15-hydroxy-5-8-11-13-eicosatetraenoic-acid and Arthritis

Topics: Animals; Arthritis; Arthritis, Experimental; Carrageenan; Cell Adhesion; Cell Division; Cells, Cultured; Dogs; Hydroxyeicosatetraenoic Acids; In Vitro Techniques; Leukotriene B4; Synovial Fluid

The pathophysiologic significance of leukotriene B4 (LTB4) in arthritis was studied in dogs by unilateral intraarticular deposition of 15-hydroxy-eicosatetraenoic acid (15-HETE), an endogenous inhibitor of the formation and the effects of LTB4, in bilateral carrageenan-induced gonarthritis. LTB4 in synovial fluid was selectively inhibited in 15-HETE treated joints, the formation of prostaglandin E2 (PGE2) being largely unaffected. The clinical symptoms, intraarticular pressure, and extractable synovial fluid volume were reduced in treated joints. No effect could be discerned regarding blood flow in the synovial membrane, capsule, or juxta-articular bone as measured by tracer microspheres; and no effect on bone metabolism was found as judged by 99mTc-diphosphonate uptake. Thus, inhibition of LTB4 reduces joint exudation, but does not seem to interfere with changes in juxta-articular hemodynamics or bone metabolism following synovial inflammation.

Topics: Animals; Arthritis; Carrageenan; Dinoprostone; Dogs; Hydroxyeicosatetraenoic Acids; Knee Joint; Leukotriene B4; Pressure; Regional Blood Flow; Synovial Fluid; Synovitis

Synovial fluid cells obtained from a carrageenan-induced chronic arthritis in the juvenile dog knee were allowed to adhere and proliferate in culture flasks. After twelve days secondary cultures were made and either 10(-8)M leukotriene B4 (LTB4), 25 microM 15-hydroxy-eicosatetraenoic acid (15-HETE), or both, were added and the cells were cultured for another 6 days. LTB4 is generated via the 5-lipoxygenase pathway of arachidonic acid metabolism and stimulates a number of phagocyte functions. Compared to control cells LTB4 increased proliferation in 9 out of 10 cell cultures (p less than 0.05). The 15-lipoxygenase product, 15-HETE, is not proinflammatory and is an endogenous inhibitor of 5-lipoxygenase. Addition of 15-HETE decreased proliferation of cell cultures by 23% (p less than 0.01). It is speculated that LTB4 in addition to its effect on phagocytes may play a role in synovial hyperproliferation observed in arthritis.

Topics: Animals; Arthritis; Arthritis, Experimental; Cell Adhesion; Cell Division; Cells, Cultured; Dogs; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Synovial Fluid

15-Hydroxy-eicosatetraenoic acid (15-HETE), a product of arachidonic acid, has no proinflammatory capacity, but can inhibit the formation and the chemotactic response of neutrophils to leukotriene B4 (LTB4), a potent mediator of inflammation. The purpose of the present study was to determine whether intraarticular administration of 15-HETE in carrageenan-induced acute arthritis might decrease the levels of LTB4 in synovial fluid and modify the arthritis. A bilateral acute knee joint arthritis was established in 7 dogs by intraarticular injections of carrageenan every third day. To the right joints, 15-HETE was administered both concomitantly with the carrageenan injections and continuously via an osmotic pump. In samples of synovial fluid obtained on day 0, 3 and 10 PGE2 and LTB4 were determined using reversed phase high performance liquid chromatography combined with radioimmunoassays and neutrophil chemokinesis. In the presence of 15-HETE the clinical severity of arthritis was significantly reduced and the volume of synovial effusate was decreased on an average by 42%. Furthermore, the relative number of neutrophils in histological sections of synovial tissue was decreased by 58%. Intraarticular caragheenan injections induced LTB4 formation, and maximum levels were obtained on day 3 (279.2 +/- 148.2 pg/joint). PGE2 was also present on day 3, but maximum levels were detected on day 10 (9.5 +/- 4.8 ng/joint). In joints injected with both carragheenan and 15-HETE the levels of LTB4 on days 3 and 10 were inhibited by 90% and 83%, respectively. For PGE2 a small but insignificant decrease was found on both day 3 and on day 10. These results show that LTB4 may be an important mediator of acute arthritis induced by carragheenan in dogs, and that intraarticular administration of 15-HETE can modify this arthritis by inhibiting LTB4 formation.

Topics: Animals; Arthritis; Carrageenan; Chemotaxis, Leukocyte; Chromatography, High Pressure Liquid; Dinoprostone; Dogs; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Neutrophils; Radioimmunoassay; Synovial Fluid

A non-suppurative chronic arthritis was induced in the juvenile dog knee by intra-articular instillations with Carrageenan. Lipoxygenase products of arachidonic acid were separated from synovial fluid by reversed-phase high-performance liquid chromatography (RP-HPLC). After ten weeks we observed an accumulation of leukotriene B4 (LTB4) in synovial fluid in five out of six experimental knees (0.94 to 5.5 ng/ml), as judged by integrated optical density. Biological activity of LTB4 was confirmed by chemokinesis. LTB4 was not detected in control knees. The 15-lipoxygenase products, 15-hydroxyeicosatetraenoic acid (15-HETE) and 13-hydroxy-9,11-octadecadienoic acid (13-HODD), being inhibitors of 5-lipoxygenase, were found in relatively high levels in the control knees compared to the arthritic knees. The results denote LTB4 as a pro-inflammatory local mediator during carrageenan-induced arthritis; possibly, the decreased levels of 15-HETE and 13-HODD in the arthritic knees may have a regulatory function, thus facilitating LTB4 generation.

Topics: Animals; Arthritis; Carrageenan; Chemotaxis, Leukocyte; Chromatography, High Pressure Liquid; Disease Models, Animal; Dogs; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Linoleic Acids; Lipoxygenase; Synovial Fluid