Housset B
Hôpital Intercommunal de Créteil.
C R Seances Soc Biol Fil. 1994;188(4):321-33.
The lung is particularly exposed to various inhaled toxic products whose toxicity can be at least partly mediated by the generation of free radicals. Oxidants burden can also result from lung metabolism of xenobiotics or from activation of phagocytes. Free radicals are mainly derived from an univalent sequential reduction of molecular oxygen. Mitochondria is the main location of intracellular production which may also result from auto-oxidation of small molecules or function of some enzymes. To prevent the deleterious effects of free radicals produced by normal metabolism, cells are equipped with an antioxidant system composed of enzymes (superoxide dismutase, catalase, glutathione peroxidase) and non enzymatic substances such as glutathione, iron chelators, vitamin E and C, ceruleoplsamin). Targets of free radicals toxicity are phospholipids by initiation of lipid peroxidation, proteins which may be activated or inactivated via oxidation of sulfhydryl residues. Another target is DNA with possible strand breaks or mutation. Transcription activities can be also altered and it has been recently reported that some transcription factors such as NF-kB can be activated by oxidants. Under these circumstances free radicals may be considered as second messengers. Lung oxygen toxicity has been largely studied. Oxygen-induced lung lesions are non specific. It is possible to induce a resistance to 100% O2 by the pre-exposure of animals to 85% O2. This tolerance phenomenon is associated with an increased lung content in antioxidant substances. The mechanisms of gene regulation of antioxidant enzymes are still poorly understood in eukaryotes. Overproduction of free radicals in the lung is also involved in various clinical settings such as ischemia-reperfusion, exposure to ozone or NO2, acute respiratory distress syndrome, drug induced lung toxicity, pathogenesis of COPD, asthma, cancer and ageing. The precise role of free radicals among other mechanisms of lung injury is still unclear. A better knowledge of free radicals mechanisms of toxicity and of antioxidant regulation is needed to develop antioxidant therapeutic strategies.
肺尤其容易接触到各种吸入的有毒产物，其毒性至少部分可由自由基的产生介导。氧化剂负荷也可能源于外源性物质的肺代谢或吞噬细胞的激活。自由基主要来源于分子氧的单价顺序还原。线粒体是细胞内产生自由基的主要场所，自由基也可能由小分子的自动氧化或某些酶的功能产生。为了防止正常代谢产生的自由基的有害影响，细胞配备了一个抗氧化系统，该系统由酶（超氧化物歧化酶、过氧化氢酶、谷胱甘肽过氧化物酶）和非酶物质如谷胱甘肽、铁螯合剂、维生素E和C、铜蓝蛋白组成。自由基毒性的靶标包括通过引发脂质过氧化作用的磷脂、可能通过巯基残基氧化而被激活或失活的蛋白质。另一个靶标是DNA，可能会发生链断裂或突变。转录活性也可能改变，最近有报道称一些转录因子如核因子-κB可被氧化剂激活。在这些情况下，自由基可被视为第二信使。肺氧中毒已得到广泛研究。氧诱导的肺损伤是非特异性的。通过让动物预先暴露于85%的氧气中，可以诱导对100%氧气的耐受性。这种耐受现象与肺中抗氧化物质含量的增加有关。在真核生物中，对抗氧化酶基因调控的机制仍知之甚少。肺中自由基的过量产生也涉及各种临床情况，如缺血再灌注、暴露于臭氧或二氧化氮、急性呼吸窘迫综合征、药物性肺毒性、慢性阻塞性肺疾病、哮喘、癌症和衰老的发病机制。自由基在肺损伤的其他机制中的确切作用仍不清楚。需要更好地了解自由基的毒性机制和抗氧化调节，以制定抗氧化治疗策略。
