A role for reactive oxygen species and other free radicals in human disease states is being proposed with increasing frequency. Reports on the detection of footprints of oxidative stress in a variety of animal models are available to corroborate these suggestions in several cases, although surprisingly few model studies have been performed in which the severity of disease has been correlated to depletion and subsequent supplementation, with natural or synthetic antioxidants, of the endogenous antioxidant defence. The question of the precise time-course of ROS production and tissue damage is much more difficult to address experimentally. As a consequence, little is known in detail concerning the role of oxidants, which may be causative or merely secondary to the primary disease process. In fact, the latter alternative is probably true for many human diseases.
Rather than reiterate free radical pathology at length in this contribution, we included this paragraph simply to allow us to list a selection of review articles available. Apart from consultation of the general texts cited in section 1.1, the references provided below should suffice to guide the reader into the wealth of literature covering free radical pathology that is now at hand.
For general discussions of the current status of antioxidant pharmacotherapy, the review articles of Rice-Evans and Diplock (1993), Bast (1994) and Halliwell (1991), for example, should provide good starting points. A Scrip report on "Reactive Oxygen and Oxidative Stress" was released during the finalization of the present manuscript. Potential sources of free radicals in tissues have been discussed, for instance, by McCord and Omar (1993). The most important indications and physiological systems where ROS are being considered as mediators are covered in monographs such as those edited by Cheeseman and Slater (1993) and Das and Essman (1990). These monographs include chapters devoted to free radical considerations in relation to indications such as atherosclerosis, carcinogenesis, inflammation, myocardial reperfusion, brain ischaemia, lung disease and liver damage, as well as the use of antioxidants in organ preservation.
The role of ROS as regulators of signal transduction pathways is subject to a growing interest (e.g. Schreck and Baeuerle, 1991; Schreck et al., 1992; Meyer et al., 1993; Schenk et al., 1994). NF-kB is a ubiquitous transcription factor with a pivotal function in the early pathogen response and activation of the immune system by initiation of the transcription of a number of genes encoding immunologically relevant proteins such as cell adhesion molecules, cytokines, acute-phase proteins, immunoreceptors and haematopoietic growth factors (Baeuerle and Henkel, 1994). The effect of several different inducers can be abrogated by various antioxidants, e.g. NDGA, ebselen, vitamin C, BHA, vitamin E derivatives and iV-acetyl-cysteine, which has led to the assumption that ROS can serve as common intracellular messengers for NF-kB activation (Schreck and Baeuerle, 1991; Schreck etal., 1992; Meyer etal., 1993; Manning and Anderson, 1994; Suzuki et al., 1994). Intracellular redox levels regulate the NF-kB signal transduction pathway by a common protein tyrosine phosphorylation step (Anderson et al., 1994). On the other hand, antioxidants do not block the activation of NF-kB triggered by inhibitors of serine-threonine protein phosphatases (Suzuki et al., 1994).
The areas of free radical pathology that have evolved into reasonable maturity have of course been the subject of numerous reviews. The tabulation below provides a few recent accounts of ROS-mediated effects in the indicated areas.
• Intestinal diseases
• Rheumatic disorders
• Reperfusion injuries
• Respiratory tract disorders
• Cardiac diseases
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