BIOCHEMISTRY OF INFLAMMATION 65 tion, infiltration and lysis of these cells provide cellular mechanisms for several systems of balances and counterbalances that control activities of interstitial fluids and connective tissues (10). Mast cells synthesize, store and release histamine which increases capillary permeability, which in turn increases the plasma proteins in the interstitial fluid (11). Increased interstitial proteins stimulate formation of the stem cells of mast cells, and further synthesis of histamine. Mast cells are also able to synthesize and release mucopolysaccharides which appear to be necessary for the dep- osition of different collagen fibrils (12, 13) and play a role in the main- tenance of normal cell permeability. Mast cells are the only cells in the connective tissues that contain acid mucopolysaccharides and they are able to release these substances to the ground substance. The concentration of tissue water is a stimulation to mucopolysaccharide release. Mast cells may be able to release histamine independently of simultaneous muco- polysaccharide release. Histamine may induce an increase in capillary permeability and produce edema the edema provokes release of muco- polysaccharides that bind the water, changing it into a hydrated gel. The presence of acid mucopolysaccharides stimulates the deposition of collagen fibrils and thus connective tissue growth. It appears that fibroblasts as well as mast cells are actively and indispensably involved (14). Mast cells are present in increased numbers in some chronic skin inflammations, such as urticaria pigmentosa (15). The fibroblasts are the precursor cells, or origin, of collagen. The collagen molecule is synthesized on the surface of the fibroblast (16) and released to the extracellular compartment, where the molecules become polymerized and oriented to collagenous fibers (17). The fibroblasts probably also secrete the ground substance (18). The ground substance is a gelatinous material permeating loose con- nective tissue, acting as a substrate through which salts, water and a variety of proteins, as well as neutral sugars and mucopolysaccharides are transported to various cells of the body. The capacity to accumulate and bind water is one of the most important functions of the ground substance. Hyaluronic acid, one of the main mucopolysaccharides, lends to the ground substance its viscosity, gelatinous character and water-binding capacity (17). The mucopolysaccharides of connective tissue ground substance are similar, but nevertheless, chemically quite distinct and probably are synthesized by different enzymes. It seems likely that these polysac- charides have different functions because they are not evenly distributed in connective tissue (19) and their proportions change with age, although they are apparently all linear unbranched polymers containing hexosamine and another sugar, usually uronic acid, arranged alternately. Apart from hyaluronic acid and chondroitin of cornea the connective tissue polysac-

66 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS charides are all sulfate esters and are therefore highly charged polyanions, which show considerable interaction with themselves and with proteins and which also bind salts and water to a marked degree. In the native state the polysaccharides of connective tissue are probably all combined with noncollagenous protein (20), forming very large complex molecules with molecular weights of several millions (21). Efforts to delineate the mechanism of action of acid mucopolysaccharides (AMP) have been severely hampered because procedures for extraction are not quantitative, methods of separating different AMP from one another are insufiqciently refined, and the knowledge of the mechanisms of their bio- synthesis is still sketchy (2:2). CHEMICAL MEDIATORS The similarity of the inflammatory cycle in many different species in re- sponse to many diverse types of injury has led to the now generally ac- cepted view that the vascular events of inflammation are due at least in part to the release of local hormones or mediators (23, 24). At some time or other, almost every active material extracted from blood or tissue has been incriminated as a causative factor in inflammation. These include potassium ions, acetylcholine, serotonin, catecholamines, adenyl derivatives (adenosine, adenylic acid, ATP), histamine, proteins, varied peptides, including particularly bradykinin, etc. (25). These substances display the most varied physiological actions. Only histamine, the kinin peptides, globulin proteins and catecholamines satisfy, in large part, the criteria for true mediators. The beginning of modern mediation theory can be considered to begin with Lewis' (26) studies on wheal formation or hives. Possibly the out- standing dermatological example of the leakage of blood plasma from dilated small blood vessels into extracellular spaces is represented by wheal formation. Whealing represents circumscribed, superficial edema of the skin as it develops in response to various chemical, mechanical, thermal and ac'tinic stimuli. There are three distinct steps in the development of wheals: local vasodilatation of the capillaries, causing local reddening local increased capillary permeability causing local wheal formation and a vasodilator axon-refiex complex with arteriolar dila•:ation, causing the red flare. This is known as Lewis' "triple response" of the skin to injury (26). Ii was Lewis who argued that these reactions, which appear quite uniformly in r•sponse to diverse physical and chemical infiamm'•tory stimuli, are so uniform because all the stimuli eliciting the response do not act directly on vascular and nervous elements, but by liberating' substances from the injured cells (24). This has led to the now generally accepted view that the release of local hormones or mediators by the injured cells reasonably explains some of the biological manifestations of inflammation. This