Biomedical subjects
Publications and source records attributed to A D Sedgwick.
Two animal models were used to investigate the mode of action of levamisole and thymopoietin. Neither compound influenced the subcutaneous carrageenan air pouch. While thymopoietin inhibited the formation of cotton pellet granulomas, levamisole enhanced it. This supports the conclusions of clinical studies reported elsewhere that levamisole and thymopoietin do not act in the same way in rheumatoid arthritis.
Synovial tissue from 6 normal pigs and from 16 patients undergoing arthrotomy for joint disease was examined by dissecting microscopy. Scale models were constructed of 3 human synovial specimens from photographic magnifications of serial sections. Surface bridging and subintimal cavitation were observed, particularly in tissue from patients with rheumatoid arthritis. These features suggest that synovial surface projections (villi) do not form simply by outgrowth. Reference to original haematoxylin and eosin stained sections suggested that tissue splitting contributes to the formation of villi.
D-penicillamine was found to have a pro-inflammatory effect when given to rats during the formation of carrageenan air pouch granulomas or simple air cavity linings. Unlike dexamethasone, D-penicillamine had no effect on the strength of the cavity lining in either system. D-penicillamine had no effect on the chemoattractant properties of the carrageenan-induced exudates or on the responsiveness of cells from such exudates to a chemoattractant. These results suggest that D-penicillamine has a short-term pro-inflammatory effect on non-immune responses to tissue injury, but the mechanism remains unclear.
Using a modified Boyden chamber system, inflammatory exudates taken from the acute carrageenan pleural model and the chronic carrageenan air-pouch model were tested for their ability to promote leukocyte locomotion in vitro. Both exudates were able to induce polymorphonuclear leukocyte (PMN) and mononuclear leukocyte (MN) migration, suggesting that cell-specific chemoattractants are not responsible for the progression of the inflammatory process from the acute to the chronic phase. Checkerboard assay were used to establish whether the observed migration was in response to chemotactic stimulation and/or chemokinetic stimulation. Both acute and chronic exudates were able to induce MN chemotaxis and chemokinesis. Acute exudate was able to induce PMN chemotaxis and chemokinesis. Acute exudate was able to induce PMN chemotaxis and chemokinesis, but chronic exudate was only able to induce PMN chemokinesis. This may partly explain the predominance of MNs in chronic inflammation. However, our present in vitro results have failed to demonstrate that cell-specific chemoattractants are responsible for the in vivo observation that migration of polymorphonuclear leukocytes precedes the migration of mononuclear cells.
Recent work in our laboratory with mouse radiation chimeras suggests that the macrophage type of synovial lining cell is derived from bone marrow. Further evidence for including this cell type in he mononuclear phagocyte system is now presented. Rosette formation with IgG coated sheep red cells, immunofluorescent staining for surface Ia antigens, and nonspecific esterase staining all show the presence in the synovial lining of a subpopulation of cells carrying these markers. The proportion of such cells in the lining is very variable, as is the proportion of 'type A' cells recognised with the electron microscope.
It has been suggested that the regulation of macrophage division may be afforded by the release of soluble mitogenic factors into inflammatory exudate. We have examined for macrophage mitogenic activity in exudates and sera obtained from animals with chronic inflammatory lesions and compared them with fluids from an acute lesions. Both acute and chronic exudates were able to promote DNA synthesis, however acute exudate had higher activity. Although we were able to detect mitogenic activity in the sera obtained from animals with acute pleurisy, we were unable to detect any activity greater than control in sera obtained from animals with chronic inflammatory lesions. We propose the presence of mitogenic factors for macrophages in both animals with acute and chronic lesions may help to explain the increasing predominance of mononuclear cells seen during the progression of acute to chronic inflammation.
We have attempted to verify the suggestion that synovial membrane is the result of mechanical disruption of connective tissue, and may occur at any site. Mechanical disruption of the subcutaneous connective tissue was achieved in rats and mice by the repeated injection of air. The resulting cavities developed a lining structure with many of the features of synovial membrane as judged by electron microscopy, and light microscopy using haematoxylin and eosin and van Gieson stains, esterase activity and immunofluorescent staining for Ia antigen. A structure closely resembling synovium is formed as early as 6 days, providing a convenient method for studying large quantities of facsimile synovial tissue under a wide variety of easily administered stimuli.
The air bleb has been studied as a cavity suitable for the production of a chronic inflammatory response. The ability of carrageenan and CPPD crystals to produce a chronic response in this cavity has been studied and the nature of the reaction described quantitatively and qualitatively. Carrageenan produced a fluid exudation predominated by mononuclear cells and histologically chronic in nature. However, CPPD failed to produce an inflammatory response apart from the formation of a few foreign body giant cells. Using the model described, experiments were undertaken to examine the ability of exudates and sera taken from animals undergoing either an acute or chronic reaction to modify two models of acute inflammation. Firstly the carrageenan complement dependent pleurisy and secondly the CPPD complement independent pleurisy. Volume of chronic and acute total cell numbers were reduced by chronic and acute exudates and sera on the carrageenan pleural model. No significant effect was on the CPPD pleural model.
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The novel non-steroidal anti-inflammatory drug (NSAID) miloxicam was administered intravenously to six New Forest ponies at a dosage rate of 0.6 mg/kg in a two-part cross-over study. In each part, three horses received miloxicam and three were given a placebo preparation. The actions of miloxicam, compared to placebo, were assessed in a carrageenan-sponge model of acute inflammation. The rise in skin temperature over the site of the acute inflammatory reaction was less in treated ponies, but differences were not statistically significant. Concentrations of the enzymes acid phosphatase (AP) and lysozyme in inflammatory exudates harvested at 4, 8, 12 and 24 h were not significantly different in drug-treated animals compared with those receiving placebo. Concentrations of protein and lactate dehydrogenase (LDH) in exudate and exudate leucocyte numbers were significantly reduced in drug-treated horses when data for all sampling times were pooled. The differences were not significant, however, at each sampling time. Exudate concentrations of the eicosanoids, bicyclic-PGE2, 6-keto-PGF1 alpha and TXB2, were reduced significantly by miloxicam at most sampling times, and serum TXB2 was also significantly reduced at 4 and 8 h but not at 12 and 24 h after drug administration. These pharmacodynamic findings correlated with the pharmacokinetic properties of miloxicam. The plasma concentration-time curve was defined by a three-compartment open model in one pony and by a two-compartment model in five ponies. Mean values for pharmacokinetic parameters for the five ponies were: t1/2 alpha 0.40 h; t1/2 beta 2.70 h; Vd area 0.158 l/kg; ClB 41.87 ml/kg/h. Exudate concentrations of miloxicam were initially similar to and eventually greater than concentrations in plasma, and this may explain the more prolonged inhibition of eicosanoid synthesis in exudate than in serum. These findings demonstrate the value of relating, in a single experimental study, drug action on a range of variables to drug fate in the body.