[Free radicals and respiratory pathology]

Abstract

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.