Lysosomal enzyme activity in rats with adjuvant-induced arthritis.

Evidence is increasing that lysosomal enzymes play an important role in inflammation (de Duve and Wattiaux, 1966; Weissmann, 1967; Houck, 1968; Fell, 1969; Dingle, 1969). Increased activities have been reported in human rheumatoid synovia and synovial membrane, and in other inflamed tissues (Smith and Hamerman, 1962; Luscombe, 1963; Barland, Novikoff, and Hamerman, 1964; Lehman, Kream, and Brogna, 1964; Kerby and Taylor, 1967; Weissmann, Spilberg, and Krakauer, 1969). Recent work suggests that cells which migrate to inflammatory sites, which include blood polymorphonuclear leucocytes and tissue macrophages, may partially discharge their lysosomal enzymes into the extracellular spaces, probably as a result of excessive endocytosis (Weissmann, 1967; Fell, 1969). It has been suggested that the acidic anti-inflammatory drugs, phenylbutazone, mefenamic and flufenamic acids, ibufenac, and indomethacin, may exert their beneficial effect by partially inhibiting some of these enzymes (Anderson, 1968, 1969a), or in common with anti-inflammatory steroids and chloroquine (de Duve, Wattiaux, and Wibo, 1963; Weissmann, 1964) by stabilizing cell and lysosome membranes (Tanaka and lizuka, 1968). Enzyme activity has also been detected in certain experimental inflammations in animals, including rat paws made oedematous by formalin, serotonin, dextran (Kalbhen, 1963; Domenjoz and Morsdorf, 1965), or carrageenin injection (Coppi and Bonardi, 1968). It appeared to be of interest to know whether similar increases in lysosomal enzyme activity occur in rats made polyarthritic by injection of Freund's complete adjuvant. This experimental model of systemic chronic inflammation (Pearson, 1956; Newbould, 1963), some symptoms of which resemble those in human rheumatoid arthritis, is used extensively for detecting and evaluating compounds with anti-inflammatory properties. It is concluded that the extensive tissue breakdown in adjuvant arthritis is due to the release and degradative action of lysosomal enzymes on connective tissue components. Effects on these inflammatory changes after the oral administration of phenylbutazone, hydrocortisone, and D-penicillamine are described and discussed. A preliminary account of part of this work has already been published (Anderson, 1969b).