Pulmonary Pathophysiologic Mechanisms of Chloropicrin and Phosgene

氯化苦和光气的肺部病理生理机制

• 批准号: 10708551
• 负责人: Laura S Van Winkle
• 金额: $ 45.32万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708551
• 关键词: Acute; Acute Lung Injury; Address; Affect; Alveolus; Animal Model; Area; Aromatase; Atmosphere; Binding; Biological; Biological Markers; Bite; Blood; Cell Proliferation; Cell Survival; Cells; Cessation of life; Chemical Actions; Chemicals; Cytochrome P450; Data; Dose; Drug Metabolic Detoxication; Elements; Environmental Exposure; Enzymes; Epithelial Cells; Epithelium; Equilibrium; Estrogens; Exposure to; Female; Gases; Glutathione S-Transferase; Histopathology; Immune; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Infiltrate; Inhalation; Inhalation Exposure; Injury; Intervention; Irritants; LoxP-flanked allele; Lung; Macrophage; Measurement; Measures; Mediating; Medical; Metabolism; Mixed Function Oxygenases; Molecular; Monitor; Mucous body substance; Mus; Naphthalene; Nose; Olfactory Epithelium; Outcome; Pathogenesis; Pattern; Phase; Phenotype; Phosgene; Poison; Positioning Attribute; Predisposition; Proteins; Pulmonary Edema; Rattus; Research; Resolution; Rodent; Role; Science; Secretory Cell; Signal Transduction; Soil; Strawberries; Structure of parenchyma of lung; Sulfhydryl Compounds; Testing; Thick; Time; Tissues; Toxic effect; Vascular Plant; Wild Type Mouse; Xenobiotic Metabolism; acute toxicity; airway epithelium; cell type; cellular targeting; chemical threat; epithelial injury; experimental study; in vivo; inflammatory marker; injury and repair; long-term sequelae; lung injury; lung repair; male; medical countermeasure; mouse model; neutrophil; repaired; respiratory; response; secretory protein; tissue repair; tissue-repair responses; ventilation

Chloropicrin (CP) and phosgene (PG) are widely available chemical threat agents, yet the mechanisms of in vivo acute toxicity and long-term pathophysiologic impacts are not well understood. CP, which is in current use as a soil fumigant to sterilize fields before planting high value crops and is widely available. CP is known to cause a biphasic death response characterized by lung edema that occurs either in the first 24 hrs or after 8-10 days. This suggests immune cell mediated and tissue repair responses are key to determining outcomes. However our new data also suggests that there is conducting airway and olfactory epithelial injury in the acute phase of toxicity. The cellular targets and the LC50 for mice is not firmly established. The pathogenesis is likely through tissue damage from binding of CP/PG or their metabolites to sulfhydryl (SH) groups in proteins impacting cell viability and potentially modulated by elements of xenobiotic metabolism in various cellular compartments, as well as instigation of an influx of immune cells into the lung, including both macrophages and neutrophils. Our team is well positioned to address the mechanism of action of these chemical threat agents due to our strong research backgrounds in lung injury and repair (Van Winkle), inhalation exposure science of toxic chemicals (Bein) and relation of tissue inflammation to biological responses (Vogel). The central hypotheses are that PG is more potent than CP in inducing toxicity in mice and that adequate repair is dependent on macrophages with functional CYP19A1, the estrogen synthesis enzyme. The hypotheses will be addressed in three Specific Aims that will 1) Define the dose response and acute injury pattern 2). Define the temporal pattern of lung injury and repair and 3) Test the hypothesis that macrophage estrogen synthesis is important for lung tissue repair following CP or PG exposure. These studies will advance our understanding of how acute injury, local metabolism and target cell type and estrogen synthesizing macrophages contribute tooutcomes following in vivo exposures to CP or PG. This will advance our understanding of tissue specific responses, a research area that is, of necessity, best investigated in animal models and which sets the stage for medical interventions.

氯丙蛋白（CP）和磷酸（PG）是广泛可用的化学威胁剂，但 体内急性毒性和长期病理生理影响的机制不是很好 理解。 CP，目前用作土壤熏蒸以对田地进行消毒的土壤 价值农作物，广泛可用。已知CP引起双相死亡反应 以肺水肿为特征，在前24小时或8-10天后发生。这暗示着 免疫细胞介导的和组织修复反应是确定结果的关键。然而 我们的新数据还表明，在 毒性的急性期。小鼠的细胞靶标和LC50尚未牢固确定。这 发病机理可能通过CP/PG或其代谢物与与 影响细胞活力的蛋白质中的硫烯基（SH）基团，并可能由元素调节 各种细胞室中异生物代谢的 免疫细胞进入肺部，包括巨噬细胞和中性粒细胞。我们的团队很好 由于我们的强大而定位解决这些化学威胁剂的作用机理 肺损伤和修复的研究背景（范·温克尔），有毒的吸入暴露科学 化学物质（BEIN）和组织炎症与生物学反应的关系（Vogel）。中央 假设是，PG比CP在诱导小鼠毒性方面更有效，并且足够 维修取决于巨噬细胞具有功能性CYP19A1，雌激素合成酶。 假设将以三个特定目的来解决1）定义剂量响应 和急性损伤模式2）。定义肺损伤和修复的时间模式，3）测试 假设巨噬细胞雌激素合成对于CP后肺组织修复很重要 或PG暴露。这些研究将促进我们对急性伤害，局部如何的理解 代谢和靶细胞类型以及雌激素合成巨噬细胞促进了tootcomes 遵循体内暴露于CP或PG。这将提高我们对组织特定的理解 回答，这是一个必要的研究领域，在动物模型中最好地研究了 为医疗干预奠定了基础。