J. T. Dingle

In vivo studies of articular tissue damage mediated by catabolin/interleukin 1.

A partially purified porcine synovial catabolin interleukin 1 (CF) preparation was injected intra-articularly into rabbit stifle (knee) joints. Radiolabelled CF was rapidly cleared from the joint (0.4 h). Repeated injections of CF caused a marked loss of articular cartilage glycosaminoglycan (GAG) and a great increase in synovial fluid GAG. 35SO4 uptake was inhibited. Time course experiments after a single injection produced similar loss of GAG from knee cartilages, which was maximal three days after injection. The above changes were significantly less with heat inactivated preparations. Loss of articular cartilage metachromasia was found histologically, and an acute synovitis occurred together with lymphocytic foci and plasma cell infiltration.

In vivo studies of cartilage regeneration after damage induced by catabolin/interleukin-1.

The response of the rabbit knee joint to a brief episode of cytokine induced damage is described. After three intra-articular injections of catabolin/interleukin-1 all joint cartilages showed an immediate extensive loss of proteoglycan (glycosaminoglycan), which was gradually replaced over three to four weeks. Glycosaminoglycan biosynthesis (measured by 35SO4 uptake) was initially depressed, but at one week had almost doubled its rate as compared with the normal side. This increased synthetic activity was further maintained throughout the duration of the experiment (28 days), though the rate gradually fell. Histological cartilage metachromasia to toluidine blue mirrored the glycosaminoglycan changes. No disturbance of the articular cartilage collagen network was found. It is considered, therefore, that during treatment for arthritis the indigenous chondrocyte must continue to be capable of carrying out regenerative matrix repair and that antiarthritic agents should first be screened for interference with that process.

Novel treatment for joint inflammation.

THE use of liposomes in the entrappment and administration of several therapeutic agents has been described for the treatment of cancer1 and heavy metal poisoning2, and in enzyme replacement therapy3. The advantages of a liposome drug over the use of free or polymer-bound agent are decreased toxicity and degradation, the use of smaller doses and the possibility of targeting the liposome towards a given tissue or site4. The localised administration of therapeutic agents, such as the intra-articular injection of cortisol esters in the treatment of rheumatoid arthritis5, is a situation where the use of liposomes as a means of providing a stable particulate suspension of entrapped steroid might be used to advantage. This method should reduce considerably the effective dose required to produce relief, and diminish side effects due to escape of steroid from the joint6. We report here that the treatment of an acute experimental arthritis in the rabbit with a liposome preparation containing cortisol results in a significant reduction in joint temperature and diameter, whereas treatment with an equivalent amount of cortisol alone, or with liposomes lacking cortisol, does not reduce these two parameters of inflammation.

Serum Antiplasmin and Plasmin in Rheumatoid Arthritis

The antitryptic activity of rheumatoid serum has been investigated by a number of workers (Coke, 1949; Ragan and others, 1949). Coke has shown that the extent and activity of the disease, in 200 cases of rheumatoid arthritis, was accompanied by an increase in the antitryptic function of serum. Todd (1949), using streptokinase-activated plasminogen, found a decrease in proteolytic activity during the acute phase of rheumatic fever. The present paper is concerned with alterations in the levels of streptokinase-activated serum plasminogen and serum antiplasmin in rheumatoid arthritis. The serum antiplasmin-plasmin (streptokinase-activated) system was chosen rather than the spontaneous fibrinolytic action of plasma, as the latter has a low degree of activity (Macfarlane and Biggs, 1946; Biggs, Macfarlane, and Pilling, 1947), is labile (Fearnley, Revill, and Tweed, 1952; Truelove, 1953; Fearnley and Tweed, 1953), and is not inhibited by normal plasma (Bidwell, 1953).

In Vitro Studies on Synovial Membrane Effect of Some Therapeutic Agents and Chemically Related Compounds

Considerable knowledge has been gained from the clinical study of various therapeutic agents in rheumatoid arthritis, yet comparatively little information is available on the metabolic action of these substances at the tissue level. A satisfactory in vitro approach to this problem could not be made until it could be established that in vitro metabolic changes occurred in the presence of rheumatoid disease in the synovium. We have shown that normal synovial membrane was a tissue with an extremely low oxidative metabolism, though its glycolysis was readily measurable. The tissue reaction to the disease involved the appearance of considerable oxidative metabolism, as well as an increase in glycolysis (Dingle and Page Thomas, 1956). It was also noted that the highest rate of metabolism was found in villous tissues, and that a positive correlation existed between the proliferative state of the disease in the knee joint and the metabolism of the excised tissue. In the cell, the synthesis of energy-rich bonds is achieved mainly by the oxidative breakdown of carbohydrate. The increase in synovial oxidative metabolism in rheumatoid disease is probably associated with the increased energy requirements of the proliferating synovium. Hence, any agent which alters this metabolic state might play a part in modifying the response of the tissue to the disease stimulus. Preliminary results have indicated that hydrocortisone is a potent inhibitor of synovial metabolism (Page Thomas and Dingle, 1955). The degree of inhibition of oxygen uptake produced in vitro by a standard concentration of hydrocortisone on rheumatoid synovia of varying degrees of metabolic activity was greatest in those tissues which exhibited the highest oxygen uptake (Page Thomas and Dingle, 1957). In this series of experiments, the in vitro action of hydrocortisone has been compared with Compound B (corticosterone), Compound S (11 -desoxy 17-hydroxycorticosterone), cortisone (1 -dehydro 17-hydroxycorticosterone), and DOCA (desoxycorticosterone acetate). Other compounds which have been investigated are o-hydroxy benzoic acid (salicylic acid), mand p-hydroxybenzoic acids, phenylbutazone (Butazolidin), and insulin. Materials