TOBACCO-BORNE IRON-BINDING SUBSTANCES

许多病理过程因铁而加剧。这些可能包括 慢性炎症、进行性肺损伤和易感性 吸烟者身上可见的肿瘤。事实上，长期吸烟者的肺部往往 由于不明原因而积聚了异常大量的铁。我们 已经测试了烟草提取物和烟草烟雾中的物质 可能结合铁，尤其是跨细胞膜转移铁。我们 在烟草和烟草烟雾中发现导致溶剂化的物质 非极性有机溶剂中的铁，如氯仿，也会引起 完整的人类细胞来积聚铁。这些物质已经被 提纯并鉴定为游离脂肪酸(以前鉴定为 烟草烟雾的主要成分)，和纯脂肪酸复制 烟雾冷凝物和烟草提取物的转铁作用。 出乎意料的是，我们还发现这种游离脂肪酸直接刺激 由人的中性粒细胞产生次氯酸，可以使 佛波醇肉豆蔻酸醋酸酯刺激产生次氯酸 中性粒细胞。拟议的工作旨在进一步定义 铁非定域化的重要性，以及游离脂肪酸本身在 吸烟相关疾病的起源。具体来说：(1)我们将 确定烟雾冷凝物和游离脂肪酸对人体健康的影响 将铁输送到整个细胞(使用人类红细胞作为模型和 培养内皮细胞和肺上皮细胞更现实 目标)。(2)我们将定义游离脂肪酸和脂肪的影响 酸性铁负荷对中性粒细胞功能的影响 靶细胞膜中的脂类物质及其氧化破坏作用 试剂氧化剂、酶氧化剂和吞噬氧化剂负载铁靶细胞的研究 起源。(3)我们还将确定铁的这种‘离域’ 可能在香烟烟雾的致癌活性中起作用， 尤其是通过施加碎裂或(通过) 非转铁蛋白依赖的铁传递)促进生长的作用。(4) 最后，计划进行有限的调查，以检查后果。 使动物长期暴露在挥发性游离脂肪酸中。它是 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和 可能会导致制定战略，尽量减少或扭转一些 长期使用烟草的病理影响。

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.