI 与急性 呼吸窘迫综合征 (ARDS) 是 ALI 的一种更严重的形式，在美国每年影响约 200,000 名患者 目前，死亡率约为40-60%。迄今为止，尚无一种有效的药理学策略 降低 ALI/ARDS 的死亡率，可能是由于大量且复杂的病理事件可以 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循环。 充氧和去除二氧化碳可以让受损的肺部愈合，但这可能会导致肺部进一步受损 如果不小心雇用。中性粒细胞已被确定为炎症的主要肇因 ALI/ARDS，它们过度迁移到肺部导致肺泡毛细血管的破坏 导致肺部水肿的屏障。事实上，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，阻止不需要的中性粒细胞积累的破坏性潜力一直是一个 ALI/ARDS 治疗开发的主要焦点。然而，之前开发药物的尝试 由于存在大量冗余，阻断中性粒细胞信号/粘附分子的成功有限 在炎症反应级联中。在这里，我们建议合理设计血管靶向颗粒（VTP） 与中性粒细胞发生物理相互作用，被动、快速地阻止中性粒细胞积聚到发炎组织中 在 ALI/ARDS 中。我们的主要假设是 VTP 通过物理方式与血液中的中性粒细胞相互作用 相互作用和竞争血管结合空间，改变中性粒细胞对血管壁的粘附，这 严重影响它们迁移到患病组织中。在这个提案中，我们利用这些阻塞交互 通过三个目标开发可生物降解、生物相容的 VTP 作为 ALI/ARDS 的有效治疗方法。 首先，我们将制造基于聚阿司匹林的 VTP 系统并评估其粒径和表面的影响 它们在体外特异性阻断中性粒细胞粘附到血管壁的能力的特征。其次，我们将 通过活体显微镜成像，可视化基于聚阿司匹林的 VTP 与血管壁的粘附 以及它们对小鼠发炎肠系膜组织体内中性粒细胞粘附的阻断。第三，我们将评估 聚阿司匹林颗粒对细菌诱导的 ALI/ARDS 小鼠的治疗功能，代表了 人类疾病的现实模型。总体而言，从这些目标中获得的知识预计将推动 治疗 ALI/ARDS 的新型基于颗粒的抗炎疗法的未来发展。这 提出 VTP 对中性粒细胞的直接作用，而不是阻断粘附或信号分子，将 确保所提出的系统能够正常运行，无论 ALI/ARDS 的主要原因是什么。