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: 2770795
• 负责人: JOHN B MORRIS
• 金额: $ 19.76万
• 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/2770795
• 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政治家立即启动 通过与鼻三叉神经C纤维相互作用而产生的鼻反应。 这样的 从吸入毒理学中的反应非常重要 观点证明了一半的电流 职业暴露指南基于此回应。 这 呼吸频率的特征下降 但是，对感官刺激物进行了充分的研究，但是局部鼻粘膜 尽管刺激的事实，效果的定义很差 已知鼻三叉神经C纤维会导致A释放 多种有效的介体，包括物质P.物质P 在人和啮齿动物鼻粘膜中发挥各种作用 包括血管舒张和血流增加，血管增加 导致渗透性和粘液分泌。 这 拟议的研究的目标是获得综合的理解 鼻粘膜对受启发剂的急性反应。 这 该提议的中心假设是感觉刺激性 响应包括特定且一致的效果 鼻粘膜部分由物质P部分介导，并且不同 在大鼠和鼠标中有点。 拟议的研究将 表征小鼠和大鼠的直接鼻反应 四个有毒刺激性：丙烯醛，丙烯酸乙烯酸乙烯酸乙醛酸乙醛酸乙醛和乙醛和 二氧化氮。 另外，物质p在 将通过使用 物质P Antagoist并通过抑制物质P降解 通过使用肽酶抑制剂的途径。 动物吸入 毒性研究是评估潜力的重要工具 职业和环境空气的不利健康影响 污染物。 我们充分理解急性刺激物的能力 缺乏可能是 直接和定量比较动物和人类之间。 这 拟议的研究旨在通过增加我们的 了解对此类药物的综合响应。 在 长期，这将大大增强我们的能力 预测和评估刺激物的潜在不良健康影响 空气污染物。