BIOCHEMISTRY OF INFLAMMATION 75 steroid. Thus, the fundamental defects in chronic inflammatory diseases may not be at the hormone supply level but may be due to altered hormone metabolism at the fibroblastic level. Perhaps it is through the preservation of cellular integrity that hydrocortisone tends to minimize the subsequent phases of the inflammatory reaction. The adrenal steroid actions contrast markedly with the effect of the estrogenic sex hormones. The sex hormones have been shown to increase the amount of intracellular water in the skin of mice, probably by increasing the amount of ground substance, while the corticoids appear to have an opposite effect (97). Hydrocortisone ointment causes progressive atrophy of collagen fibers, disappearance of interfibrillar mucopolysaccharides, dissociation of elastic fibers and atrophy of fibroblasts (98). A most interesting observation has been made that corticosteroids can chelate potassium ions and are capable of binding copper (99). Cortisone causes a redistribution of copper in the body, with an increased renal and urinary concentration and a decreased concentration in other tissues and in serum. It was suggested that the anti-inflammatory effects of the steroids may occur because of the chelation of an essential metal activator of an undefined enzyme (99). A recent study (100) suggests that the ability to form complexes or chelates in or across a lipid phase is of anti-inflammatory importance. The potency of a number of anti-inflammatory drugs could be correlated with at least two physical properties: ability to form complexes with metal ions and the lipophilic character, favoring partition into the lipid rather than aqueous phase. As an index of potency, the investigator used the ability of the compounds to inhibit incorporation of inorganic sul- fate into cartilage and corneal polysaccharides. It has been well demonstrated that administration of cortisone will be followed by a diminished amount of circulating antibody (101). Cortisone inhibits the incorporation of labeled amino acids into tissue protein (102). Under most circumstances, it appears that cortisone has a distinct antianabolic effect on proteins, generally inhibiting the synthesis of protein. On a cellular level, corticosteroids inhibit the inflammation, which can readily be observed during the course of immunization with adjuvants such as alum, killed tubercle bacilli, and various vehicles and irritants (77). This may also be regarded as a kind of anti-inflammatory action of cortisone which results in inhibition of antibody synthesis. While the corticosteroids are used principally for their anti-inflammatory effects, the mass of diverse effects cause additional actions which have come to be regarded as "side effects." While this paper is concerned chiefly with mechanisms, it will be concluded with a brief review of the broad side effects resulting from excess levels of corticosteroids. Hydrocortisone indirectly controls adrenocortical secretion by restraining the secretion of adrenocorticotropic hormone (ACTH) by the pituitary.

76 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS It is becoming iffcreasingly evident that the pituitary secretes ACTH in response to influences reaching it from the central nervous system. Hydro- cortisone may suppress ACTH secretion by altering the rate at which corticotropin-releasing factors are elaborated by the central nervous system or by diminishing the responsiveness of the adenohypophysis to corticotropin-releasing factors. Whatever the mechanism, the higher the level of hydrocortisone, the greater is the restraint on ACTH secretion. Thus, when supraphysiologic doses of hydrocortisone are used in the treat- ment of inflammatory conditions, ACTH secretion is suppressed, and this leads to cessation of adrenocortical secretory activity, diminished re- sponsiveness to exogenous ACTH, and progressive atrophy of the adrenal cortex. These changes in adrenocortical function are generally reversible if exogenous ACTH is administered or if hydrocortisone administration is discontinued, permitting recovery of endogenous ACTH secretion (103). There are so many other diverse manifestations of supraphysiologic levels of hydrocortisone that they cannot all be treated here. It should be mentioned that the corticoids affect protein metabolism in a variety of ways. Which of the effects will ultimately come to be regarded as primary and which secondary cannot be judged with certainty. There is both an anabolic effect by uptake of amino acids by the liver (104) and catabolic interference with cellular uptake of amino acids (105). As a consequence of these actions, hydrocortisone causes clinical manifestations of protein wasting. Corticosteroids, in excess dosage, promote the deposition of adipose tissue in the facial, abdominal and shoulder areas, as well as promoting sodium retention and potassium excretion by stimulating cation exchange by the renal tubule. Opposing this effect is the tendency of hydrocortisone to increase glomerular filtration rate which promotes sodium excretion. (Received September 9, 1962) REFERENCES (1) Menkin, V., "Dynamics or Inflammation, New York, The MacMillan Co. (1940). Reprinted 1950. (2) Anderson, W. A.D., "Pathology," St. Louis, C. V. Mosby Co. (1960). (3) Schade, H., "Die Molekular-pathologie der Entztindung," Dresden and Leipzig, Theodore Steinkopff (1935). (4) Menkin, ¾., •lm. J. Pathol., 10, 193 (1934). (5) Rugiero, H. R., and Tanturi, C. A., Semana reed. (Buenos •lires), 8, 13 (1942). (6) Bennett, I. L., Jr., J. Exptl. Med., 88, 279 (1948). (7) Menkin, V., In Mills, I,. C., and Moyer, J. H. (Eds.) "Inflammation and Diseases of Connective Tissue," Philadelphia, W. B. Saunders Co. (1961), p. 55. (8) Jackson, S. F.,Ibid., p. 6. (9) Riley, J. F., "The Mast Cells," Baltimore, Williams and Wilkins Co. (1959). (10) Kelsall, M. A., and Crabb, E. D., "Lymphocytes and Mast Cells," Baltimore, Little, Brown and Co. (1959). (11) Riley, J. F., and West, G. B., J. Physiol. (London), 120, 528 (1953). (12) Kramer, H., Lect. Sci. Basis Med., 2, 77 (1952). (13) Jackson, S. F., and Randall, J. T., "The Nature and Structure of Collagen," London, Butterworth's Scientific Publications (1953).