TOBACCO-BORNE IRON-BINDING SUBSTANCES

许多病理过程是由铁加剧。 这些作用可能包括 慢性炎症、进行性肺损伤和易患 在吸烟者中发现的肿瘤。 事实上，长期吸烟者的肺往往 不正常地积累大量的铁，原因不明。 我们 已经测试了烟草和烟草烟雾的提取物中的物质， 可能会结合，特别是，跨细胞膜转运铁。 我们 在烟草和烟草烟雾中发现导致溶剂化的物质 铁在非极性有机溶剂如氯仿中， 完整的人体细胞积累铁。 这些物质已经 纯化并鉴定为游离脂肪酸（先前鉴定为 烟草烟雾的主要成分），纯脂肪酸复制了 烟冷凝物和烟草提取物的铁转化作用。 出乎意料的是，我们还发现，这种游离脂肪酸直接刺激 次氯酸由人类嗜中性粒细胞产生，并可使 肉豆蔻酸佛波酯刺激的次氯酸输出 中性粒细胞 拟议的工作旨在进一步界定 铁离域的重要性，和游离脂肪酸本身在 与吸烟有关的疾病。 具体而言：（1）我们 确定烟雾冷凝物和游离脂肪酸在 将铁递送到整个细胞中（使用人红细胞作为模型， 培养的内皮细胞和肺上皮细胞作为更现实 目标）。(2)我们将定义游离脂肪酸和脂肪酸 酸介导的铁负荷对中性粒细胞功能， 脂质在靶细胞膜和氧化破坏 通过试剂、酶和吞噬细胞的氧化剂负载铁的靶细胞 起源(3)我们还将确定铁的这种“非定域化” 可能在香烟烟雾的致癌活动中发挥作用， 特别是通过施加染色体断裂或（通过 非转铁蛋白依赖性铁递送）生长促进作用。（四） 最后，计划进行有限的调查，以审查后果 动物长期暴露在挥发的游离脂肪酸中。 是 希望了解吸入游离脂肪酸对细胞的影响 将有助于阐明吸烟相关疾病的发病机制， 可能会导致制定战略，以尽量减少或扭转一些 长期吸烟的病理影响。

Many pathologic processes are exacerbated by iron. These may include the chronic inflammation, progressive pulmonary damage and predisposition to neoplasia seen in smokers. Indeed, the lungs of long-term smokers tend to accumulate abnormally large amounts of iron for unknown reasons. We have tested extracts of tobacco and tobacco smoke for substances which might bind and, especially, translocate iron across cell membranes. We find materials in tobacco and tobacco smoke which cause the solvation of iron in non-polar organic solvents such as chloroform and also cause intact human cells to accumulate iron. These substances have been purified and identified as free fatty acids (previously identified as major constituents of tobacco smoke), and pure fatty acids duplicate the iron-translating effects of smoke condensates and tobacco extracts. Unexpectedly, we also find that such free fatty acids directly stimulate hypochlorous acid production by human neutrophils and can double the output of hypochlorous acid by phorbol myristate acetate stimulated neutrophils. The proposed work is aimed at further definition of the importance of iron delocalization, and of free fatty acids per se in the genesis of smoking-related diseases. Specifically: (1) We shall determine the effectiveness of smoke condensates and free fatty acids in delivering iron into whole cells (using human red cells as a model and cultured endothelial and pulmonary epithelial cells as more realistic targets). (2) We shall define the effects of free fatty acids and fatty acid-mediated iron loading on neutrophil function, the oxidation of lipids in target cell membranes and on oxidative destruction of iron-loaded target cells by oxidants of reagent, enzymatic and phagocytic origin. (3) We shall also determine whether this 'delocalization' of iron might play a part in the carcinogenic activities of cigarette smoke, especially through exerting either clastogenic or (through non-transferrin-dependent iron delivery) growth-promoting effects. (4) Finally, limited investigations are planned to examine the consequences of long term exposure of animals to volatilized free fatty acids. It is hoped that knowledge of the cellular effects of inhaled free fatty acids will help elucidate the pathogenesis of smoking-related disorders and might lead to the development of strategies to minimize or reverse some of the pathologic effects of long-term tobacco use.