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.

氯苦(CP)和光气(PG)是广泛使用的化学威胁剂，但 体内急性毒性和长期病理生理影响的机制尚不清楚 明白了。CP，目前用作土壤熏蒸剂，用于在种植高粱之前对田地进行消毒 价值高的作物，并且广泛可用。已知CP可引起双相死亡反应 以头24小时或8-10天后出现的肺水肿为特征。这表明 免疫细胞介导的和组织修复反应是决定结果的关键。然而， 我们的新数据还表明，慢性阻塞性肺疾病患者存在传导性呼吸道和嗅觉上皮损伤。 急性毒性阶段。小鼠的细胞靶点和半数致死量(LC_(50))尚未确定。这个 其发病机制可能是通过CP/PG或其代谢产物结合到 影响细胞活力并可能受元素调控的蛋白质中的巯基(SH) 外源新陈代谢在不同的细胞隔间，以及煽动 免疫细胞进入肺，包括巨噬细胞和中性粒细胞。我们队打得很好 定位于解决这些化学威胁剂的作用机制，因为我们强大的 肺损伤与修复(Van Winkle)、有毒物质吸入暴露科学的研究背景 化学物质(Bein)和组织炎症与生物反应的关系(Vogel)。中环 假设PG比CP对小鼠的毒性更强，并且足以 修复依赖于具有功能性CYP19A1的巨噬细胞，这是雌激素合成酶。 这些假设将在三个具体目标中得到解决，这三个目标将：1)定义剂量反应 急性损伤类型2)。确定肺损伤和修复的时间模式，并3)测试 巨噬细胞雌激素合成在CP后肺组织修复中的重要作用假说 或PG暴露。这些研究将促进我们对急性损伤、局部损伤 代谢和靶细胞类型以及合成雌激素的巨噬细胞对结果有影响 在活体暴露于CP或PG后。这将促进我们对组织特异性的理解 反应，这是一个必要的研究领域，最好是在动物模型中进行研究，并且 为医疗干预奠定了基础。