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: 2019188
• 负责人: JOHN B MORRIS
• 金额: $ 20.69万
• 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/2019188
• 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.

许多职业和环境空气污染物会立即引发 通过与鼻三叉神经C纤维相互作用的鼻反应。 等 吸入毒理学反应非常重要 事实证明，目前有一半的 职业接触准则是根据这一反应制定的。 的 呼吸频率的特征性降低， 感官刺激物已得到充分研究，然而，局部鼻粘膜 影响是非常不明确的，尽管事实上，刺激的 已知鼻三叉神经C纤维可导致 包括P物质在内的多种有效介质。 在人和啮齿动物鼻粘膜中发挥多种作用 包括血管舒张和血流量增加， 渗透性导致水肿和粘液分泌过多。 的 本研究的目的是获得一个综合的理解， 鼻粘膜对吸入刺激物的急性反应。 的 这一建议的中心假设是， 反应包括一系列具体和一致的影响， 鼻粘膜部分由P物质介导， 在老鼠和老鼠身上。 拟议的研究将 表征小鼠和大鼠中的即刻鼻反应， 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 对这些毒物的即时反应将通过使用 通过抑制P物质降解， 通过使用肽酶抑制剂的途径。 动物吸入 毒性研究是评估潜在的 职业和环境空气对健康的不良影响 污染物 我们完全理解急性刺激物的能力 人类的反应受到缺乏数据的阻碍， 在动物和人类之间进行直接和定量的比较。 的 拟议的研究旨在通过增加我们的 了解对这些制剂的综合反应。 在 从长远来看，这将大大提高我们的能力， 预测和评估刺激物对健康的潜在不良影响 空气污染物