A. R. Moore

The local modulation of vascular permeability by endothelial cell derived products

Abstract— Endothelin has been shown to suppress increased vascular permeability in the rat at doses of 0.01 pmol. The agonists used were nitric oxide and nitroprusside, which have the same activity as endothelial‐derived relaxing factor. Histamine, 5‐hydroxytryptamine, platelet activating factor and carrageenan were the other agonists used. It is proposed that endothelin and EDRF act as local hormones produced by endothelial cells to control local vascular permeability.

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 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.

Comparison of endothelin-1 and-3 on models of inflammation

Yanagisawa et al. [1] isolated a peptide from cultured porcine aort ic endothelial cells which they termed endothelin (ET). Structural studies of ET has revealed that it is composed of a 21 amino acid chain with two intrachain disulphide bonds. In vitro ET has been shown to elicit potent vasoconstrictor activity in numerous blood vessel preparations including: rat aor ta and porcine coronary artery, l=urthermore, when ET is injected intravenously into rats it causes a sustained prcssor effect. Hence it is possible that ET may be important in the regulation of systemic blood pressure and local blood flow. The contractile effects of ET are dependent on cxtracellular calcium ions and in the presence of Ca 2~ channel blocker, nicardipine, these responses can be at tenuated. Yanagisawa c ta l . [1] therefore suggested that ET potentiates the Ca 2 t influx through the d ihydropyr idine sensitive Ca 2 + channels. We have recently examined the contractile ability of ET and showed that this peptide could be a potential ant i inf lammatory agent because of its inhibi tory effects on mediators of increased vascular permeabil i ty [2]. ET has been derived from various species, but shows different contractile potencies. Consequently, ET was classified into types 1, 2 and 3. In the present communicat ion, we have compared the activities of ET-I with ET-3 on 1) increased

Indomethacin and cartilage breakdown

Jhamandas, K., Yaksh, T. L., Go, V. L. W. (1984) Acuteandchronic morphine modifies the in vivo release of methionine enkephalinlike immunoreactivity from the cat spinal cord and brain. Brain Res. 297: 91-103 Marshall, H., Porteus, C., McMillan, I., MacPherson, S. G., Nimmo, W. S. (1985) Relief of pain by infusion of morphine after operation: does tolerance develop? Br. Med. J. 291: 19-21 Olley, J. E., McLean, A. J.. Boura. A. L. A. (1986) Pharmacokinetics COI. 35: 3415-3417 of buprenorphine in normal volunteers and orthopaedic patients. Proceedings of the 2nd International Symposium: The Pain Clinic, Lille Reid, R. L., Hoff, J. D.. Yen, S. S. C., Li, C. H. (1981) Effects of exogenous b-endorphin on pituitary hormone secretion and its disappearance rate in normal human subjects. J. Clin. Endocrinol. Metab. 52: 1179-1 184 Tiong, G. K. L., Olley, J. E. (1987) An enzyme-linked immunoassay for buprenorphine. Clin. Exp. Pharmacol. Physiol. (Suppl) 11: 74 Villiger, J. W., Boas, R. A,, Taylor, K. M. (1981) A radioreceptor assay for opiate drugs in human cerebrospinal Ruid and plasma. Life Sci. 29: 229-233

Polyarthritis and the air pouch reaction: dissimilarity of adjuvant and collagen models

The formation of an air pouch in the subcutaneous tissues of a rat previously inoculated intradermally with Freunds mycobacterial adjuvant for the induction of arthritis, provokes a marked but transient inflammatory reaction in the cavity lining of the pouch. The dependence of this reaction on arthritis development was investigated. It was found that rats inoculated with mycobacterial adjuvant by subcutaneous or intraperitoneal injection failed to produce either a pouch reaction or develop arthritis. Intradermal injections of carrageenan, mycobacteria (M. tuberculosis in saline), Freunds incomplete adjuvant alone or containing Salmonella typhimurium lipopolysaccharide and Bordetella pertussis organisms or mycobacterial adjuvant containing egg albumin were also ineffective. Intradermal injections of type II collagen in Freunds incomplete adjuvant did induce arthritis but no pouch reaction; however, this could be elicited after direct challenge with antigen. Pretreatment of rats intraperitoneally with saline suspensions of mycobacteria or a moderate dose of cyclophosphamide prevented both the pouch reaction and arthritis developing to intradermal mycobacterial adjuvant. Pretreatment of rats with mycobacteria was without effect on type II collagen-induced arthritis. From the results of this study it would appear that the air pouch reaction and arthritis induced by adjuvant are directly associated. The inability of collagen to induce a similar reaction demonstrates a fundamental dissimilarity with mycobacterial adjuvant in its mechanism of production of arthritis.

The effect of indomethacin on cartilage breakdown

The effects of recombinant interleukin-1α (rIL-1α) and indomethacin on the glycosaminoglycan (GAG) content of rat femoral head cartilage (FHC) were studiedin vitro. Net GAG loss was observed from cartilage cultured in the presence of indomethacin plus rIL-1α. Indomethacin and rIL-1α alone caused no net loss of GAG from cartilage unless the cartilage was cultured in the presence of fibroblasts.

Significance of connective tissue proliferation in the breakdown of cartilage: a novel in vivo model.

The implantation of homologous femoral head cartilage in subcutaneous tissues of random bred Wistar rats results in both subchondral and articular surfaces becoming overlaid by an adherent granulation tissue comprising predominantly fibroblast-like cells. The response of the tissue to cartilage encapsulated with cotton fibres was also similar but erosions, mainly subchondral, were more evident and proteoglycan loss markedly greater. The connective tissue response to cotton was the progressive formation of a foreign body granuloma comprising mononuclear cells, multinucleated giant cells, and fibroblasts with very few polymorphonuclear leucocytes.

A hypothesis for the mode of action of anti-rheumatic drugs in a model of cartilage destruction

We have been using as a model rats and mice with air pouches which develop lining cells closely resembling synovium (Edwards et al 1982; Sedgwick et al 1983). These pouches when sufficiently mature, i.e. 6 days, will respond to a variety of stimuli both immune and non‐immune with long lasting exudates containing many migrated leucocytes (Sedgwick et al 1983, 1984a).

Adjuvant polyarthritis and the pseudosynovitis

The cavity lining of a six day old subcutaneous air pouch in rats resembles normal synovium in morphology and responds in a comparable manner during development of polyarthritis. The ability of newly formed pouches (one and two days old) to respond similiarly to polyarthritogen was examined here. Positive macro and microscopic changes similiar to those seen in the six day old pouch were observed in rats previously inoculated with adjuvant. The intensity of some of these changes varied between pouches. The results of this study indicate that the adjuvant induced air pouch reaction does not depend on the presence of synovial-like lining for its production.