The involvement of free radicals and lipid peroxidation in inflammation: pharmacological implications

In 1954, Duboulez and Dumas showed that 1 ipid peroxidation is involved in acute inflammation. Many years later, it was recognized that after injury prostaglandins and related substances are formed by endoperoxidation of polyunsaturated fatty acids. Thus, dihomo-y-1 inolenic acid and arachidonic acid are converted to prostaglandin endoperoxides by cycle-oxygenase. These endoperoxides are then converted to the stable prostaglandins, thromboxane, prostacycl in, hydroxy-fatty acid and malonaldehyde. Thus, it is possible that the peroxides detected by Duboulez and Dumas were prostaglandin endoperoxides. The aim of our studies were to investigate whether 1 ipid peroxidation occurs at the site of inflammation independently of the biosynthesis of prostaglandins. This seemed likely, as fatty acid precursors are abundant at the inflamed site and since initiators of 1 ipid peroxidation, namely free radicals, are constantly generated and released by granulocytes and mononuclear phagocytes, during phagocytosis. Malonaldehyde is a stable end product of the decomposition of endoperoxides formed during 1 ipid peroxidation, which has been used as a monitor of the extent of 1 ipid peroxidation in chemical and biological systems. As locally formed malonaldehyde may originate from the arachidonate cascade and, more specifically, from the thromboxane synthetase pathway, it was planned to investigate time-dependent changes in prostaglandin biosynthesis, for which purpose radioactively label led arachidonic acid was to be injected into the inflamed site. An inflammation model which allows the accurate injection of drugs and local hormone precursors into the inflamed site, namely the model of cannulated sponge implants in the rat, was in routine use within our laboratory. However, the sponges do not allow for the collection of inflammatory exudate from the granulomata around the sponges, without surgical intervention. Therefore, an analogous model was to be developed which permitted the collection by perfusion of inflammatory exudate containing the radioactively labelled metabolites of arachidonic acid