Studies on Endogenous and Other Anti-Inflammatory Substances in Rheumatic Diseases

Abstract

This investigation was concerned with the possibility that there are endogenous proteins with anti-inflammatory activity. These proteins may occur under normal physiological conditions or may be produced pathologically in response to inflammatory stimuli. Two of the proteins investigated were alpha1-antitrypsin and alpha2-macroglobulin from normal human plasma. Alpha1 -antitrypsin possessed anti-inflammatory activity against carrageen in induced inflammation n the rat. Alpha2-macroglobulin was irritant in this model but this was probably due to traces of denatured protein. High molecular weight proteins were detected in human rheumatoid synovial fluid. These had the property of stabilising lysosomes invitro. It appears likely that these proteins are of plasma origin and that they possess some anti-inflammatory activity. Two drugs established in the treatment of other diseases were also examined for anti-inflammatory activity. Aprotinin, a polypeptide antiproteinase, derived from bovine lung, used in the treatment of acute pancreatitis and with a molecular weight of 6,500 daltons was found to have some activity against carrageenin induced inflammation, cotton pellet granuloma and adjuvant induced arthritis in the rat. Dapsone, which is chemically similar to the sulphonamides, is used in the treatment of leprosy. It was found to have anti-inflammatory activity when assessed by the same tests as aprotinin. It also possessed some biochemical properties common to established non-steroidal anti inflammatory drugs. The pharmacology and biochemistry of aprotinin and dapsone are discussed in relation to the clinical results. Prednisolone has been investigated in in vivo animal tests at anti-inflammatory doses and at doses high enough to show possible toxic effects. The in vivo results are discussed in relation to the in vitro properties of prednisolone. Radiological and visual studies have been made of the changes produced by the administration of Freund's complete adjuvant to rats. Suggestions are made for the future development of this research.