[Free radicals and antioxidants: physiology, human pathology and therapeutic aspects (part II)]

Although they are considered as destructive agents, free radicals can sometimes become useful. Their presence is intimately coupled with the activity of certain hemal oxydases which insert an atom of oxygen into their substrate by a stereospecific radical mecanism. The cytochromes P450 and the enzymes of the eicosanoide metabolism are some examples. The free radicals can act as second cellular messengers, especially to modulate the metabolism of arachidonic acid and the prostaglandin tract or to infer a myorelaxation. They can even play the role of neurotransmitters such as azote monoxyde. The activation of phagocytes, which is an essential event in the inflammatory reaction, integrates these notions at several levels: in the mechanisms of bacterial death, in the spread of the inflammatory reaction and in the alteration of the extra-cellular matrix. The inflammatory reaction is initiated by interactions between vascular endothelium, platelets and leukocytes including signal exchanges, adhesion molecule expression and secretion of chimiotactic mediators. Activation of vascular endothelium is a key event in the initiation of the phenomenon. The cells intervening in the precocious inflammatory phase were tissular mastocytes and platelet-liberating mediators (histamine) and neutrophile cells responsible for vascular injuries induced by oxygen free radicals and nitric oxide. Reactive oxygen intermediates play a critical role, primarily to limit tissue damage and prevent or inhibit infection, secondary to enhancing and prolonging reaction. The monocytes and platelets liberate cytokines early, which appears to be important in activation and production of an inflammatory response. In fact, cytokines, especially TNF alpha and IL-1, induce synthesis and secretion endothelial adhesion molecules such as ICAM-1, VCAM-1 and E-selectin, which have been demonstrated to mediate leukocyte recruitment to sites of inflammation. The cytokines also activate the fibroblasts and endothelial cells that produce, among others, free radicals and other chimiotactic cytokines of which some (IL-8 and related) can induce neutrophil degranulation and stimulate oxidative stress and formation of free radicals. Furthermore, endothelial cells have been shown to make use of a broad repertoire of cytokines including IL-1, IL-6, IL-8, MCP-1 and gro/MGSA, which may be secreted during an inflammatory response and exercise pro-inflammatory functions. Under the influence of the inflammatory mediators, other enzymes are also activated. The inducible isoforms of cyclo-oxygenase (COX-2) and nitric oxide synthase (iNOS) play an important role in inflammatory reactions via the production respectively of prostaglandins and nitric oxide. The induction of cell adhesion molecules (ICAM-1, VCAM-1 and E-selectin), cytokines, acute phase proteins, growth factors, COX-2 and iNOS expression is mediated by the activation of transcriptional factors, especially the nuclear factor kappa B (NF-kappa B). The NF-kappa B system is essentially involved in immediate early expression of various immunoregulatory genes and has been demonstrated to represent an important regulatory system of endothelial activation. The target genes for NF-kappa B comprise a growing list of genes intrinsically linked to a coordinated inflammatory response. The NF-kappa B is a heterodimer composed of two subunits (p65 and p50). In non-stimulated cells, NF-kappa B resides in the cytoplasm as an inactive complex bound to its inhibitor, I kappa B. Upon stimulation with various agents including cytokines, mitogenes, viruses and reactive oxygen intermediates, I kappa B dissociates from the NF-kappa B-I kappa B complex and translocates to the nucleus, binding with high affinity to specific sites in the promoter regions of target genes and stimulating their transcription. In the case of any weakness of this anti-oxidizing defence or any over-production of radical species, a state of oxidative stress occurs. (ABSTRACT TRUNC