leukotriene-a4 and Hypersensitivity

Metabolites of arachidonic acid have important regulatory functions within several areas of concern to the otolaryngologist. Prostaglandins, composing one group, are involved in smooth-muscle contraction, regulation of renal glomerular blood flow, and in the modulation of immune and allergic responses, inflammation, fever, pain, and tumor growth. A second group, the leukotrienes, may be even more important than prostaglandins in allergy and inflammation. The elusive slow-reacting substance of anaphylaxis belongs in this group. Two other metabolites, thromboxane and prostacyclin, seem to be critical in hemostasis and the metastatic spread of tumors.

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Arachidonic Acid; Arachidonic Acids; Aspirin; Blood Platelets; Cyclooxygenase Inhibitors; Epoprostenol; Humans; Hypersensitivity; Indomethacin; Inflammation; Leukotriene A4; Lipoxygenase; Neoplasms; Phospholipases; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Thromboxanes

The family of eicasanoids, biologically active metabolites of polyunsaturated C20 fatty acids such as arachidonic acid, has recently been enlarged by the recognition of a new biosynthetic pathway leading to the leukotrienes, including the compounds described two decades ago as 'slow reacting substances'. These biologically potent substances are involved in regulation of the immune response and also as mediators in various disease states. This account presents a brief history of this field, an overview of the biological relevance of leukotrienes, and a discussion of the investigations which led to the clarification of the molecular structures, pathway of biosynthesis and total chemical synthesis of the leukotrienes, including leukotrienes A, B, C, D and E (LTA-LTE). As a result of the synthetic work these rare substances are available for the first time in pure form and in quantities sufficient for biological and medical studies. Also reviewed are recent discoveries with regard to the development of inhibitors of leukotriene biosynthesis and anti-leukotrienes.

Topics: Animals; Arachidonic Acids; Asthma; Autacoids; Chemical Phenomena; Chemistry; Humans; Hydroxyeicosatetraenoic Acids; Hypersensitivity; Leukotriene A4; Leukotriene B4; Leukotriene E4; Leukotrienes; Lipoxygenase Inhibitors; Macrophages; Mast Cells; Molecular Conformation; Neutrophils; SRS-A; Stereoisomerism; Structure-Activity Relationship

Immunological and non-immunological injury induce as a result of the action of the enzyme lipoxygenase the release of a series of arachidonic acid metabolites known as leukotrienes. The leukotrienes play an important role in allergic and inflammatory disease. Leukotrienes C4, D4 and E4 which recently have been recognized as constituents of the allergic mediator slow reacting substance of anaphylaxis (SRS-A) induce powerful bronchoconstriction, plasma exudation and weal and flare responses. Leukotriene B4 is involved in the regulation of chemotaxis, chemokinesis and other aspects of both cellular and vascular inflammation. The development of specific lipoxygenase inhibitors may lead to a new class of drugs for the treatment of bronchial asthma and chronic inflammatory diseases.

Topics: Arachidonic Acids; Asthma; Biotransformation; Chemotaxis, Leukocyte; Humans; Hypersensitivity; Inflammation; Leukotriene A4; Leukotriene B4; Leukotriene E4; Lipoxygenase; Lipoxygenase Inhibitors; Neutrophils; SRS-A

Topics: Animals; Arachidonic Acids; Autacoids; Guinea Pigs; Humans; Hypersensitivity; Inflammation; Leukotriene A4; Leukotriene B4; Molecular Conformation; Neutrophils; Rats; SRS-A; Structure-Activity Relationship; Terminology as Topic

We investigated the effects of cysteinyl-leukotriene (cysLT) type 1 receptor antagonist montelukast (MK) and compared them with those of methylprednisolone (MP) in an allergic asthma model. Rats sensitized to ovalbumin (OVA) received repeated intratracheal exposure to OVA for up to 3 consecutive days. Pretreatment with MK or MP before OVA exposure inhibited late airway response (LAR) and reduced cellular infiltration into the bronchial submucosa after the triple OVA. The amount of N-acetyl-leukotriene E(4) in the bile was significantly reduced by pretreatment with MK or MP, suggesting that both drugs reduced the production of cysLTs in the lungs. In the in vitro study, when the fragments of lungs that had been repeatedly pretreated with MK or MP and exposed to OVA were removed and incubated with OVA, the coaddition of either drug significantly reduced cysLT production. In contrast, the cysLT production following the addition of OVA to the lung fragments that had not received in vivo pretreatment with either drug was inhibited by MK but not by MP. These results indicate that MK and MP inhibit LAR by suppressing the infiltration of inflammatory cells into the bronchial submucosa, thereby inhibiting the production of cysLTs in the lungs, and that MK but not MP may inhibit cysLT production directly. The different effects on cysLT production between the two drugs may provide a rationale for the use of combination therapy with cysLT(1) receptor antagonists and steroids for the treatment of asthma.

Topics: Acetates; Airway Resistance; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Bile; Bronchoalveolar Lavage Fluid; Cyclopropanes; Cysteine; Hypersensitivity; In Vitro Techniques; Leukocyte Count; Leukotriene A4; Leukotriene Antagonists; Leukotrienes; Lung; Methylprednisolone; Quinolines; Rats; Rats, Inbred BN; Receptors, Leukotriene; Sulfides

The leukotrienes are a family of potent mediators of hypersensitivity and inflammation. The application of sensitive and specific radioimmunoassays for leukotrienes has revealed the generation of significant quantities of several leukotrienes by leukocytes exposed to natural stimuli in the absence of exogenous arachidonic acid. The C6 peptide leukotrienes, LTC4 and LTD4, are potent vasoactive and smooth muscle contractile factors. LTB4 and other di-HETEs stimulate polymorphonuclear leukocyte function and suppress T-lymphocyte activities. The effects of LTB4 on T lymphocytes are subset-specific and include the activation of suppressor and cytotoxic T cells. Receptors for LTB4 on polymorphonuclear leukocytes are specific but exhibit considerable heterogeneity of binding affinity and may mediate different functional effects. The complexity of the pathways of generation and metabolism of leukotrienes, and of the leukotriene receptors, suggest that carefully defined systems will be needed to test the effects of pharmacological inhibitors and antagonists.

Topics: Arachidonic Acid; Arachidonic Acids; Drug Therapy; Humans; Hypersensitivity; Inflammation; Leukocytes; Leukotriene A4; Leukotriene B4; Lipoxygenase; Lymphocytes; Muscle, Smooth, Vascular; Neutrophils; Receptors, Immunologic; Receptors, Leukotriene B4; SRS-A

Topics: Allergens; Animals; Arachidonic Acids; Ascaris; Bronchi; Bronchial Provocation Tests; Bronchial Spasm; Hypersensitivity; Indomethacin; Leukotriene A4; Leukotriene B4; Lung; Saimiri; SRS-A

The recent definition of the pathways of generation and structures of diverse products of the lipoxygenation of arachidonic acid has established the identity of a new family of mediators of hypersensitivity and inflammation. Studies of the effects of these mediators have shown that leukotrienes C, D, and E, the constitutents of the slow-reacting substance of anaphylaxis (SRS-A), are extremely potent smooth muscle contractile and vasoactive factors. Leukotriene B is a highly active stimulus of neutrophil and eosinophil functions and suppresses the immunological capabilities of T lymphocytes. The development of specific and sensitive radioimmunoassays has permitted the detection of elevated concentrations of leukotrienes in tissues or exudates in several diseases, including asthma, diverse allergic states, adult respiratory distress syndrome, psoriasis, spondyloarthritis, and gout. The application of selective inhibitors and antagonists of leukotrienes will clarify their pathogenetic contributions in human diseases and may yield new therapeutic approaches.

Topics: Arachidonate Lipoxygenases; Arachidonic Acids; Arthritis; Asthma; Cystic Fibrosis; Humans; Hypersensitivity; Leukotriene A4; Leukotriene B4; Leukotriene E4; Lipoxygenase; Psoriasis; SRS-A; Tears

Topics: Arachidonic Acids; Humans; Hypersensitivity; Inflammation; Leukotriene A4; Leukotriene B4; SRS-A

Topics: Arachidonic Acids; Asthma; Humans; Hypersensitivity; Inflammation; Leukotriene A4; Leukotriene B4; Leukotriene E4; SRS-A