Biomedical subjects
A D Sedgwick
Publications and source records attributed to A D Sedgwick.
Studies into the association between leucocyte accumulation and oedema formation.
We have treated rats with methotrexate to reduce their circulating leucocyte numbers and in particular their polymorphonuclear leucocytes. Injection of zymosan, calcium pyrophosphate dihydrate crystals, carrageenan or dextran into rat pleural cavities induced leucocyte accumulation and oedema formation both of which were reduced by prior methotrexate treatment. The observation that the depletion of circulating leucocytes reduces both inflammatory cell accumulation and oedema formation suggests that these two processes are closely linked. In contrast treatment of animals with the anti-complementary agent K76COONa blocked leucocyte accumulation but had no effect on oedema formation indicating the two processes can occur independently. This conflicting data suggests that the association between leucocyte accumulation and oedema formation is complex.
The transition from acute to chronic inflammation.
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A hypothesis for the mode of action of anti-rheumatic drugs in a model of cartilage destruction.
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Studies into the influence of carrageenan-induced inflammation on articular cartilage degradation using implantation into air pouches.
We describe a novel system for examining the degradation of articular cartilage in vivo. Implantation of rat femoral head cartilage into six day old subcutaneous air pouches allows the examination of the degradation of cartilage in contact with a synovial lining-like structure. Femoral head cartilage was removed 1, 2 or 3 weeks after implantation and the proteoglycan content measured using 1,9-dimethyl methylene blue. Chondrocyte viability was confirmed using 35S sulphate incorporation. Increasing proteoglycan loss was observed over 3 weeks. Loss was similar in transplants between inbred and between outbred animals, suggesting that allograft rejection did not contribute significantly. Introduction of the irritant carrageenan into pouches produced a massive and prolonged inflammatory response characterized by exudation of leucocyte-rich fluid. Induction of inflammation with carrageenan did not alter the profile of proteoglycan loss from whole, minced, live or dead cartilage, as compared to that seen in non-inflamed pouches. These results indicate that when the relationship between articular cartilage and its normal tissue surroundings is disturbed, rapid proteoglycan loss may occur. The conditions induced by carrageenan inflammation have, in comparison, little or no effect on cartilage degradation. This raises the possibility that the direct effects of inflammatory products are of relatively minor importance to cartilage destruction in human arthritis.
The immune response to pertussis in the 6-day air pouch: a model of chronic synovitis.
We have developed a model of prolonged immunological inflammation in the rat which has a structural resemblance to the synovial changes in rheumatoid arthritis. Pertussis vaccine was injected into 6-day-old subcutaneous air pouches in animals previously sensitized with pertussis vaccine. The resulting inflammatory response persisted up to 30 days. Examination of exudates showed a wave of polymorphonuclear leucocytes over a 13-day period followed by a mononuclear cell predominance up to 30 days. Histologically, an early polymorphonuclear cell infiltration was followed by the formation of a lining layer of large eosinophilic mononuclear cells, together with deep collections of lymphocytes and plasma cells. Concentrations of the acute-phase reactant alpha 1-glycoprotein, in both serum and exudate, peaked at 3 days. This suggests that the local production of interleukin I in this type of tissue reaction is more closely related to the acute inflammatory phase than to more chronic interactions between monocyte derived cells and lymphocytes.
Studies on the mechanism of cartilage degradation.
An in vivo study of cartilage breakdown in mice was carried out by implanting living and dead, intact or finely minced autologous cartilage back into newly elicited inflammatory tissue of the original donor. At various time intervals, the implants were removed and their loss of proteoglycan and collagen analysed both histologically and biochemically. The results show that only a modest loss of proteoglycan and collagen occurs in the living intact cartilage. Severe loss of proteoglycan was detected in the minced living and dead intact cartilage. The present findings clearly demonstrate that mechanical damage during the mincing of cartilage predisposes this tissue to attack by various types of mediators known to degrade cartilage.
Enhancement of colloidal clearance in normal rats by sodium diethyl dithiocarbamate (DTC).
Enhancement of colloidal clearance in normal rats is induced by sodium diethyldithiocarbamate, administered by the oral route. Enhancement is only observed after a lag period of greater than seven days. The study evidences the efficacy of oral administration of DTC and a weekly frequency of dosing in this clearance model.
The effect of therapeutic agents on cartilage degradation in-vivo.
Implantation of minced autologous cartilage into inflamed air pouches in mice allows the study of therapeutic agents on both the inflammatory process and cartilage degradation. Non-steroidal anti-inflammatory agents were found to reduce cell accumulation in response to carrageenan, but were unable to prevent proteoglycan loss from cartilage. In contrast, D-penicillamine had no effect on the inflammatory process but significantly reduced proteoglycan loss. Our findings suggest that the autologous cartilage transplantation model in the mouse may be useful for studying novel anti-arthritic agents.
Studies into the mode of action of non-steroidal anti-inflammatory drugs using a model of facsimile synovium.
The effect of non-steroidal anti-inflammation produced in the 6-day old air pouch by carrageenan or calcium pyrophosphate crystals has been examined. The system is a very reproducible way of studying the cellular and vascular components of inflammation. Non-steroidal drugs have different profiles of activity when tested on the inflammation produced with the two irritants. In general, however, the tested compounds showed similar activity on individual models.
Effects of local administration of hydrocortisone on cartilage degradation in vivo.
The effect of corticosteroid on autologous minced cartilage transplanted into facsimile synovial cavities has been studied. The soluble form of hydrocortisone, as the sodium succinate, reduced proteoglycan loss from cartilage in a dose-dependent manner. In contrast, insoluble hydrocortisone acetate, if given directly into the cartilage-containing cavity, enhanced proteoglycan loss. Injection of the same dose of drug into the inflamed lining tissue reversed this effect. These findings suggest that intra-articular steroid injection may enhance cartilage damage if insoluble preparations are used, but that this may be overcome by injecting into the inflamed lining tissue rather than into the cavity itself.
Studies on the clearance of calcium pyrophosphate crystals from facsimile synovium.
Calcium pyrophosphate dihydrate crystals have been injected into the air pouch model of facsimile synovium. At various time intervals after crystal injection both infiltrating exudate cells and lining tissue were examined for the presence of crystalline material. The results show that the crystals are initially engulfed by mononuclear cells and to a lesser extent by polymorphonuclear cells in the exudate. Later, crystals became embedded in the lining tissue either within mononuclear cells or as crystal masses confined within granulomas. These studies suggest that the mesenchymal cells ( facsimile synovium) lining rat air pouches can clear calcium pyrophosphate dihydrate crystals from the air pouch cavity. It is therefore inferred that crystals found in the lining of human joint synovium may be incorporated therein by a similar mechanism.
Effect of a lymphocyte-derived pro-inflammatory factor on carrageenan pleurisy in the rat.
An intravenous injection of a lymphocyte pro-inflammatory factor (LpIF), obtained from rat spleen, restored diminished fluid and cellular responses in carrageenan pleurisy in leucopenic animals. A similar filtrate of bone marrow cells had no restorative properties. Previous results from elsewhere indicated a single pro-inflammatory activity on the fluid component of inflammation. We propose that LpIF has a more significant effect by influencing both components of inflammation and suggest that the discrepancy may be due to the different models used.
Immune inflammation in newly developing facsimile synovia.
The injection of air into the subcutaneous tissue of the back in rodents has previously been shown to induce a lining which closely resembles synovial lining tissue. Air pouches of different ages represent the developmental stages of such tissue. We have found that pouches of 1 day in age induced in animals previously sensitised with bovine serum albumin (BSA) respond with low numbers of infiltrating leucocytes and a small fluid exudate volume 4 h after challenge into the pouch with BSA. In contrast, 3- and 6-day-old pouch tissue when challenged with antigen responds with a greater influx of leucocytes and a larger fluid exudate. These findings suggest that the constituent make-up of the air pouch-lining tissue is important for the full expression of the inflammatory response.
The effects of levan on the acute inflammatory response.
The fructose polymer levan has been shown to affect the accumulation of leucocytes in inflammatory lesions. The present study has investigated the effect of levan on experimental pleurisy induced by carrageenan and calcium pyrophosphate dihydrate (CPPD) crystals. Total pleural polymorphonuclear leucocyte counts and exudate volumes were significantly reduced by levan treatment. We were, however, unable to detect any effect on mononuclear cell numbers. Furthermore, levan treatment significantly reduced peripheral leucocyte numbers. The counter-irritant activity of levan was compared with that of a known counter-irritant, dextran. The ability of levan to reduce pleural polymorph numbers and exudate volume could not be accounted for totally by counter-irritation. Studies using an in-vitro leucocyte adhesion assay system indicate that levan affects leucocyte adhesion to vascular endothelium.
Studies into the effects of the iron chelator desferrioxamine on the inflammatory process.
We have examined the effect of the iron chelating agent, desferrioxamine on different models of acute inflammation initiated by the irritants carrageenan or calcium pyrophosphate crystals. Depending on the dose of drug used and the time at which the lesion is examined both pro- and anti-inflammatory effects were observed as judged by measurement of leucocyte accumulation and oedema formation. The anti-inflammatory effects of desferrioxamine were supported by a decrease in concentration of the acute phase reactant alpha 1 glycoprotein. Our findings suggest that iron has a complicated relationship with the inflammatory process.
The role of plasma factors in the adherence of leucocytes to vascular endothelial cells.
Studies have been undertaken to search for humoral factors present in the plasma from animals undergoing inflammation which may promote specific cell types to adhere to vascular endothelium. We have tested both plasma from animals with "acute" pleural inflammation and animals with "chronic" carrageenan air pouch granulomata for the presence of leucocyte pro-adhesive activity. Plasma from animals with carrageenan pleurisy had augmented polymorph adhesive activity. This activity was absent in the plasma from animals with air pouch granulomata. No such pro-adhesive activity for mononuclear cells was detected in this plasma. We conclude that the initial influx of polymorphs during the early stages of inflammation may in part be due to systemic pro-adhesive factors. It is proposed that these factors in combination with chemotaxins released at the lesion site are responsible for the early dominance of polymorphs.
Increased inflammatory reactivity in newly formed lining tissue.
The air pouch has been shown to provide a convenient model for studying the behaviour of synovial lining tissue. Air pouches of different ages were used to study the reactivity of newly developing lining tissue towards irritants known to cause inflammation. Pouches of 1 day in age were relatively inert in their reactivity as judged by the number of cells and volume of the exudate accumulating in the pouch. In contrast, 3-day-old pouches responded to a much greater extent, and 6-day-old pouches were highly responsive with a further increase in cell numbers and fluid volume. The different responses of 1-, 3- and 6-day-old pouches could be explained by (a) developing vascularity of the pouch, (b) formation of an organised lining of phagocytic cells, or (c) an increasingly organised mechanical barrier that retains the irritant and products of the inflammatory response. These studies of air pouch lining development permit a dissection of those components necessary for inflammatory reactivity of a lining tissue and may help explain the sensitivity of synovium to chronic inflammation.