BIOCHEMISTRY OF INFLAMMATION 73 permeability factors such as histamine may act by altering the electrolyte and water balance of these cells. These speculations have gained some support by electron microscopy which has indicated that protein appears to leave histamine-treated vessels by transport through the endothelial cytoplasm rather than by passage through channels of molecular dimensions between the cells (74). A new point of view has related the inflammatory processes and blood coagulation (75). There is no experimental proof that all the aforemen- tioned mediators exert their effects by a simple direct action on the vascular wall. It is suggested that the intervention of a coagulating mechanism or fibrinogen production is a prerequisite to typical inflammatory vascular reaction. The assumed coagulation process in the vascular wall may be initiated by the inflammatory agent itself or by endogenous thromboplastic factors produced under the influence of these agents. ANTI-INFLAMMATORY DRUGS /I. Corticosteroids. Clinical anti-inflammatory agents, in order of their importance, are the corticosteroids, salicylates, phenylbutazone-antipyrine type, gold salts, antimalarial aminoquinoline compounds and enzymes. This review shall only discuss the corticosteroids since mechanistic data is sadly lacking in all the others. The corticosteroids represent the most successful anti-inflammatory drugs yet found. There are few physiologic processes which are not influenced directly or indirectly by the corticoster- olds. Yet they do not appear to start any physiologic activity, but merely influence rates. Apparently, corticosteroids are not consumed in the process of exerting their physiologic effects, but rather they act as catalysts. Corticoids tend to suppress the whole process of inflammation, inhibiting to various degrees the maximum development of any of the stages of inflammation (76). Unlike other inhibitors of inflammation they can check the inflammatory response at any stage from the initial swelling and increased capillary permeability to final dissolution of connective tissue (77). Hydrocortisone acts in a dose-response fashion, inhibiting to various degrees the maximum development of any of the stages of inflammation, depending on the nature and amount of the inflammatory stimulus (78-80). The processes of regeneration and growth depend on well regulated proc- esses in connective tissues. The mast cells and fibroblasts are the major active components. These processes of regeneration and growth are inhibited by the glucocorticoids. Mast cells diminish, become vacuolated and acquire irregular outlines. The number of demonstrable cells is diminished (81). The most consistent effect of the steroids appears to be an inhibition of mucopolysaccharide synthesis by the connective tissue. At a metabolic level, several investigators have demonstrated an inhibition of the incorporation of radioactive sulfate into the mucopolysaccharides of

74 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS connective tissue under the influence of cortisone or hydrocortisone (82-85). Inhibition of mucopolysaccharide synthesis by steroids was also demon- strated, following depletion of cartilage matrix by papain (85). When animals are intravenously injected with crystalline papain protease, all of the basophilic and metachromatic components of cartilage disappear within a few hours. This is associated with a loss of chondroitin sulfate from the cartilage and its appearance in the circulating blood. Reconstitution of cartilage matrix begins two days after the injection of papain, and chondro- mucoprotein is completely restored within the next three or four days. When cortisone is administered after papain, reconstitution of matrix is completely prevented. This inhibition seems to involve a direct action of cortisone on the cartilage. This inhibition of chondroitin sulfuric acid synthesis has been demonstrated in delaying the healing of wounds (86). Cortisone inhibits the acccumulation of liberated histamine in the con- nective tissue (87). The steroid is a very effective inhibitor of the mast cell-histamine chain. Cortisone appears to maintain the tonus of small arterioles which are injured by histamine (10) and decreases permeability of existing capillaries and interstitial substances, possibly by inhibiting the action of hyaluronidases (10, 33), of histidine decarboxylase (88), and of histaminase (89). Early in the process of inflammation, degenerative changes occur in the fibroblasts. The administration of hydrocortisone also produces mor- phological changes in many of the fibroblasts of loose connective tissue (90). Fibroblasts are among the first cells showing degeneration when con- nective tissue becomes inflamed. It appears that one essential action of the corticosteroids is the inhibition of the progressive destruction of fibro- blasts in an area of potential inflammation (77, 91-93). The fibroblast appears to be the most common and dominating cell in connective tissue which sequesters and metabolizes hydrocortisone (94). It has been suggested (77, 95) that the degree of inflammation is enhanced by the auto- catalytic destruction of fibroblasts, in which the destruction of one cell adds to the amount of inflammatory substances such as histamine or a kinin and leads to the destruction of other inflammatory substances. This chain reaction of cell breakage is interrupted by the action of hydrocortisone, which increases the resistance of some fibroblasts. While different re- search groups may differ upon the importance of steroidal effects on fibroblasts, it is clear that hydrocortisone is metabolized by fibroblasts. Even if a sufficient amount of hydrocortisone is produced by the adrenal cortex in individuals having inflamed tissue, if the hormone is inactivated at the fibroblastic site of action more rapidly than under usual normal conditions, anti-inflammatory influence could be insufficient to inhibit the inflammation (96). According to this theory, the peripheral cells may influence the disease process by their own capacities to metabolize the