BIOCHEMISTRY OF INFLAMMATION 67 hypothesis has gained support from the discovery of naturally occurring substances with effects on small blood vessels similar to those seen in inflammation. In recent years the theory has been strengthened further by the demonstration of active forms of such compounds at the site of injury at the time when they should be exerting their effect (23). ,4. Histamine. Lewis drew attention to the similarity of the action of histamine and the vascular events of early inflammation and postulated the release, by injury, of histamine or a histamine-like substance. Histamine is a diamine derived from the amino acid histidine_ It is very widely dis- tributed in the tissues of all mammals. It is formed by the enzyme histidine decarboxylase and destroyed by the diamine oxidase, histaminase (27). Mast cells synthesize, store and release histamine. Endogenous and exogenous histamine are potent inductors of hyperemia and of increased capillary and tissue permeability (10, 28, 29, 30, 31). Pathological tissues rich in mast cells contain very high concentrations of histamine. Analysis of tissue homogenates indicates that histamine is loosely held in the mast cells within definite granules in the mitochondrial fraction of the cell. It is evidently held in a readily diffusible form. Histamine is readily released from suspensions of these mitochondrial particles by freezing, hypotonic media, surface-active agents and a large variety of organic bases (24). The release of histamine from mast cells speedily induces dilatation of capillaries and increased permeability and reduces the viscosity of hyaluronic acid in interstitial fluid. Usually these changes result in increased passage of plasma proteins with the formation of protein rich edema (10, 32). This edema has been considered a factor in initiating and continuing collagen degeneration. Swelling of collagen fibers is one of the early changes in collagen diseases (33, 34). The release of histamine from the granules of mast cells primes the mast cell-histamine chain and possibly indicates a contributing factor in the predilection of the following tissues or organs to lesions in the collagen diseases (35): (a) abundance of mast cells in the pleura in pleurisy of rheumatoid arthritis (36) (b)"cuffing" of mast cells around arterioles in periarteritis nodosa (37) (c) foreign protein release of mast cell-histamine in serum sickness. Edema appears in skeletal muscle also in dermatomyositis (38) and in degeneration of muscle fibers. The discovery of a group of drugs, the antihistamines, that antag•)nized more or less specifically the effects of histamine led to further advances. Treatment with these compounds greatly reduced the inflammation caused by antigen-antibody reactions in certain diseases such as allergic thiniris and urticaria. However, the majority of inflammatory lesions were not af- fected by the antihistamine drugs (39). As a result it seemed that hista- mine played a minor part in the total infiamm'atory reaction. Ano.ther weakness of the "generalized" histamine theory is the case of the sunburn reaction (15), which has a latent period of one to several hours. Sub-

68 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS sequently, reddening develops which is sharply limited to the area of irradiation. This limitation cannot be compared to the widespread, suddenly appearing flare of Lewis' triple response (26). In burn reactions, e•½zematous types of dermatitis and tuberculin-type hypersensitivities, the role of histamine in the inflammation is also negligible. There are hardly •ver any transitions between the urticarial and eczematous type of inflam- mations. Such transitions should be expected if the reactions depended only on the rate of histamine liberation and on its concentration in the tissue. The same lack of histamine liberation is found in the case of erythematous-edematous blistering reactions and other diseases with prevailing blister formation, such as smallpox, chicken pox, herpes simplex, herpes zoster and persistent papules (15). The consensus of results (24, 40, 41) appears to indicate that the role of histamine in inflammation is to initiate the vascular changes, especially in- creased capillary permeability, and the subsequent sustenance of these changes is due to other mechanisms independent of histamine release (23). The rapidity with which the effects of histamine occur after injury may be explained by assuming that the histamine is rapidly released from the mast cells, which disrupt and liberate their granules in response to injury. The precise mechanism of the release is a complicated process not yet completely clarified, but appears to involve formation of ATP, dependent on the glycolytic cycle of carbohydrate metabolism. There is a possible final activation of lyric enzymes capable of lysing the structure of the mast cells (25, 42), and injury activates the enzymes. It has been suggested that the release of histamine follows from the rupture of a peptide or polar bond linking histamine to a protein, or an ion exchange reaction, releasing histamine from loose combination with an acidic body compound (43). There is also evidence that injury may cause increased activity of histidine decarboxylase and this leads to increased synthesis of histamine (44). B. Serotonin. Serotonin, 5-hydroxy tryptamine, is a monoamine de- rived from the amino acid tryptophane. 1'he primary role of serotonin is unknown but it is believed to have a part in the transmission of nerve impulses (45). In very low concentrations serotonin increases capillary permeability (46) and will cause local progressive collagenous and fibrous proliferation within the dermis on long-term injection, in the rat (47). However, it does not produce these effects in most other species and even in the rat the evidence of an important role in inflammation is meagre (48). Compounds exist which are more or less specific antagonists to serot•onin, such as l-methyl-d-lysergic acid butanolamide and cyproheptadine. Dosage with such substances considerably reduces the inflammatory re- action caused by serotonin in rats. These studies (48) however, did not prove that the observed effects were due to the inhibition of serotonin or related compounds. It is possible that some unknown pharmacologic action was responsible.