BIOCHEMISTRY OF INFLAMMATION 71 inflammation have all been active dilatators of blood vessels, increasing capillary permeability. Vasoconstrictor forces have been ignored. Yet the first vascular event following an acute injury is a momentary and transitory contraction of local blood vessels. A newer concept has re- cently arisen explaining initial vasoconstrictor forces, following the observa- tion that the manifestations of rheumatoid arthritis and related diseases could be altered by the administration of small doses ofiproniazid, an amine oxidase inhibitor (68, 69). This appeared to indicate that the vascular changes of acute inflammation are partly due to the destruction of an amine that would otherwise constrict and reduce the permeability of capillaries and oppose the action of compounds such as histamine and kinins. The most important endogenous compounds with these "antipermeability" actions on blood vessels are the catechol monoamines: adrenalin and nor- adrenalin. They are present in platelets, leukocytes and vessel walls, and at least two enzymes destroy them in the body, monoamine oxidase and catechol-O-methyl transferase. Administration of specific monoamine oxidase inhibitor• greatly reduces the increased capillary permeability con- sequent to thermal or chemical injury. This result is explicable on the basis that inflammatory phenomena are partly due to inactivation of vaso- constrictor arnines by monoamine oxidase. Competitive inhibitors of catechol-O-methyl transferase failed to modify the inflammatory reaction. Recent evidence (70) dealing with the genesis of tissue destruction fol- lowing locally administered bacterial extracts suggests that epinephrine is an important factor in mediating the subsequent inflammation. The mechanism by which catechol amines accelerate tissue damage is not well understood. Epinephrine does not seem to be involved in the local in- flammatory response per se (71), but rather in the subsequent development of endothelial damage. While the evidence is not yet well substantiated, Cameron and Spector (23) postulated that, following injury, an adrenalin- like substance and an amine oxidase may be brought into contact. As a re- sult the vasoconstrictor amine may be destroyed, and inflammation allowed to proceed. It seems possible that in the wall of the normal small blood vessel, adrenalin-like and histamine-like compounds compete for receptor sites, the interplay of their actions making for normal vascular reactions. In inflammation, not only are the vasodilator forces greatly augmented but the vasoconstrictor forces may be inactivated. The enzymic inactivation of the adrenalin-like substance could be precipitated either by local activa- tion of monoamine oxidase or release of the amine from a site inaccessible to the enzyme (23). MECHANISM OF INCREASED CAPILLARY PERMEABILITY Cameron and Spector (23) attempt to illustrate schematically the sequence of events of increased capillary permeability as follows:

72 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS •--- .•LOCAL INJURY • .•Activa•tion ActivationofInactivof Histamine of Itelease Proteases Serum Globulin Vasoconstrictor • • J Amine • 1%romfatiøn •ff • Alter•n vKai!l•ir E ndothel• Ie.g. Activation of Enzymes in vessel wall] INCREASED CAPILLARY PERMEABILITY It is suggested that the initial event appears to be a release of histamine from mast cells by a mechanism not yet fully understood but possibly involving activation of lyric enzymes which break down the structure of the mast cells. Histamine appears to exert its effects within a minute or two of injury, but continues to dilate capillaries and increase their permeability for some time afterward, for at least one to two hours. At the same time as histamine is released, it is postulated that an adrenalin-like substance is brought into contact with the enzyme monamine oxidase which destroys it. The hypothetical destruction of the adrenalin-like substance leads to dilatation and increased permeability of small vessels that begins rapidly and may last for twenty-four hours or even longer. Soon after these initial events there may be an activation of globulins and peptides that increase capillary permeability. Little to nothing is known of the intimate mechanism whereby histamine, globulins, and peptides increase capillary permeability. There is some evidence that all endogenous mediators of increased capillary permeability may exert their effects by activating an enzyme of the esterase-protease group in or near the vessel wall (72). The substrate of this enzyme could be a protein or phospholipid in the capillary wall of the precursor of yet another mediator substance which then acts on the blood vessel (73). It is of interest that high concentrations of some antihistamine drugs not only exert a general antagonism to increased capillary permeability but also cause a general inhibition of electrolyte movements in damaged cells and mitochondria (23). This may possibly mean that increased capillary permeability to protein is in some way secondary to, or at least associated with, electrolyte disturbance in the vascular epithelium and that capillary