TOXIC RESPONSES OF NASAL MUCOSA TO INHALED IRRITANTS

鼻粘膜对吸入刺激物的毒性反应

• 批准号: 6055961
• 负责人: JOHN B MORRIS
• 金额: $ 20.36万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-10 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6055961
• 关键词: acetaldehyde; acrolein; biomarker; edema; environmental toxicology; histopathology; inhalation drug administration; irritation /irritant; laboratory mouse; laboratory rat; mucosa; neuropeptide receptor; nitrogen oxides; polyacrylate; protease inhibitor; respiratory pharmacology; species difference; substance P; vasodilation

Many occupational and environmental air polutants initiate immediate nasal responses via interaction with nasal trigeminal C fibers. Such responses are very important from an inhalation toxicological perspective as evidenced by the fact that one-half of current occupational exposure guidelines are based on this response. The characteristic decrease in breathing frequency that results from such sensory irritants is well studied, however, the local nasal mucosal effects are very poorly defined despite the fact that stimulation of nasal trigeminal C fibrers is known to result in the release of a variety of potent mediators including substance P. Substance P exerts a variety of effects in human and rodent nasal mucosa including vasodilation and increased blood flow, increased vascular permeability leading to edemagenesis, and mucous hypersecretion. The goal of the proposed research is to gain an integrated understanding of the acute response of the nasal mucosa to inspired irritants. The central hypothesis of this proposal is that the sensory irritant response includes a specific and consistent array of effects in the nasal mucosa that are mediated in part by substance P and differ somewhat in the rat and mouse. The proposed research will characterize the immediate nasal responses in the mouse and rat to four toxic irritants: acrolein, ethyl acrylate, acetaldehyde and nitrogen dioxide. In addition, the role of substance P in the immediate response to these toxicants will be studied via the use of a substance P antagoist and via inhibition of substance P degradation pathways through use of peptidase inhibitors. Animal inhalation toxicity studies are an essential tool for assessing potential adverse health effects of occupational and environmental air pollutants. Our ability to fully understand the acute irritant response in humans has been hampered by the lack of data that can be directly and quantitatively compared between animals and humans. The proposed research is aimed at filling this gap by increasing our understanding of the integrated response to such agents. In the long-term, this will serve to significantly enhance our ability to predict and evaluate the potential adverse health effects of irritant air pollutants.

许多职业性和环境空气污染者立即 通过与鼻三叉神经C纤维相互作用的鼻部反应。是这样的 吸入毒物的反应是非常重要的 事实证明，目前一半的人口 职业暴露指南就是基于这种反应制定的。这个 导致呼吸频率下降的特征 感官刺激物研究得很好，然而，局部鼻黏膜 效果是非常模糊的，尽管事实是刺激 已知鼻三叉神经C纤维导致一种 包括P物质在内的各种有效的介体 在人和啮齿动物的鼻黏膜中发挥多种作用 包括血管扩张和血流量增加，血管增加 通透性导致水肿症和粘液高分泌。这个 拟议研究的目标是获得一个完整的理解 鼻黏膜对刺激性刺激的急性反应。这个 这一提议的中心假设是感官刺激物 响应包括特定且一致的效果数组 部分由P物质介导的鼻黏膜和不同 在大鼠和小鼠身上有一些。拟议的研究将 描述小鼠和大鼠的鼻部即刻反应 四种有毒刺激物：丙烯醛、丙烯酸乙酯、乙醛和 二氧化氮。此外，P物质在细胞周期中的作用 对这些毒物的即时反应将通过使用 一种P物质拮抗剂并通过抑制P物质的降解 通过使用多肽酶抑制剂的途径。动物吸入 毒性研究是评估潜力的重要工具 职业性和环境性空气对健康的不良影响 污染物。我们完全理解急性刺激性疾病的能力 人类的反应由于缺乏数据而受到阻碍 动物和人类之间的直接和定量比较。这个 拟议的研究旨在通过增加我们的 了解对这类病原体的综合反应。在 从长远来看，这将有助于显著增强我们的能力 预测和评估刺激物对健康的潜在不利影响 空气污染物。