calcimycin and Arthritis

Phorbol 12-myristate 13-acetate (100 nM), a potent protein kinase C and macrophage activator, has a biphasic affect on 25(OH)D3-1 alpha-hydroxylase activity in synovial fluid macrophages from arthritis patients. After 5 h, 1 alpha, 25(OH)D3 synthesis fell from 5.2 +/- 0.1 to 1.6 +/- 0.2 pmol/h per 10(6) cells, however, after 24 h and 48 h, synthesis increased to 17.4 +/- 0.3 and 22.3 +/- 1.4 pmol/h per 10(6) cells, respectively. Although an independent short-term mechanism is suggested, protein kinase C may promote macrophage activation, thus increasing long-term 25(OH)D3-1 alpha-hydroxylase expression. Intracellular calcium and cAMP are unlikely to activate the enzyme, since 0.1 microM of the calcium ionophore, A23187, and 1 mM dibutyryl-cAMP inhibited synthesis by 87% and 79%, respectively, after 24 h.

Topics: Arthritis; Arthritis, Gouty; Arthritis, Rheumatoid; Bucladesine; Calcimycin; Calcitriol; Cells, Cultured; Dose-Response Relationship, Drug; Humans; Macrophages; Synovial Fluid; Tetradecanoylphorbol Acetate

Intraperitoneal and intra-articular (knee joint) injection of zymosan in the rat caused two phases of increased vascular permeability, a rapid increase (0.25-0.5 h) and a secondary increase (2-3 h) which was temporally associated with the onset of leukocyte infiltration. Intraperitoneal injection of zymosan led to a single peak of eicosanoid production (LTB4, C4, D4, E4 and 6-oxo-PGF1 alpha) which was maximal at 0.125-0.25 h. Intra-articular injection led to an initial peak of LTB4 production (maximal at 0.25 h) and a secondary peak of LTB4 and PGE2 production (maximal at 3 h). Oral administration of the 5-lipoxygenase (5-LO) inhibitors phenidone, BW A4C (N-hydroxy-N-[3-(3-phenoxyphenyl)-2-propenyl] acetamide), A63162 (N-hydroxy-N-[1-(4-(phenylmethoxy) phenyl)ethyl] acetamide and ICI 207 968 (2-[3-pyridylmethyl]-indazolinone inhibited LTB4 production in A23187 stimulation blood ex vivo. The glucocorticosteroid dexamethasone had no effect in this model. The initial phase of increased vascular permeability in the peritoneal cavity and LTB4 production was dose dependently inhibited by the 5-LO inhibitors phenidone, BW A4C, A63162, and ICI 207 968 but not by dexamethasone or colchicine. The initial phase of increased permeability in the joint was unaffected by phenidone, BW A4C, dexamethasone or colchicine. However the latter two drugs inhibited the later phase of increased permeability and leukocyte infiltration in the joint and peritoneal cavity. These results demonstrate that zymosan induces eicosanoid production in vivo but the relative importance of these mediators varies depending on the inflammatory site.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arthritis; Benzeneacetamides; Calcimycin; Colchicine; Dexamethasone; Dinoprostone; Disease Models, Animal; Hydroxamic Acids; Inflammation; Kinetics; Knee Joint; Leukocytes; Leukotriene B4; Leukotrienes; Lipoxygenase Inhibitors; Male; Peritonitis; Pyrazoles; Rats; Zymosan

An animal model, antigen-induced arthritis in the rabbit, was used to investigate the synthesis of arachidonic acid oxidation products (eicosanoids) by tissues of the knee joints during the initiation and early phase of this developing chronic destructive lesion. High concentrations of immunoreactive prostaglandin E2 and immunoreactive leukotriene B4 were found to be present in the synovial fluid in the early lesion. These levels rapidly declined, as did the ability of the infiltrating cells of the arthritic joint fluids to synthesize leukotriene B4. Articular cartilage and synovial lining were maintained for 24 hours in nonproliferative organ culture, and the synthesis of eicosanoids was measured by assay of the culture fluids. The synovial lining was the major source of eicosanoids. Synthesis of prostaglandin E2, prostacyclin, thromboxane A2, and leukotriene B4 by the arthritic synovial lining was low during the first few days, but reached maximal values between day 5 and day 15 of disease duration. Maximal eicosanoid production occurred around the time that damage to articular cartilage and bone has been reported to occur, though it is not certain that these two events are linked. It was demonstrated that, in chronic lesions, the arthritic synovial lining was still producing elevated levels of eicosanoids compared with levels in the control tissue.

Topics: Animals; Arachidonic Acids; Arthritis; Arthritis, Experimental; Calcimycin; Cartilage, Articular; Cyclooxygenase Inhibitors; Dinoprostone; Epoprostenol; Joints; Leukotriene B4; Lipoxygenase Inhibitors; Male; Organ Culture Techniques; Oxidation-Reduction; Prostaglandins E; Rabbits; Synovial Fluid; Synovial Membrane; Thromboxane A2