Leukotrienes are powerful inflammatory lipid mediators derived from the 5-lipoxygenase (5-LO) cascade of arachidonic acid. Recent clinical, population genetic, cell biological, and mouse studies indicate participation of the 5-LO pathway in atherogenesis and arterial wall remodeling. 5-LO is expressed by leukocytes including blood monocytes, tissue macrophages, dendritic cells, neutrophils, and mast cells.
Biol Pharmacolgy Bull. 2011. Leukotrienes in nociceptive pathway and neuropathic/inflammatory pain. The purpose of this review is to summarize the recent studies examining the expression of leukotrienes (LTs) and their receptors in nociceptive pathways, and their crucial roles in pathological pain conditions. LTs belong to a large family of lipid mediators, termed eicosanoids, which are derived from arachidonic acids and released from the cell membrane by phospholipases. LTs are known to be important factors in a variety of local and systemic diseases and allergic/inflammatory diseases. We examined whether LTs were implicated in neuropathic pain following peripheral nerve injury. Using the SNI model in rats, we investigated the expression of LT synthases and receptors mRNAs in the spinal cord and the roles on the pain behaviors. We found the expression of 5-lipoxygenase (5-LO), FLAP and the cysteinyl leukotrienes (CysLT1) mRNAs in spinal microglia, LTA4h and LTC4s mRNAs in both spinal neurons and microglia, and BLT1 mRNA in spinal neurons. Administration of the 5-LO inhibitor or the receptor antagonists suppressed mechanical allodynia. Our findings suggest that the increase of LT synthesis in spinal microglia produced via p38 mitogen-activated protein kinase (MAPK) plays a role in the generation of neuropathic pain. We also examined the expression and roles on pain behaviors of LT receptors in the dorsal root ganglion (DRG) using a peripheral inflammation model. The data indicate CysLT2 expressed in DRG neurons may play a role as a modulator of P2X3, and contribute to the potentiation of the neuronal activity following peripheral inflammation. This review summarizes the hypothesis that LTs might work in the spinal cord and primary afferent in pathological pain conditions.
Natural Herbs and supplements
that Influence leukotriene formation, along with food
There are many herbs and supplements that influence the formation. Diet has a strong influence, for instance fish oils are likely to reduce inflammation partly through reduction of leukotriene formation. Many herbs could be helpful such as boswellia, pygeum and butterbur.
Leukotriene Inhibitor or
modifier side effects, safety
Long term side effects with the use of a leukotriene inhibitor drug are still being evaluated.
Leukotrienes and allergic rhinitis
Leukotrienes are synthesized via 5-lipoxygenase metabolism of arachidonic acid by mast cells and basophils during the early-phase response to antigen and by eosinophils and macrophages during the late phase. The Leukotriene levels in nasal secretions are elevated after short-term allergen instillation and in allergy season in patients with allergic rhinitis. These lipid mediators act locally and systemically by interacting with receptors, particularly the cysLT1 receptor, on target cells. Evidence derived from topical application of Leukotrienes in the nose and from the effects of Leukotrienes indicates that Leukotrienes contribute to nasal mucous secretion, congestion, and inflammation. Leukotrienes promote allergic inflammation by enhancing immune responses and the production, adhesion, migration, and survival of inflammatory cells such as eosinophils. They also increase the generation of an array of other proinflammatory mediators, such as cytokines, which in turn increase the production of and receptors for Leukotrienes. Clinical trials have demonstrated that Leukotrienes have significant but modest efficacy as single agents but additive efficacy when used with other classes of agents.
Allergic Rhinitis treatment
Potential approaches to the treatment of allergic rhinitis are the avoidance of allergens and medication with chromone compounds, antihistaminics and glucocorticosteroids. The sole causally effective treatment is specific immunotherapy. Leukotriene receptor antagonists, anti-IgE antibodies and monoclonal CD-4-molecules, as also soluble cytokine receptors are potential therapeutic options, the value of which currently remains unknown.
Nat Commun. 2015. Leukotriene C4 is the major trigger of stress-induced oxidative DNA damage. Endoplasmic reticulum (ER) stress and major chemotherapeutic agents damage DNA by generating reactive oxygen species (ROS). Here we show that ER stress and chemotherapy induce leukotriene C4 (LTC4) biosynthesis by transcriptionally upregulating and activating the enzyme microsomal glutathione-S-transferase 2 (MGST2) in cells of non-haematopoietic lineage. LTC4 inhibitors, commonly used for asthma, could find broad clinical use in major human pathologies associated with ER stress-activated NOX4.
A leukotriene modifier is a drug often used for the treatment of asthma. A leukotriene modifier blocks the body's production of leukotrienes and hence helps to prevent inflammation to help keep airways open. Two types of leukotriene modifier - based medications have been developed: leukotriene inhibitors that interfere with the actual synthesis of leukotrienes, and leukotriene antagonists that block the action of leukotrienes by blocking leukotriene receptor sites.
Two leukotrienes inhibitors are available: once a day Singulair and twice a day Accolate. These leukotriene inhibitor drugs are sold in pill form. They often begin to work within 1 or 2 days. Singulair is also indicated for children in an easy-to-take chewable form or powder granules, once a day. One added bonus is that allergies cause leukotrienes to be active in other parts of the body, leading to allergy symptoms, hives and/or sinusitis. Singulair, in fact has been approved for treatment of allergic rhinitis. Leukotriene inhibitors are used for mild to severe asthma and mild asthma induced by aspirin and exercise.
Anti leukotriene drugs, i.e. leukotriene receptor antagonists and synthesis inhibitors, are a new class of anti-inflammatory drugs that have shown clinical efficacy in the management of asthma. Could antileukotriene drugs be useful in urticaria? Montelukast might be effective in chronic urticaria associated with aspirin or food additive hypersensitivity or with autoreactivity to intradermal serum injection when taken with an antihistamine but not in moderate chronic idiopathic urticaria. Evidence for the effectiveness of zafirlukast and the 5-lipoxygenase inhibitor, zileuton, in chronic urticaria is mainly anecdotal. In addition, there is anecdotal evidence of effectiveness of antileukotrienes in primary cold urticaria, delayed pressure urticaria and dermographism. No evidence exists for other physical urticarias, including cholinergic, solar and aquagenic urticarias, vibratory angio-oedema, and exercise-induced anaphylaxis.
Changes during pregnancy
Pregnancy is accompanied by major immunological changes to maintain both tolerance for the fetus and immune competence. Leukotriene-related diseases (e.g., asthma, allergic rhinitis) change during pregnancy. 5-Lipoxygenase product formation in stimulated blood of pregnant women is significantly higher than in non-pregnant females. Although a pregnancy-related increase in neutrophil and monocyte counts may explain these observations, granulocytes of pregnant donors have lower leukotriene-synthetic capacities. On the other hand, granulocytes from non-pregnant woman produced more leukotrienes when resuspended in plasma of pregnant women than of non-pregnant females.