Alveolar socket healing in 5-lipoxygenase knockout aged female mice treated or not with high dose of zoledronic acid.

This study investigated the role 5-lypoxigenase (5-LO) on alveolar socket healing in aged female mice treated with zoledronic acid (ZL). Forty 129/Sv female mice (64-68 weeks old), 20 wild type (WT) and 20 5-LO knockout (5LOKO) were equally distributed according to ZL treatment: WT Control, WT ZL, 5LOKO Control, and 5LOKO ZL. ZL groups were treated with an intraperitoneal injection of 250 µg/Kg of ZL, while controls were treated with saline. Treatments were administered once a week, starting four weeks before surgery for tooth extraction and until 7 and 21 days post-surgery. Mice were euthanized for a comprehensive microscopic analysis (microCT, histomorphometry and immunohistochemistry). WT ZL mice presented intense inflammatory infiltrate (7 days), delayed bone formation (21 days), reduced collagenous matrix quality, and a deficiency in Runx-2 + , TRAP + , and macrophages as compared to controls. 5LOKO ZL animals presented decreased number of Runx-2 + cells in comparison to 5LOKO Control at 7 days, but no major changes in bone healing as compared to WT or 5LOKO mice at 21 days. The knockout of 5LO favored intramembranous bone healing in aged female mice, with a direct impact on inflammatory response and bone metabolism on the development of ONJ-like lesions.

5-Lipoxygenase-deficient mice infected with Borrelia burgdorferi develop persistent arthritis.

The enzyme 5-lipoxygenase (5-LO) catalyzes the conversion of arachidonic acid into the leukotrienes, which are critical regulators of inflammation and inflammatory diseases, such as asthma and arthritis. Although leukotrienes are present in the synovial fluid of Lyme disease patients, their role in the development of Lyme arthritis has not been determined. In the current study, we used a murine model of Lyme arthritis to investigate the role 5-LO products might have in the development of this inflammatory disease. After infection of Lyme arthritis-susceptible C3H/HeJ mice with Borrelia burgdorferi, mRNA expression of 5-LO and 5-LO-activating protein was induced in the joints, and the 5-LO product leukotriene B(4) was produced. Using C3H 5-LO-deficient mice, we demonstrated that 5-LO activity was not necessary for the induction of Lyme arthritis, but that its deficiency resulted in earlier joint swelling and an inability to resolve arthritis as demonstrated by sustained arthritis pathology through day 60 postinfection. Although production of anti-Borrelia IgG was decreased in 5-LO-deficient mice, bacterial clearance from the joints was unaffected. Phagocytosis of B. burgdorferi and efferocytosis of apoptotic neutrophils was defective in macrophages from 5-LO-deficient mice, and uptake of opsonized spirochetes by neutrophils was reduced. These results demonstrate that products of the 5-LO metabolic pathway are not required for the development of disease in all models of arthritis and that caution should be used when targeting 5-LO as therapy for inflammatory diseases.

5-Lipoxygenase as a putative link between cardiovascular and psychiatric disorders.

There is evidence of an association between depression and anxiety and cardio- cerebro-vascular conditions, but the mechanisms of this association are unknown. Here we review a possible role for the 5-lipoxygenase (5-LOX) pathway. 5-LOX is an enzyme that, in association with 5-LOX-activating protein (FLAP), leads to the synthesis of leukotrienes from omega-6 arachidonic acid. Production of active leukotrienes can be reduced by dietary omega-3 fatty acids, which also are beneficial in cardiac and psychiatric (e.g., depression) pathologies. Human 5-LOX and FLAP gene polymorphisms are a risk factor in atherosclerosis and cardio-cerebro-vascular pathologies; an overactive 5-LOX pathway is found in these diseases. Studies with 5-LOX-deficient transgenic mice suggest that 5-LOX activity may contribute to anxiety- and depression-like behaviors. Future research should characterize the role of the 5-LOX pathway in comorbid cardio-cerebro-vascular and psychiatric disorders and in the therapeutic actions of dietary omega-3 fatty acids.

A novel role of cysteinyl leukotrienes to promote dendritic cell activation in the antigen-induced immune responses in the lung.

Although the critical role of cysteinyl leukotrienes (cysLTs) in the inflammation, especially eosinophilic lung inflammation, in asthma has been well documented, their role in the early stage of Ag-specific immune response has not been completely clarified. In the present study, with a mouse model of asthma and in vitro studies we demonstrated that cysLTs potentiated dendritic cell (DC) functions such as Ag-presenting capacity and cytokine production. The cysLT-1 receptor antagonist (LTRA) strongly suppressed the activation of these DC functions and led to inhibition of subsequent not only Th2, but also Th1, responses in the early stage of immune response. Moreover, treatment with LTRA during the early stage of the immune response potently suppressed the development of Ag inhalation-induced eosinophilic airway inflammation, mucus production, and airway hyper-reactivity in vivo. Treatment with LTRA significantly increased PGE(2) production in the lung, and treatment with the cyclooxygenase inhibitor indomethacin abolished LTRA's suppressive effect on DCs and deteriorated the Th2 and Th1 responses and airway inflammation. With in vitro studies, we also confirmed that cysLTs production by DCs increased with LPS stimulation, and that LTRA directly suppressed the alloantigen-presenting capacity of DCs. These results suggested that cysLTs potentiate DC functions both in vivo and in vitro, and that LTRA could be beneficial to suppress the initial immune response in many immune-mediated disorders beyond asthma.