Identification of AMD3100 (Plerixafor) as a potential lead compound for chlorine toxicity

AMD3100 (Plerixafor) 被鉴定为潜在的氯毒性先导化合物

基本信息

批准号：
10669052
负责人：
Saurabh Aggarwal
金额：
$ 42.41万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-21 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10669052
关键词：
AMD3100 Accidents Acute Acute Lung Injury Adverse effects Alveolar Animals Antineoplastic Agents Attenuated Binding Bleomycin Blood Vessels Body Weight Bromine Bronchoalveolar Lavage Fluid C57BL/6 Mouse CXCR4 Receptors Cells Cessation of life Chlorine Chronic Chronic Lung Injury Circulation Clinical Data Dose Endothelial Cells Epithelial Cells Exposure to Extravasation FDA approved Fibroblasts Gases HIV-1 Heme Hemolysis Hemolysis Induction Homing Hour Human Hypoxia Hypoxia Inducible Factor Immune Impairment In Vitro Inflammation Inflammatory Inhalation Intramuscular Irrigation Irritants Lead Leukocytes Ligands Lipopolysaccharides Liquid substance Literature Lung Lymphocyte Macrophage Measures Mediating Morbidity - disease rate Mus Nuclear Translocation Peripheral Phosgene Plants Plasma Play Production Proteins Pulmonary Edema Pulmonary Emphysema Pulmonary Inflammation Pulmonary Pathology Regimen Regulation Respiratory Failure Respiratory Mechanics Role Signal Transduction South Carolina Structure of parenchyma of lung Surface Survivors Testing Therapeutic Therapeutic Agents Time Tissues Toxic effect Training Treatment Efficacy United States cancer cell chemokine chlorine gas dosage efficacy evaluation hypoxia inducible factor 1 improved in vivo indexing innovation leukocyte activation leukocyte homing lung injury migration mortality neutrophil novel nuclear respiratory factor prevent seven-transmembrane G-protein-coupled receptor small molecule small molecule inhibitor targeted delivery water treatment

项目摘要

PROJECT SUMMMARY/ABSTRACT Statement of problem: Chlorine (Cl2) gas is the most common inhalational irritant in the United States, which results in serious adverse effects including lung injury and death. Previous studies by the PI and others have demonstrated that migration and homing of leukocytes (neutrophils and macrophages) into lungs play a critical role in lung morbidity and mortality post Cl2 gas exposure. The binding of the chemokine ligand, stromal- derived-factor-1 (SDF-1), to the C-X-C chemokine receptor type 4 (CXCR4) on lung immune, epithelial, and endothelial cells promote the migration of leukocytes from the circulation to lungs. The SDF-1/CXCR4 axis also propagates the activation and survival of leukocytes in the lungs. Our preliminary data shows that both SDF-1 and CXCR4 levels are elevated in the lungs of Cl2 exposed animals. Therefore, our hypothesis is that SDF- 1/CXCR4 axis is involved in the migration, homing, and survival of leukocytes in lung post exposure to Cl2 and therefore inhibiting this axis by an FDA approved compound, AMD3100 (Plerixafor), would attenuate Cl2- induced lung morbidity and mortality. Specific aims: 1) Establish the role of SDF-1/CXCR4 axis in Cl2-induced lung leukocyte migration, activation, and survival. 2) Optimize the dosage regimen of AMD3100 for Cl2 toxicity. 3) Delineate the mechanisms of SDF-1/CXCR4 regulation post-Cl2 exposure. Experimental approach: C57BL/6 mice will be exposed to Cl2 gas (500ppm, 30min) and then the SDF-1 concentration in broncholaveolar lavage fluid and the CXCR4 surface expression on the alveolar leukocytes and whole lung tissue will be measured over time. It will also be analyzed whether, the SDF-1/CXCR4 axis mediates Cl2 dependent migration, activation, and survival of lung leukocytes. Next the Cl2 exposed mice will be administered a clinically safe dose (0.01-0.16 mg/kg) of AMD3100 intramuscularly and the indices of acute and chronic lung injury and mortality will be measured. Finally, the role of Cl2-induced hemolysis and hypoxia in the regulation of lung SDF-1 and CXCR4 levels post Cl2 exposure will be studied in vitro and in vivo. Anticipated results: We anticipate that AMD3100 will attenuate leukocyte translocation to lungs and subsequently mitigate lung injury and improve survival in mice exposed to Cl2. Innovation: The study is the first to propose the use of a novel, FDA-approved, small molecule compound, AMD3100, to mitigate lung injury and mortality post exposure to Cl2 gas. AMD3100 may be beneficial in mitigating lung injury post exposure to other toxic gases such as bromine and phosgene, which are also associated with hemolysis and increased migration of leukocytes into lung.

项目摘要/摘要问题陈述：氯 (Cl2) 气体是美国最常见的吸入刺激物，导致严重的不良反应，包括肺损伤和死亡。 PI 和其他人之前的研究表明证明白细胞（中性粒细胞和巨噬细胞）迁移和归巢到肺部起着至关重要的作用 Cl2 气体暴露后肺部发病率和死亡率的作用。趋化因子配体、基质的结合衍生因子 1 (SDF-1)，针对肺免疫、上皮细胞和肺免疫的 C-X-C 趋化因子受体 4 型 (CXCR4) 内皮细胞促进白细胞从循环系统迁移到肺部。 SDF-1/CXCR4 轴还促进肺部白细胞的活化和存活。我们的初步数据显示 SDF-1 暴露于 Cl2 的动物肺部的 CXCR4 水平升高。因此，我们的假设是 SDF- 1/CXCR4轴参与暴露于Cl2和Cl2后肺中白细胞的迁移、归巢和存活。因此，通过 FDA 批准的化合物 AMD3100 (Plerixafor) 抑制该轴会减弱 Cl2- 诱发肺部发病率和死亡率。具体目标：1）建立SDF-1/CXCR4轴在Cl2诱导中的作用肺白细胞迁移、激活和存活。 2）针对Cl2毒性优化AMD3100的给药方案。 3) 描述Cl2暴露后SDF-1/CXCR4调节的机制。实验方法： C57BL/6 小鼠将暴露于 Cl2 气体（500ppm，30 分钟），然后将 SDF-1 浓度暴露在支气管肺泡灌洗液及肺泡白细胞和全肺CXCR4表面表达随着时间的推移，组织将被测量。还将分析SDF-1/CXCR4轴是否介导Cl2 肺白细胞的依赖性迁移、激活和存活。接下来，暴露于 Cl2 的小鼠将被肌内注射临床安全剂量（0.01-0.16 mg/kg）AMD3100，急性和将测量慢性肺损伤和死亡率。最后，Cl2 诱导的溶血和缺氧在细胞中的作用将在体外和体内研究 Cl2 暴露后肺 SDF-1 和 CXCR4 水平的调节。预期的结果：我们预计 AMD3100 将减弱白细胞向肺部的易位，并随后减轻肺损伤并提高暴露于 Cl2 的小鼠的存活率。创新：该研究首次提出使用一种经 FDA 批准的新型小分子化合物 AMD3100，可减轻术后肺损伤和死亡率暴露于 Cl2 气体。 AMD3100 可能有助于减轻暴露于其他有毒气体后的肺损伤例如溴和光气，它们也与溶血和增加迁移有关白细胞进入肺。