l-663536 and Acute-Disease

Respiratory infection with Francisella tularensis (Ft) is characterized by a muted, acute host response, followed by sepsis-like syndrome that results in death. Infection with Ft establishes a principally anti-inflammatory environment that subverts host-cell death programs to facilitate pathogen replication. Although the role of cytokines has been explored extensively, the role of eicosanoids in tularemia pathogenesis is not fully understood. Given that lipoxin A

Topics: Acute Disease; Animals; Apoptosis; Arachidonate 5-Lipoxygenase; Bone Marrow Cells; Cell Death; Chemokines; Chronic Disease; Dinoprostone; Disease Susceptibility; Down-Regulation; Francisella tularensis; Immunity; Indoles; Inflammation Mediators; Leukotriene B4; Lipoxins; Macrophages; Metabolome; Mice, Inbred C57BL; Organ Specificity; Respiratory Tract Infections; Tularemia

Hymenoptera stings are quite common and can cause inflammatory reactions (in nonallergic individuals) or serious reactions (in allergic individuals). Hymenoptera venom contains histamine, vasoactive kinins, serotonin, phospholipase A, phospholipase B, hyaluronidase, antigen 5 and mastoparans. Some of these substances are responsible for local pain, as well as for activation of complement and endothelial cells. Polybia paulista is a wasp typically found in the state of São Paulo, Brazil. In the present study, we evaluated inflammatory reactions in the peritoneal cavities of rats injected with P. paulista venom (PPV). We evaluated leukocyte recruitment and edema formation at the site of inflammation. After i.p. inoculation with PPV, there was dose-dependent and time-dependent recruitment of neutrophils, eosinophils and mononuclear cells. At 4 to 48 h after stimulus, administration of MK 886, a leukotriene synthesis inhibitor, completely abolished granulocyte recruitment to the peritoneal cavity. Therefore, leukotrienes seem to be the primary mediators of PPV-induced neutrophil and eosinophil recruitment. Inoculation with PPV also induced protein extravasation into the peritoneal cavity. This phenomenon was not inhibited by treatment with MK 886 or indomethacin (a prostaglandin synthesis inhibitor), demonstrating that neither leukotrienes nor prostaglandins are involved in this inflammatory reaction. However, edema formation was significantly inhibited by treatment with pyrilamine, indicating that the histamine H1 receptor plays a critical role in PPV-induced formation of acute edema.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cimetidine; Dose-Response Relationship, Drug; Edema; Eosinophils; Histamine H1 Antagonists; Histamine H2 Antagonists; Indoles; Indomethacin; Leukocytes; Male; Neutrophil Infiltration; Peritoneal Cavity; Pyrilamine; Rats; Rats, Wistar; Wasp Venoms

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 present study was designed to determine the role of leukotrienes in aspirin-induced acute gastric mucosal injury in rats. We examined the effects of aspirin, indomethacin, and sodium salicylate on gastric mucosal injury, and on eicosanoid synthesis and content. Aspirin, indomethacin, and acidified salicylate caused significant mucosal injury, while salicylate at pH 7 did not induce significant injury. Aspirin and indomethacin significantly reduced mucosal prostaglandin synthesis and content. No significant changes in mucosal leukotriene C4 synthesis and content were observed. There were no correlations between changes in mucosal leukotriene B4 synthesis and the extent of mucosal injury. We also evaluated the effects of MK-571 (a leukotriene D4 receptor antagonist) and MK-886 (a leukotriene biosynthesis inhibitor) on aspirin-induced gastric mucosal injury. Neither MK-571 nor MK-886 could reduce the mucosal lesions induced by aspirin. These findings suggest that leukotrienes are not involved in aspirin-induced acute gastric mucosal injury in rats.

Topics: Acute Disease; Animals; Aspirin; Gastric Mucosa; Indoles; Indomethacin; Leukotriene Antagonists; Leukotrienes; Male; Propionates; Quinolines; Rats; Rats, Inbred Strains; Sodium Salicylate; SRS-A