l-663536 and Arthritis

Leukotrienes, the 5-lipoxygenase (5LO) products of arachidonic acid metabolism, have many proinflammatory actions that have been implicated in the pathogenesis of a variety of inflammatory diseases. To investigate the role of LTs in autoimmune disease, we generated an MRL-lpr/lpr mouse line with a targeted disruption of the 5lo gene. MRL-lpr/lpr mice spontaneously develop autoimmune disease that has many features resembling human systemic lupus erythematosus, including sex-related survival differences; female MRL-lpr/lpr mice experience significant early mortality compared with males. Unexpectedly, we found that mortality was accelerated in male 5LO-deficient MRL-lpr/lpr mice compared with male wild-type MRL-lpr/lpr animals. In contrast, the 5lo mutation had no effect on survival in females. Mortality was also accelerated in male MRL-lpr/lpr mice that were treated chronically with a pharmacological inhibitor of LT synthesis. Furthermore, LT-dependent inflammatory responses are enhanced in male MRL-lpr/lpr mice compared with females, and the 5lo mutation has greater impact on these responses in males. Because immune complex-mediated glomerulonephritis is the major cause of death in MRL-lpr/lpr mice and has been related to arachidonic acid metabolites, we also assessed kidney function and histopathology. In male MRL-lpr/lpr mice, renal plasma flow was significantly reduced in the 5lo-/- compared with the 5lo+/+ group, although there were no differences in the severity of renal histopathology, lymphoid hyperplasia, or arthritis between the groups. These findings suggest that the presence of a functional 5lo gene confers a survival advantage on male MRL-lpr/lpr mice and that, when 5LO function is inhibited, either genetically or pharmacologically, this advantage is abolished.

Topics: Acute Disease; Animals; Arachidonate 5-Lipoxygenase; Arthritis; Autoantibodies; Female; Glomerular Filtration Rate; Indoles; Kidney; Lipoxygenase Inhibitors; Lupus Erythematosus, Systemic; Lymphoproliferative Disorders; Male; Mice; Mice, Inbred MRL lpr; Mice, Knockout; Renal Circulation; Sex Factors

The participation of lipid mediators and tumor necrosis factor (TNF) on an experimental model of immune-complex arthritis was investigated. Male Wistar rats received intraarticular injection of rabbit antibodies to bovine serum albumin into the knee joint followed by i.v. injection of the antigen. The levels of eicosanoids and TNF released into the synovial exudates were then assessed using ELISA and the L929 lytic cell assay, respectively. Increase in the levels of LTB4, TXB2 and PGE2 were detected 5 min, 5 min, and 6 h after arthritis induction, respectively. Pretreatment with the PAF receptor antagonist WEB 2170 decreased the levels of PGE2 and increased those of LTB4, without altering TXB2 levels. Increase in the levels of TNF was detected at 3 h of arthritis. Pretreatment with either the cycloxygenase inhibitor indomethacin or the 5-lipoxygenase inhibitor L-663,536 had no effect on TNF levels. Pretreatment with WEB 2170 significantly decreased TNF levels. These results are the first demonstration of eicosanoids and TNF release in immune-complex arthritis. The data also suggest that PAF had both a positive and negative modulatory role on the release of PGE2 and LTB4, respectively. Moreover, TNF release into the synovial exudate did not depend on eicosanoids whereas platelet activating factor (PAF) appeared to mediate the release of this cytokine in the model.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Arthus Reaction; Cattle; Dinoprostone; Eicosanoids; Indoles; Indomethacin; Injections, Intra-Articular; Leukotriene B4; Lipoxygenase Inhibitors; Male; Platelet Activating Factor; Rabbits; Rats; Rats, Wistar; Synovial Fluid; Thromboxane B2; Tumor Necrosis Factor-alpha

To determine the role of 5-LO regulation of IL-1 in synovial tissues, we examined the effects of 5-LO inhibitors compared with standard IL-1 synthesis inhibitors on IL-1 production by human synovial tissue explants from patients with inflammatory arthropathies. MK886, L-656,224, PF-5901, and tepoxalin all inhibited IL-1 production in concentrations up to 10 microM, whereas other 5-LO inhibitors (ICI-211,965, zileuton), as well as IL-1 synthesis inhibitors (IX-207,887, tenidap), were inactive. LT products, thus regulate IL-1 production and inhibition thereof is one strategy for inhibiting this cytokine.

Topics: Arthritis; Benzofurans; Culture Media; Culture Techniques; Humans; Hydrocortisone; Indoles; Interleukin-1; Leukotriene Antagonists; Lipoxygenase Inhibitors; Quinolines; Synovial Membrane

Studies in pigs and rats were undertaken to explore further the role of leukotrienes following administration of NSAIDs on the development of gastrointestinal damage. Increased leukotriene C4 production occurred in the gastric circulation in the early stages after administration of a single dose of indomethacin (10 mg/kg i.g.) to pigs. Gastric and intestinal mucosal lesions by NSAIDs were prevented by both prior (2-5 h)+ 0.25 or 0h oral dosing of the 5-lipoxygenase inhibitor, MK-886, but not when only one of these doses was given. These results show the importance of enhanced peptidoleukotriene production in relation to microvascular damage from cyclooxygenase inhibition by NSAIDs.

Topics: Administration, Oral; Animals; Arthritis; Aspirin; Female; Gastric Mucosa; Indoles; Indomethacin; Injections, Subcutaneous; Intestinal Mucosa; Leukotriene Antagonists; Leukotriene C4; Lipoxygenase Inhibitors; Rats; Rats, Inbred Lew; Stomach; Stomach Ulcer; Swine