Oxidative pathology

Cassarino DS, Bennett JP Jr. 1999. An evaluation of the role of mitochondria in neurodegenerative diseases Mitochondrial mutations and oxidative pathology, protective nuclear responses, and cell death in neurodegeneration. Brain Res Brain Res Rev 29 1-25. 

A long-standing and fundamental problem that has frustrated attempts to directly demonstrate free radical-mediated toxicity relates to the inability to verify various reaction products seen in vivo as being derived from specific radical species. The ability of various antioxidants, such as ascorbate, tocopherol, glutathione, and cysteine, to limit or prevent injury in various models is suggestive of oxidative pathology but offers little with regard to... 

In the past number of years a number of studies have shown that in a variety of diseases there is a significant oxidation of Met residues to Met(O) in specific proteins that results in a loss of biological activity. These diseases include cataracts, rheumatoid arthritis, adult respiratory distress syndrome and emphysema. The most convincing evidence that Met(O) in proteins may be involved in the etiology of a pathological condition comes from studies with a-l-PI. It is well accepted that a-l-PI is inactivated upon oxidation of its Met residues. A decreased activity of a-l-PI in lung tissue that would result in an increased elastase activity has been associated with pulmonary emphysema. In patients who have a... 

Evidence from cellular studies in vitro initially showed how oxidative processes could play a central role in the pathological changes involved in the genesis of atherosclerosis. LDL can be oxidatively modified in culture by a range of cell types including endothelial cells (Henriksen et a.1., 1981), arterial smooth muscle cells... 

There is a long-standing hypothesis that the microvasculature plays a pathological role in forms of chronic inflammatory polyarthritis, particularly RA (Rothschild and Masi, 1982). One of the proposed mechanisms of vascular damage in connective tissue disease is the direct action of a cytotoxic serum factor inducing endothelial cell damage. Blake et al. (1985) have su ested that the vascular abnormalities associated with RA may be linked to oxidized lipoproteins because they are cytotoxic to endothelial cells. 

Free-radical generation occurs normally in the human body, and rates of free-radical generation are probably increased in most diseases (see Table 13.1). Their importance as a mechanism of tissue injury is still uncertain, largely because the assays used to measure them have, until recently, been primitive. The development of new assays applicable to humans (such as the assays of oxidative DNA damage described above) should allow rapid evaluation of the role of free radicals in disease pathology and provide a logical basis for the therapeutic use of antioxidants. A rationale is presented in Fig. 13.3. Attempts to use antioxidants in the treatment of human disease can be divided into three main areas ... 

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