MEMBRANE OZONOLYSIS AND EPITHELIAL CELL ACTIVATION

膜臭氧分解和上皮细胞激活

• 批准号: 2155388
• 负责人: George Douglas Leikauf
• 金额: $ 19.75万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 1996-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2155388
• 关键词: aldehydes; cell membrane; cytokine; cytotoxicity; eicosanoids; high performance liquid chromatography; human tissue; hydrogen peroxide; inflammation; ion transport; mucus; ozone; platelet activating factor; prostaglandin E; prostaglandin F; radioimmunoassay; respiratory epithelium; statistics /biometry; tissue /cell culture

Ozone exposure (in concentrations at or near the current ambient air quality standard: 120 ppb) results in airway epithelial cell injury and inflammation. When inhaled, ozone reacts with phospholipids and proteins in the extracellular fluid or the plasma membrane. We hypothesize that a portion of ozone's toxicity is due to secondary reaction products that, in turn, have biological activity. We propose that these reaction products can activate constitutive airway cells and lead to the synthesis and release of mediators including eicosanoids and cytokines. These mediators have biological activities important to the mechanisms of ozone toxicity in the lung through their modulatory effects on ion transport and mucus secretion (local responses) and inflammation and possibly smooth muscle tone (systemic responses). One macromolecular site of ozone attack is the carbon-carbon double bonds in unsaturated fatty acids (molecules present in the extracellular lining fluid and plasma membrane). Ozonolysis of unsaturated fatty acids leads principally to the formation of 3-, 6-, or 9-carbon aldehydes and hydroxyhydroperoxides. In aqueous environments, the hydroxyhydroperoxides can subsequently degrade into another aldehyde and hydrogen peroxide. The specific aims of this proposal are: (1) to synthesize and purify 3-, 6-, 9-carbon saturated and unsaturated aldehydes and hydroxyhydroperoxides, and (2) to investigate the effects of these compounds (and hydrogen peroxide) on eicosanoid and cytokine release from human airway epithelial cells. This study is designed to provide evidence to evaluate the relative toxicity of ozonolysis intermediates and the role of epithelial-derived mediators in ozone-induced airway inflammation. These findings will be helpful in explaining why ozone (which is very reactive and unlikely to penetrate the apical membrane of the airway epithelium) can initiate effects distant to the site of ozone- macromolecule chemical interactions.

臭氧暴露（以当前环境空气或附近的浓度为 质量标准：120 ppb）导致气道上皮细胞损伤和 炎。吸入时，臭氧与磷脂和蛋白质反应 在细胞外液或质膜中。 我们假设一个 臭氧毒性的一部分是由于次级反应产物引起的 转弯，具有生物学活性。 我们建议这些反应产物 可以激活构型气道细胞并导致合成和 介质的释放在内，包括类花生素和细胞因子。 这些调解人 拥有对臭氧毒性机制重要的生物学活动 在肺部通过其对离子传输和粘液的调节作用 分泌（局部反应）和炎症以及可能的平滑肌 音调（系统性响应）。 臭氧攻击的一个大分子位点是 不饱和脂肪酸中的碳碳双键（存在分子 在细胞外衬里和质膜中）。 臭氧解析 不饱和脂肪酸主要导致形成3-，6-或 9碳醛和羟基毒素。 在水性环境中 羟基毒素随后会降解到另一种醛中 和过氧化氢。 该提议的具体目的是：（1） 合成并纯化3-，6-，9碳饱和和不饱和醛 和羟基毒素，以及（2）研究这些作用 eicosanoid和细胞因子释放的化合物（和过氧化氢）从 人气道上皮细胞。 这项研究旨在提供证据 评估臭氧溶解中间体的相对毒性和角色 臭氧引起的气道炎症中上皮衍生的介体的介质。 这些发现将有助于解释为什么臭氧（这非常 反应性，不太可能穿透气道的顶膜 上皮）可以发起臭氧部位远处的效应 大分子化学相互作用。