BIOCHEMISTRY OF INFLAMMATION 69 C. Peptides. The possible role of peptides in inflammation has been suspected for over a hundred years, but the study of the effect of peptides on capillaries really dates from the observations of Menkin in the middle 1930's (49, 50). His early studies indicated that injured cells at the site of inflammation release a permeability and chemotactic factor which was called "leukotaxine," and which appears to be a polypeptide. Leukotaxine is capable of essentially reproducing the effect of the whole exudate as far as increasing local capillary permeability and inducing the emigration of polymorphonuclear leukocytes (51). Unfortunately, leukotaxine has never been purified, its detailed structure is unknown and its significance not adequately defined. It might also be noted that leukotaxine appears after the inflammation is established. Later work demonstrated that large numbers of different peptides from various sources were able to increase capillary permeability and that the most likely requisite for this peptide property was a molecule containing eight to twelve amino acids (52). These observations culminated in the discovery (53), purification (54), and synthesis (55) of one or the most important members of this group, bradykinin, a peptide derived by pro- teolysis from plasma globulin. It is released by proteolytic and coagulating venoms and by trypsin from the globulin fraction of normal plasma. The name "bradykinin" was given to indicate the slow movement of the guinea pig ileum produced by it, diflvring from the more rapid contractions of the ileum by histamine or acetyl choline. It is now customary to refer to all inflammatory peptides by the term "kinins." In addition to stimulating smooth muscle, bradykinin causes all the inflammatory reactions of vasodilatation, increased capillary permeability, accumulation and migration of leukocytes, and especially pain (56, 57). Bradykinin is also known to have some effect on the nervous system, but precisely what it does is still not known. It will cause pain when injected under the skin and at the same time there will be a flushing of the skin in the region, but if the area is denervated the flushing will not take place• This appears to indicate that the redness is due to a specific effect of the bradykinin on the nerves. When tissues are damaged by severe burns, or animal skins are experi- mentally heated, there is a marked increase in bradykinin concentration in the interstitial fluid and urine (58). Unfortunately, there is, as yet, little quantitative data to correlate the amount of cell damage. These findings, however, provide substantial evidence that a plasma kinin, possibly bradykinin, takes part in the inflammatory response. Fortunately, there exists an efficient bodily system for the destruction of excess bradykinin and other kinins (58). If there were no such system, the kinins would keep building up in the blood stream and continue to enlarge the entire system of blood vessels, continually increasing their permeability.

70 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS This would result in general vascular collapse. A bradykinin-inactivating enzyme, kininase, is present in blood and extracts of renal tissue. In addition, an inactivator of kallikrein, mentioned as the bradykinin-forming enzyme, is present in high concentration in lymph nodes. This destruction by peptidases may in fact be a homeostatic mechanism for inactivating these powerful kinin substances once they escape from the site of inflam- matory reactions. Natural bradykinin was isolated in pure form (59, 60) after the release by trypsin from bovine plasma globulins. It was actually synthesized (61, 62) before its structure was known. The structure is now known to be a linear nonapeptide of the following amino acid sequence (58, 63, 64): (H--Arg--Pro--Pro--Gly--Phe--Ser--Pro--Phe--Arg--OH) However, bradykinin is not the only active peptide formed by the action of enzymes on the plasma globulins. A decapeptide, called kallidin, differing from bradykinin only by the addition of one amino acid residue, lysine, at one end, has been isolated and characterized from blood (65). The structure of kallidin is: (H--Lys--Arg--Pro--Pro--Gly--Phe--Ser--Pro--Phe--Arg--OH) Kallidin is less active than bradykinin on most tissues but has a similar spectrum of activity. Another potentially important kinin is the recently isolated peptide known so far only as "substance P" (66). The purified material has many of the properties of bradykinin, but its structure contains at least six amino acids not found in bradykinin. Since different pro- teolytic enzymes not only give rise to bradykinin, but to other peptides with similar properties, it has greatly complicated the problems of relating the various "kinins" to body function and particularly to inflammatory function. D. Proteins. Kallikrein, the bradykinin-forming enzyme and certain globulin fractions of plasma have been shown to be capable of increasing capillary permeability, in very low concentration (41, 67). The plasma globulin is present normally as an inert precursor that can be activated by a variety of procedures, including dilution with saline, contact with organic solvents and incubation with minced tissues (23). It is thus an obvious candidate for the role of mediator of the vascular changes of acute in- flammation. The protein could act directly on vessels (possibly enzymi- cally) or could be either a protease, or less likely, a substrate in formation of kinin peptides. Kallikrein obviously exerts its effects on capillaries and smooth muscle by catalyzing the formation of kinins from globulin sub- strates (24). E. t/asoconstrictor •fmines. The previously discussed mediators of