leukotriene-b4 and Hypersensitivity

Leukotrienes (LTs), both LTB4 and the cysteinyl LTs (CysLTs) LTC4, LTD4 and LTE4, are implicated in a wide variety of inflammatory disorders. These lipid mediators are generated from arachidonic acid via multistep enzymatic reactions through which arachidonic acid is liberated from membrane phospholipids through the action of phospholipase A2. LTB4 and CysLTs exert their biological effects by binding to cognate receptors, which belong to the G protein-coupled receptor superfamily. LTB4 is widely considered to be a potent chemoattractant for most subsets of leukocytes, whereas CysLTs are potent bronchoconstrictors that have effects on airway remodeling. LTs play a central role in the pathogenesis of asthma and many other inflammatory diseases. This review will provide an update on the synthesis, biological function, and relevance of LTs to the pathobiology of allergic diseases, and examine the current and future therapeutic prospects of LT modifiers.

Topics: Animals; Arachidonate 5-Lipoxygenase; Cysteine; Humans; Hypersensitivity; Leukotriene B4; Leukotrienes; Metabolic Networks and Pathways; Receptors, Leukotriene B4

Itch is a sensation that provokes a desire to scratch. Mast-cell histamine was thought to be a key itch mediator. However, histamine and mast-cell degranulation were reported not to elicit scratching in animals. It was difficult to investigate the pathophysiology of itching and to evaluate the antipruritic efficacy of chemical agents in the early 1990 s. We showed that hind-paw scratching and biting were elicited by stimulation with pruritogenic agents in mice. Those results demonstrated for the first time that cutaneous itching could be evaluated behaviorally in animals. We established various animal models of pathological itch of the skin (dry skin, mosquito allergy, surfactant-induced pruritus, and herpes zoster) and mucus membranes (pollen allergy). Mast-cell histamine did not play a key role in itching in any animal model examined except for the pollen allergy model. Histamine is not an exclusive itch mediator of mast cells; tryptase and leukotriene B4 released from mast cells also act as itch mediators. Epidermal keratinocytes release several itch mediators, such as leukotriene B4, sphingosylphosphorylcholine, thromboxane A2, nociceptin, nitric oxide, and histamine, which may play important roles in pathological itching. Appropriate animal models of pathological itching are needed for pharmacological evaluation of the antipruritic efficacy of chemical agents.

Topics: Animals; Antipruritics; Disease Models, Animal; Drug Evaluation, Preclinical; Histamine; Humans; Hypersensitivity; Leukotriene B4; Mast Cells; Mucous Membrane; Pruritus; Skin; Tryptases

Topics: Animals; Asthma; Humans; Hypersensitivity; Immune System Diseases; Leukotriene B4; Leukotrienes; Membrane Proteins; Pulmonary Fibrosis; Receptors, Leukotriene; Receptors, Leukotriene B4; Signal Transduction

Topics: Aged; Animals; Humans; Hypersensitivity; Inflammation; Leukotriene B4; Receptors, Leukotriene B4

Topics: Arachidonate 5-Lipoxygenase; Arachidonate Lipoxygenases; Epoxide Hydrolases; Humans; Hypersensitivity; Inflammation; Leukotriene B4; Leukotrienes; SRS-A

The potent mediators generated by the 5- and 15-lipoxygenation of arachidonic acid have diverse effects on smooth muscles, blood vessels, leukocytes, epithelial cells and glands, and sensory neurons, which suggest possible roles in the initiation and regulation of physiological and biochemical events. The responses to leukotrienes and related mediators are attributable to binding by stereospecific cellular receptors and consequent activation of biochemical transductional sequences analogous to those characteristic of other receptor systems. The elevated concentrations of these mediators in lesional fluids and tissues of inflammatory bowel disease and other hypersensitivity and inflammatory states are, in some instances, clearly related to the time course of development of the disease process. Systematic application of specific inhibitors and antagonists that are becoming available will define more clearly the involvement of leukotrienes in health and disease and possibly lead to new therapeutic approaches.

Topics: Arachidonate 15-Lipoxygenase; Arachidonate 5-Lipoxygenase; Colitis, Ulcerative; Crohn Disease; Humans; Hypersensitivity; Inflammation; Leukotriene B4; SRS-A

Topics: Arachidonate 5-Lipoxygenase; Arachidonic Acid; Arachidonic Acids; Chemotaxis, Leukocyte; Dietary Fats; Fatty Acids; Humans; Hypersensitivity; Inflammation; Leukotriene B4; Lymphocyte Activation; Neutrophils; Receptors, Immunologic; Receptors, Leukotriene; Receptors, Leukotriene B4; Receptors, Prostaglandin; SRS-A

1. Sensitized guinea pig lungs release substantial amounts of prostaglandin E2, 6-keto-prostaglandin F1 alpha, thromboxane B2 and leukotrienes B4 and D4 upon challenge with the specific antigen. 2. A specific Platelet Activating Factor (PAF) antagonist (BN-52021) significantly inhibited the release of these mediators from anaphylactic lungs, suggesting the existence of interactions between PAF and eicosanoids. 3. The injection of PAF into unsensitized guinea pig lungs induced the release of prostaglandin E2, thromboxane B2 and leukotrienes B4 and D4 as well as spasmogens having contractile effects on the trachea, bronchus and parenchyma strips. 4. Our studies on the mechanism of action of PAF suggest that the actions of PAF are mediated by leukotriene B4 which in turn release thromboxane A2. Recent results suggest that similar interactions between PAF and eicosanoids are likely in immune-complex hypersensitivity reaction in the rat.

Topics: Animals; Arachidonic Acids; Dinoprostone; Diterpenes; Eicosanoic Acids; Enzyme Activation; Ginkgolides; Guinea Pigs; Hypersensitivity; Inflammation; Lactones; Leukotriene B4; Lung; Muscle Contraction; Phospholipases; Phospholipases A; Platelet Activating Factor; Prostaglandins E; SRS-A; Thromboxane B2

The leukotrienes (LTs) are 5-lipoxygenase metabolites of arachidonic acid. The synthesis and release of LTs have been demonstrated in many cells and organs, and LTs are considered to be normal products of continuous metabolism of arachidonic acid. However, although evidence in favor of a critical role for LTs in regulation of physiological functions is still scarce, a growing body of evidence suggests a role for LTs in mediation of several pathophysiological processes such as generalized or local immune reactions, inflammation, asthma, shock, and trauma. LTs have been shown to have potent actions on many essential organs and systems, including the cardiovascular system (heart, blood vessels, microcirculation), the pulmonary system (lung, airways), the central nervous system (neural, glial, and vascular elements), the gastrointestinal tract, and the immune system. In these organs the effects of LTs are mediated by specific LT receptors. Identification of LTs and characterization of their regional and systemic pathological effects, together with characterization of their receptors and elucidation of their structure-activity relationships, are fundamental to developing LT antagonists or synthesis inhibitors that might prevent or reverse LT-dependent reactions. Preliminary reports have already shown that such pharmacological agents ameliorate some aspects of disease processes in experimental animals as well as in humans. In this brief review we intend to highlight the evidence that implicates LTs in normal physiological functions as well as in disease processes.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Central Nervous System; Central Nervous System Diseases; Humans; Hypersensitivity; Inflammation; Leukotriene B4; Respiration Disorders; Respiratory Physiological Phenomena; SRS-A; Vasomotor System; Wounds and Injuries

Topics: Acne Vulgaris; Bacteria; Chemotactic Factors; Chemotaxis, Leukocyte; Child; Communicable Diseases; Complement C3; Complement C5; Disease Susceptibility; HLA Antigens; Humans; Hypersensitivity; Leukotriene B4; Neutrophils; Psoriasis; Skin Diseases; Wiskott-Aldrich Syndrome

The role played by immunomodulation in allergy is critically reviewed. The prospective mechanisms of immunomodulation, specifically including those showing relation with allergic phenomena, are taken into consideration, examining the main interfering factors. Type I, IgE-mediated immunoreaction, in its two aspects, IgE synthesis and mediator's release, is analyzed, bearing in mind some agents involved or affecting these processes, mimicking immunomodulation. Other agents, such as Corynebacterium granulosum derivatives and glucocorticoids have been also appraised, to highlight their action in this connection.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Animals; Annexins; Antibody Specificity; Calcium Channel Blockers; Calmodulin; Chemotaxis, Leukocyte; Cimetidine; Circadian Rhythm; Corynebacterium; Cromolyn Sodium; Drug Administration Schedule; Epitopes; Glycoproteins; Histamine; HLA Antigens; Humans; Hypersensitivity; Immune System; Immunoglobulin E; Immunoglobulin Fc Fragments; Immunotherapy; Interferons; Killer Cells, Natural; Leukotriene B4; Levamisole; Macrophages; Prostaglandins; Ranitidine; Receptors, Complement; Receptors, Complement 3b; Steroids; T-Lymphocytes

A problem of leukotrienes--metabolites of arachidonic acid is reviewed in immunological aspects. Their nomenclature is given; basic pathways of biosynthesis, transformation and mode of leukotriens participation in hypersensitivity and inflammatory reactions are considered. The possibility of application of leukotrienes antagonists and inhibitors of their formation for allergic diseases treatment is discussed.

Topics: Animals; Antigens; Arachidonic Acids; Drug Synergism; Guinea Pigs; Humans; Hypersensitivity; Inflammation; Leukotriene B4; Neurotransmitter Agents; Rabbits; Receptors, Immunologic; SRS-A; Structure-Activity Relationship; Terminology as Topic; Thromboxane A2

It is now recognized that, in addition to the preformed mast cell granule mediators, newly generated lipid compounds are likely to be exceedingly important in the mediation of allergic asthma and other atopic diseases. That the initiating event in allergic diseases evokes a far more complex set of biochemical events than those that only lead directly to the release of histamine and other preformed mediators, and that the functional efficacies of the leukotrienes, PGD2, and PAF are significant for allergic pathobiology mandate that the latter compounds will necessarily be subject to efforts for future therapeutic intervention in allergic patient populations.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Asthma; Cricetinae; Humans; Hypersensitivity; Leukotriene B4; Lipid Bilayers; Lung; Mast Cells; Mice; Receptors, Leukotriene; Receptors, Prostaglandin; Skin; SRS-A

Topics: Animals; Arachidonic Acids; Arthritis, Rheumatoid; Edema; Eosinophils; Guinea Pigs; Humans; Hypersensitivity; Leukotriene B4; Mast Cells; Mice; Muscle Contraction; Nephritis; Prostaglandin D2; Prostaglandins; Prostaglandins D; Rabbits; Rats; Receptors, Fc; Receptors, IgE; Receptors, Immunologic; SRS-A; Thromboxanes

Topics: Animals; Calcium; Chemotaxis; Cricetinae; Guinea Pigs; Homeostasis; Humans; Hypersensitivity; Immunity; In Vitro Techniques; Inflammation; Leukotriene B4; Mice; Microcirculation; Neutrophils; Phagocytes; SRS-A; T-Lymphocytes, Cytotoxic; Vasoconstriction

Various substances considered as mediators responsible for regulation of both cellular and humoral components of inflammatory and allergic reactions are produced in course of oxidation of arachidonic acid by means of lipoxygenase. These substances included a number of stereochemically different monohydroxyeicosatetraenoic acids as well as leukotrienes. Components of slowly acting substance in anaphylaxis (leukotrienes C4 and D4) caused contraction of smooth muscles, constriction of bronchopulmonary system, alteration in permeability and tonus of capillary blood vessels in skin and other tissues. Leukotriene B and 5-monohydroxyeicosatetraenoic acid caused mobilization of neutrophils in the reaction of hypersensitivity of the delayed type. Contrary to prostaglandins, formed from arachidonic acid by cyclooxygenase, monohydroxyeicosatetraenoic acids and leukotrienes are considered as pathological agents only. Distinct and long-term effect of these substances on tissues suggest that the lipid mediators of inflammation will be important in studies of pathogenesis of various acute and chronic diseases.

Topics: Animals; Arachidonic Acids; Calcium; Carboxy-Lyases; Humans; Hypersensitivity; Inflammation; Leukotriene B4; Leukotrienes; Methyltransferases; Muscle, Smooth; Oxidation-Reduction; Phospholipases; SRS-A

Prostaglandins, thromboxanes and leukotrienes are oxygen metabolites of arachidonic acid forming a family of lipidic substances with intrinsic biological activities. The significance of biosynthesis of these mediators in response to cell stimulation remains unclear. Numerous data suggest that these compounds, produced by blood cells and vascular cells, play an important role in cardiovascular pathology, allergy or inflammation. The concept, based on biochemistry, of distinct metabolic pathways should be reappraised, using a physiological approach that involves a biological effect resulting from a synergistic action of different compounds. The development of specific assay methods will permit to investigate compounds obtained from biological fluids or from cells present in recognized pathological situations. Such in vitro data should help to clarify the role of these autacoids in cardiovascular, allergic or inflammatory diseases.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Cardiovascular Diseases; Humans; Hypersensitivity; Inflammation; Leukotriene B4; Lipoxygenase; Prostaglandin-Endoperoxide Synthases; Prostaglandins; SRS-A; Thromboxanes

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Basophils; Capillary Permeability; Cell Adhesion; Cell Aggregation; Chemotaxis, Leukocyte; Eosinophils; Guinea Pigs; Humans; Hypersensitivity; Inflammation; Leukotriene B4; Lymphocytes; Macrophages; Muscle, Smooth; Neutrophils; Rabbits; Rats; SRS-A; Superoxides

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

Topics: Animals; Arachidonic Acids; Chemical Phenomena; Chemistry, Physical; Cytoplasmic Granules; Histamine Release; Humans; Hypersensitivity; Inflammation; Leukotriene B4; Mast Cells; Membrane Lipids; Methylation; Phospholipids; Rats; Receptors, Fc; Receptors, IgE; Receptors, Immunologic; SRS-A

Topics: Animals; Anti-Inflammatory Agents; Arachidonic Acids; Chemotaxis, Leukocyte; Humans; Hypersensitivity; Inflammation; Leukotriene B4; Prostaglandins

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

Topics: Eye Diseases; Humans; Hypersensitivity; Leukotriene B4; T-Lymphocytes, Helper-Inducer; Th2 Cells

Leukotriene B4 (LTB4) is a potent lipid mediator involved in the recruitment and activation of neutrophils, which is an important feature of tissue injury and inflammation. The biological effects of LTB4 are primarily mediated through the high-affinity LTB4 receptor, BLT1. Postoperative incisional pain is characterized by persistent acute pain at the site of tissue injury and is associated with local inflammation. Here, we compared the role of LTB4-BLT1 signaling in postoperative incisional pain between BLT1-knockout (BLT1KO) and wild-type (BLT1WT) mice. A planter incision model was developed, and mechanical pain hypersensitivity was determined using the von Frey test before and after incision. Local infiltration of neutrophils and inflammatory monocytes was quantified by flow cytometry. Inflammatory cytokine levels in the incised tissue were also determined. Mechanical pain hypersensitivity was significantly reduced in BLT1KO mice compared to BLT1WT mice at 2, 3, and 4 days after incision. LTB4 levels in the tissue at the incision site peaked 3 hours after the incision. Infiltrated neutrophils peaked 1 day after the incision in both BLT1KO and BLT1WT mice. The accumulation of inflammatory monocytes increased 1-3 days after the incision and was significantly more reduced in BLT1KO mice than in BLT1WT mice. In BLT1KO mice, Interleukin-1β and Tumor Necrosis Factor-α levels 1 day after the incision were significantly lower than those of BLT1WT mice. Our data suggest that LTB4 is produced and activates its receptor BLT1 in the very early phase of tissue injury, and that LTB4-BLT1 signaling exacerbates pain responses by promoting local infiltration of inflammatory monocytes and cytokine production. Thus, LTB4-BLT1 signaling is a potential target for therapeutic intervention of acute and persistent pain induced by tissue injury.

Topics: Animals; Cytokines; Hypersensitivity; Inflammation; Interleukin-1beta; Leukotriene B4; Mice; Mice, Knockout; Nociception; Pain; Receptors, Leukotriene B4; Tumor Necrosis Factor-alpha

Leukotriene B

Topics: Animals; Biomarkers; Cell Differentiation; Cell Membrane; Cell Movement; Cell Proliferation; Chemokine CCL21; Dendritic Cells; Dermatitis, Atopic; Hypersensitivity; Inflammation; Interleukin-12; Leukotriene B4; Lymph Nodes; Mice, Inbred C57BL; Receptors, Leukotriene B4; Skin; Th1 Cells; Transcriptome

Epithelial cells (ECs) play a crucial role in allergic sensitization to inhaled protease allergens by instructing type 2 innate lymphoid cells (ILC2) and dendritic cells (DCs) via release of pro-type 2 cytokines, particularly interleukin-33 (IL-33). Leukotriene B4 (LTB4) is a well-known leukocyte chemoattractant via engagement of its receptor 1 (BLT1). However, the role of LTB4-BLT1 axis in allergic sensitization via activation of ECs is still unknown.. We evaluated the effect of LTB4-BLT1 axis on IL-33 expression and ILC2 activation in vivo and in vitro. Chimeric mice were established to evaluate the contribution of BLT1 expression in nonimmune cell to allergic sensitization.. Genetical or pharmacological interruption of LTB4-BLT1 axis during sensitization phase markedly reduced papain-induced IL-33 expression, decreased ILC2 activation and DC migration, thereby impairing the priming of allergic Th2 responses. Furthermore, papain inhalation induced a rapid release of LTB4 preceding IL-33, and intranasal administration of LTB4 to naïve WT mice significantly increased IL-33 expression and ILC2 activation in lung, which was absent in Il33. Our study reveals a functional role of LTB4-BLT1 axis in nonimmune cells, most likely lung ECs, in controlling allergic sensitization as an upstream regulator of IL-33.

Topics: Allergens; Animals; Cytokines; Epithelial Cells; Hypersensitivity; Immunization; Interleukin-33; Leukotriene B4; Lymphocyte Activation; Lymphocytes; Mice; Papain; Proto-Oncogene Proteins c-akt; Receptors, Leukotriene B4; Signal Transduction; T-Lymphocyte Subsets

Allergic diseases, such as asthma and allergic rhinitis, are common. Therefore, the discovery of therapeutic drugs for these conditions is essential. Methyleugenol (ME) is a natural compound with antiallergic, antianaphylactic, antinociceptive, and anti-inflammatory effects. This study examined the antiallergic effect of ME on IgE-mediated inflammatory responses and its antiallergy mechanism in the mast cell line, RBL-2H3. We found that ME significantly inhibited the release of β-hexosaminidase, tumor necrosis factor- (TNF-) α, and interleukin- (IL-) 4, and was not cytotoxic at the tested concentrations (0-100 μM). Additionally, ME markedly reduced the production of the proinflammatory lipid mediators prostaglandin E2 (PGE2), prostaglandin D2 (PGD2), leukotriene B4 (LTB4), and leukotriene C4 (LTC4). We further evaluated the effect of ME on the early stages of the FcεRI cascade. ME significantly inhibited Syk phosphorylation and expression but had no effect on Lyn. Furthermore, it suppressed ERK1/2, p38, and JNK phosphorylation, which is implicated in proinflammatory cytokine expression. ME also decreased cytosolic phospholipase A2 (cPLA2) and 5-lipoxygenase (5-LO) phosphorylation and cyclooxygenase-2 (COX-2) expression. These results suggest that ME inhibits allergic response by suppressing the activation of Syk, ERK1/2, p38, JNK, cPLA2, and 5-LO. Furthermore, the strong inhibition of COX-2 expression may also contribute to the antiallergic action of ME. Our study provides further information about the biological functions of ME.

Topics: Animals; Arachidonic Acid; beta-N-Acetylhexosaminidases; Cell Line, Tumor; Cell Respiration; Dinoprostone; Eugenol; Extracellular Signal-Regulated MAP Kinases; Hypersensitivity; Immunoenzyme Techniques; Immunoglobulin E; Inflammation; Interleukin-4; Leukotriene B4; Leukotriene C4; Mast Cells; Mutagens; Prostaglandin D2; Rats; Tumor Necrosis Factor-alpha

Garlic (Allium sativum) has been used as a food as well as a component of traditional medicine. Aged black garlic (ABG) is known to have various bioactivities. However, the effect of ABG on allergic response is almost unknown. In the present study, we investigated whether ABG can inhibit immunoglobulin E-mediated allergic response in RBL-2H3 cells as well as in vivo passive cutaneous anaphylaxis (PCA). In in vitro tests, ethyl acetate extract (EBG) of ABG significantly inhibited the release of β-hexosaminidase (IC₅₀, 1.53 mg/mL) and TNF-α (IC₅₀, 0.98 mg/mL). Moreover, BG10, an active fraction of EBG, dramatically suppressed the release of β-hexosaminidase (IC₅₀, 53.60 μg/mL) and TNF-α (IC₅₀, 27.80 μg/mL). In addition, BG10 completely blocked the formation of prostaglandin E₂ and leukotriene B₄ at ≥25 μg/mL. When the effect of BG10 on FcɛRI receptor cascade was investigated, BG10 significantly inhibited the phosphorylation of Syk, but not Lyn. Furthermore, BG10 dose dependently decreased the phosphorylation of cytosolic phospholipase A₂ (cPLA₂) and 5-lipoxygenase (5-LO) as well as the expression of cyclooxygenase-2 (COX-2). Consistent with what has been mentioned earlier, BG10 also significantly inhibited the PCA reaction in mice. In conclusion, these results indicate that ABG suppresses the allergic response, and the mechanism for its anti-allergic action may involve suppressions of Syk, cPLA₂, 5-LO, and COX-2. The anti-allergic actions of ABG, EBG, or BG10 suggest that they may be useful as functional foods for allergic diseases.

Topics: Animals; Anti-Allergic Agents; beta-N-Acetylhexosaminidases; Cell Line; Dinoprostone; Female; Garlic; Humans; Hypersensitivity; Immunoglobulin E; Leukotriene B4; Male; Mice; Mice, Inbred ICR; Passive Cutaneous Anaphylaxis; Plant Extracts; Tumor Necrosis Factor-alpha

Leukotrienes constitute a group of lipid mediators, which may be subdivided into two groups, with leukotriene B4 on the one hand and cysteinyl leukotrienes on the other. Although leukotrienes are abundantly expressed in skin affected by diverse chronic inflammatory diseases, including atopic dermatitis, psoriasis, pemphigus vulgaris and bullous pemphigoid, their pathological roles in these diseases have remained elusive. Recent data now reveal that both leukotriene B4 and cysteinyl leukotrienes are indispensable in the pathogenesis of atopic dermatitis, with leukotriene B4 initiating the recruitment of inflammatory cells, particularly neutrophils and TH 2 cells into the skin, and cysteinyl leukotrienes later inducing characteristic structural alterations of chronically affected skin, specifically skin fibrosis and keratinocyte proliferation. Thus, these results reveal a sequential cooperation of LTB4 and cysteinyl leukotrienes to initiate and perpetuate allergic skin inflammation. These new insights highlight leukotrienes as promising therapeutic targets in allergic skin inflammation and should encourage more research into the role of leukotrienes in other inflammatory skin diseases.

Topics: Animals; Cell Proliferation; Dermatitis, Atopic; Fibrosis; Humans; Hypersensitivity; Inflammation; Keratinocytes; Leukotriene B4; Lipids; Mice; Neutrophils; Receptors, Leukotriene; Skin; Skin Diseases; Th2 Cells

Topics: Allergens; Animals; Antineoplastic Agents; Boronic Acids; Bortezomib; Cattle; Female; Glycogen Storage Disease Type II; Human papillomavirus 16; Human papillomavirus 18; Humans; Hypersensitivity; Immunotherapy; Leukotriene B4; Melanoma; Milk; Milk Proteins; Papillomavirus Infections; Pyrazines; Receptors, Leukotriene B4; Skin Neoplasms; Tumor Escape; Uterine Cervical Neoplasms; Viral Vaccines

Andrographis paniculata has been known to possess widespread traditional application in the treatment of allergy and inflammatory diseases. In the current study, we sought to examine the effects of an extract of Andrographis paniculata leaves on inhibition of lipopolysaccharide (LPS) induced [nitric oxide (NO), prostaglandin E(2) (PGE(2)), interleukin-1beta (IL-1 beta), and interleukin-6 (IL-6)] and calcimycin (A23187) induced [leukotriene B(4) (LTB(4)), thromboxane B(2) (TXB(2)) and histamine] mediators in diverse cell based models.. Effect of an extract of Andrographis paniculata leaves (AP) was studied on inhibition of LPS induced NO, PGE(2), IL-1 beta and IL-6 in J774A.1 murine macrophages; A23187 induced LTB(4) and TXB(2) in HL-60 promyelocytic leukemic cells and histamine in RBL-2H3 rat basophilic leukemia cells.. AP illustrated significant alleviation of pro-inflammatory, inflammatory, and allergic mediators. However, no inhibition was observed against histamine release. This outcome has been summed up to deduce that AP is fairly potent in attenuating the inflammation by inhibiting pro-inflammatory (NO, IL-1 beta and IL-6), inflammatory (PGE(2) and TXB(2)) and allergic (LTB(4)) mediators.

Topics: Andrographis; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Calcimycin; Cell Line; Cell Line, Tumor; Humans; Hypersensitivity; Inflammation Mediators; Leukotriene B4; Lipopolysaccharides; Macrophages; Mice; Plant Extracts; Plant Leaves; Rats

We investigated the role of leukotriene (LT) B(4) in 5-lipoxygenase metabolite- and allergy-induced itch-associated responses using SA6541, an LTA(4) hydrolase inhibitor. Itch-associated responses were induced by intradermal injection of 5-hydroperoxyeicosatetraenoic acid (HPETE), a precursor of 5-lipoxygenase metabolites, and passive cutaneous anaphylaxis in ICR mice. By screening molecules related to arachidonic acid metabolism or pruritus, SA6541 was found to be a specific inhibitor of LTA(4) hydrolase. Pharmacokinetic studies confirmed the specificity of SA6541 at an oral dose of 100 mg/kg in mice. 5-HPETE induced scratching behavior, which was inhibited by SA6541 (100 mg/kg). However, SA6541 (100 mg/kg) hardly attenuated the 5-HPETE-induced increase in vascular permeability. Moreover, SA6541 (100 mg/kg) partially attenuated scratching behavior, but did not affect the increase in vascular permeability caused by passive cutaneous anaphylaxis. On the other hand, ketotifen fumarate, a histamine H1 antagonist, strongly inhibited the scratching behavior and the increase in vascular permeability caused by passive cutaneous anaphylaxis. These results suggest that LTB(4) is an endogenous itch mediator in the skin and is involved in the pruritus response in allergic reactions.

Topics: Animals; Arachidonic Acid; Behavior, Animal; Capillary Permeability; Epoxide Hydrolases; Histamine H1 Antagonists; Hypersensitivity; Ketotifen; Leukotriene B4; Lipoxygenase; Male; Mice; Mice, Inbred ICR; Passive Cutaneous Anaphylaxis; Protease Inhibitors; Pruritus; Skin

Allergies are highly complex disorders with clinical manifestations ranging from mild oral, gastrointestinal, recurrent wheezing, and cutaneous symptoms to life-threatening systemic conditions. The levels of arachidonic acid, eicosanoids, histamine, organic acids and valine are considered to have a variety of physiological functions in connection with allergies. In this research, we have developed a RP-LC/MS method to separate and quantitate six different potential endogenous biomarkers, including leukotriene B(4) (LTB(4)), prostaglandin D(2) (PGD(2)), arachidonic acid (AA), histamine (HI), lactic acid (LA) and valine (VAL), from serum of rats with ovalbumin (OVA)-induced allergy and normal rats, and the discrepancies between the model group and the control group were compared. The separation was performed on a Prevail C18 column (250 mm x 4.6 mm, 5 microm) with a gradient elution of acetonitrile with 0.1% formic acid (v/v) and 10 mM ammonium formate (adjusted to pH 4.0 with formic acid) at a flow rate of 0.5 mL min(-1) The method was validated and shown to be sensitive, accurate (recovery values 76.16-92.57%) and precise (RSD < 10% for all compounds) with a linear range over several orders of magnitude. The method was successfully applied to rat serum and shown to be indicative of the endogenous levels of biomarkers within the rat body. The analysis of the biomarkers can provide insight into the allergic mechanisms associated with related diseases.

Topics: Animals; Arachidonic Acid; Biomarkers; Chromatography, Liquid; Histamine; Hypersensitivity; Lactic Acid; Leukotriene B4; Mass Spectrometry; Ovalbumin; Prostaglandin D2; Rats; Sensitivity and Specificity; Valine

To determine Th1/Th2 cytokines and chemokines in patients with allergic diseases and its clinic significance.. Serum levels of IFN-gamma, IL-4, IL-5, IL-13, Eotaxin, RANTES and LTB4 were determined from peripheral blood of 64 allergic patients and 21 healthy controls with ELISA.. IL-4, IL-5, IL-13 and Eotaxin, LTB4 were increased significantly in serum of allergic patients compared with those of controls (P<0.05). There were no significant differences in serum levels of IFN-gamma and RANTES between patients and controls (P>0.05). Serum levels of IL-4, IL-5, IL-13 and LTB4 were correlated with each other (P<0.01). Eotaxin, RANTES and IFN-gamma levels were also significantly correlated with each other (P<0.05). LTB4 was correlated with Eotaxin as well (P<0.01).. A wide range of cytokines and chemokines is involved in allergic diseases,which may play their roles in a complex interactive manner.

Topics: Adolescent; Adult; Aged; Chemokines; Child; Child, Preschool; Cytokines; Female; Humans; Hypersensitivity; Interferon-gamma; Interleukin-13; Interleukin-4; Leukotriene B4; Male; Middle Aged; Th1 Cells; Th2 Cells; Young Adult

Leukotrienes (LTs) have been identified as central mediators in asthma and allergy. Pharmacological inhibition of cysteinyl-LT activity improves asthma symptoms and control. Accumulating evidence suggests a role for the dihydroxy leukotriene LTB(4) in airway disease. LTA(4) hydrolase and 5-lipoxygenase activating protein have key roles in LTB(4) production. Single nucleotide polymorphism (SNPs) and haplotypes spanning the LTA4H and ALOX5AP genes have been associated with LTB(4) production and myocardial infarction (MI).. To assess the contribution of LTA4H and ALOX5AP polymorphism to asthma and allergy susceptibility.. Three hundred and forty-one Caucasian families (two asthmatic siblings) were genotyped for eight SNPs spanning ALOX5AP and five SNPs spanning LTA4H. Association analyses of asthma and related phenotypes (total IgE, atopy, bronchial hyper-responsiveness, FEV(1)) were undertaken using the Family Based Association Test.. Single point analyses identified association (P < 0.05) between SNPs SG13S114, SG13S89, SG13S41 (ALOX5AP), rs1978331 (LTA4H) and asthma and/or related phenotypes. Haplotype analyses using all LTA4H SNPs identified a single key risk haplotype for the development of asthma (P = 0.006) and related phenotypes (P = 0.042-0.005). Haplotype analyses using all ALOX5AP SNPs identified several asthma and atopy risk and protective haplotypes. There was limited correlation with previously identified MI risk haplotypes in both genes. Carriers of both ALOX5AP SG13S41 and LTA4H rs1978331 alleles had an increased risk of developing asthma (OR 2.17, CI 1.41-3.32).. These data provide evidence for the role of SNPs spanning the ALOX5AP and LTA4H genes in asthma and atopy susceptibility in the Caucasian population and support a role for LTB(4) in disease pathogenesis.

Topics: Adolescent; Adult; Arachidonate 5-Lipoxygenase; Asthma; Child; Epoxide Hydrolases; Female; Humans; Hypersensitivity; Leukotriene B4; Male; Polymorphism, Single Nucleotide; Risk Factors

This study investigated endogenous mediators involved in mosquito allergy-associated itching in mice. An intradermal injection of an extract of mosquito salivary gland elicited marked scratching in sensitized mice. The 5-lipoxygenase inhibitor zileuton (100 mg/kg), the 5-lipoxygenase activating peptide inhibitor MK-886 (10 mg/kg), and the glucocorticoid betamethasone 17-valerate (3 mg/kg) inhibited the scratching. The scratching was not affected by the cyclooxygenase inhibitors indomethacin and ketoprofen, the TP prostanoid receptor antagonist SQ-29548, the leukotriene B(4) antagonist ONO-4057, the cysteinyl leukotriene antagonist pranlucast, the leukotriene D(4) antagonist MK-571, the platelet-activating factor antagonist CV-3988, the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester, the H(2) histamine-receptor antagonist cimetidine, the H(1) histamine-receptor antagonist terfenadine plus cimetidine, and cypoheptadine that blocks the 5-HT(1/2) serotonin receptors. Zileuton (100 mg/kg) inhibited the increased activity of the cutaneous nerve branch induced by an intradermal injection of the extract, suggesting the peripheral action. Zileuton and MK-886 (10 and 100 microM) did not affect high K(+)-induced increase in intracellular Ca(2+) concentration in cultured dorsal root ganglion neurons. The results suggest that 5-lipoxygenase metabolite(s) other than leukotriene B(4) and cysteinyl leukotrienes are involved in mosquito allergy-associated itching.

Topics: Animals; Arachidonate 5-Lipoxygenase; Betamethasone Valerate; Bridged Bicyclo Compounds, Heterocyclic; Calcium; Chromones; Cimetidine; Culicidae; Dose-Response Relationship, Drug; Fatty Acids, Unsaturated; Hydrazines; Hydroxyurea; Hypersensitivity; Indoles; Indomethacin; Ketoprofen; Leukotriene B4; Lipoxygenase Inhibitors; Male; Mice; Mice, Inbred ICR; NG-Nitroarginine Methyl Ester; Phenylpropionates; Phospholipid Ethers; Propionates; Pruritus; Quinolines; Terfenadine

Eosinophils are important inflammatory cells in allergic diseases. In the present study, we have investigated the effects of CCL22 on the recruitment of eosinophils in vivo and in vitro. CCL22 induced a dose- and time-dependent recruitment of eosinophils into the pleural cavity of mice, and this was dependent on the release of platelet-activating factor (PAF) and subsequent generation of CCL11. However, in an allergic pleurisy model, an anti-CCL22 polyclonal antibody given during sensitization or before challenge had no significant effect on eosinophil recruitment. CCL22 did not induce eosinophil chemotaxis in vitro but was able to induce eosinophil degranulation in vitro and in vivo. In conclusion, we show that although exogenously added CCL22 may induce eosinophil migration in vivo via release of PAF and CCL11 (eotaxin), endogenous production of CCL22 does not drive eosinophil migration during allergic inflammation. However, CCL22 may be an important activator of eosinophils once these cells have migrated into tissue.

Topics: Animals; Antibodies; Cell Degranulation; Chemokine CCL11; Chemokine CCL22; Chemokines, CC; Chemotactic Factors, Eosinophil; Chemotaxis; Eosinophils; Hypersensitivity; Leukotriene B4; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Platelet Membrane Glycoproteins; Pleurisy; Receptors, Cell Surface; Receptors, G-Protein-Coupled

1. We investigated the mediators responsible for mechanical hypersensitivity induced by antigen challenge in rats immunised with ovalbumin (OVA). 2. Challenge with OVA (12.5-100 micro g, intraplantar) caused a dose- and time-dependent mechanical hypersensitivity, which peaked 3 h after, decreased thereafter and reached control levels 24 h later. 3. Levels of TNFalpha, IL-1beta and cytokine-induced neutrophil chemoattractant 1 (CINC-1) were increased in paw skin after antigen challenge. 4. OVA-evoked hypersensitivity was partially inhibited (about 51%) by pretreatment with anti-TNFalpha, IL-1beta and IL-8 sera or with IL-1 receptor antagonist (IL-1ra), but not anti-NGF serum. Pretreatment with thalidomide (45 mg kg(-1)) or pentoxifylline (100 mg kg(-1)) also partially inhibited the hypersensitivity at 1-3 h after challenge. 5. Pretreatment with indomethacin (5 mg kg(-1)) or atenolol (1 mg kg(-1)) reduced the OVA-induced hypersensitivity at 1 and 3 h, but not at 5 h after challenge, while the combination of B(1) and B(2) bradykinin receptor antagonists was ineffective over the same times. 6. Pretreatment with MK886 (5-lipoxygenase-activating protein inhibitor, 3 mg kg(-1)), CP 105696 (LTB(4) receptor antagonist; 3 mg kg(-1)) or dexamethasone (0.5 mg kg(-1)) inhibited the hypersensitivity from 1 to 5 h. Furthermore, LTB(4) levels were increased in the paw skin of challenged rats. 7. In conclusion, our results suggest that the TNFalpha-, IL-1beta- and CINC-1-driven release of prostaglandins, sympathetic amines and LTB(4) mediates the first 3 h of mechanical hypersensitivity induced by antigen challenge in rats. At 5 h after OVA administration, although TNFalpha has some role, LTB(4) is the critical nociceptive mediator.

Topics: Animals; Antigens; Dose-Response Relationship, Drug; Dose-Response Relationship, Immunologic; Hyperalgesia; Hypersensitivity; Injections, Subcutaneous; Leukotriene B4; Male; Ovalbumin; Pain Measurement; Physical Stimulation; Rats; Rats, Wistar; Skin; Up-Regulation

Pustulosis palmaris et plantaris (PPP) is a chronic inflammatory disease consisting of polymorphonuclear leukocyte infiltration, and is often exacerbated by focal infections such as tonsillitis. In some cases, metal allergy has been reported.. The purpose of this study was to evaluate (1) the significance of metal allergy in the formation of pustules, and (2) the participation of leukotriene (LT) B(4) in the formation of pustules of PPP.. Patch tests with metals were performed on 7 patients with PPP, and both pustular and plasma levels of LTB(4) were measured in these 7 patients before and 48 hours after metal patch tests.. Palmoplantar pustules were exacerbated after the metal patch tests in all 7 patients. The mean levels of LTB(4) in plasma and pustules of the volar surface at 48 hours after the metal patch tests were significantly higher than those before the metal patch tests.. Metals can be important in the pathogenesis of PPP by contributing to the induction of high LTB(4) concentration in the pustules.

Topics: Administration, Topical; Female; Humans; Hypersensitivity; Leukotriene B4; Male; Metals; Middle Aged; Patch Tests; Psoriasis

We previously demonstrated that captopril (CP) exhibited a high ability to inhibit enzymatically generated leukotrienes, particularly LTB(4), from stimulated intact human neutrophils. This finding together with the immunosuppressive effect of CP have proposed a possible antiinflammatory activity for the drug. Thus, the present study was conducted to investigate the effect of CP on immunologically mediated chronic inflammation; two models were chosen, namely, Freund's adjuvant arthritis and mixed-type hypersensitivity in rat. The effect of CP was assessed on the basis of physical parameter (paw edema) and biochemical markers in blood and inflammatory exudate. CP was given daily during the course of inflammation development. It was administered ip at three doses, viz. 1, 10, and 100 mg/kg. The results claimed that CP succeeded in suppressing edema evolution in hind paws of Freund's arthritic animals, during all phases of the disease. During the chronic phase of inflammation, in either model, CP reduced the elevated serum and exudate (local) LTB(4) and IL-6 levels. The effect on LTB(4) was more pronounced in the exudate and tended to be dose-related. The antiarthritic effect of CP was also accompanied by augmentation of serum level of protein thiols, with reduction or normalization of elevated systemic and/or local levels of lipid peroxide, superoxide dismutase, and glutathione. It could be concluded that long-term treatment with CP confers a good antiinflammatory activity against arthritis in rat, leading to improvement of the oxidative stress induced by the arthritic insult. The reparative effect of the drug could be mediated via reduction of LTB(4) and IL-6.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Captopril; Edema; Exudates and Transudates; Freund's Adjuvant; Hindlimb; Hypersensitivity; Inflammation; Interleukin-6; Leukotriene B4; Male; Oxidative Stress; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; Thiobarbituric Acid Reactive Substances

Allergic rhinitis is an inflammatory disease associated with local leukotriene release during periods of symptoms. Zileuton, a leukotriene synthesis inhibitor, is known to inhibit the release of leukotriene B4. Because we previously showed that leukotriene B4 is a potent mediator of neutrophil-dependent nasal secretion, we investigated whether Zileuton inhibited allergen-induced nasal secretion. Using a newly developed method for isolating and superfusing a nasal segment, we examined the effect of Zileuton on nasal secretion and neutrophil recruitment in ragweed-sensitized dogs. Instillation of ragweed into the nasal segment caused time-dependent increases in the volume of airway fluid and the recruitment of neutrophils. Zileuton prevented ragweed-induced neutrophil recruitment and nasal secretion. These results indicate that leukotrienes are important mediators of allergy-induced nasal secretion in dogs. Future clinical studies in allergic patients will determine whether there is a therapeutic role for leukotriene synthesis inhibitors in modulating neutrophil recruitment and hypersecretion in the nose.

Topics: Animals; Dogs; Hydroxyurea; Hypersensitivity; Leukotriene Antagonists; Leukotriene B4; Nasal Mucosa; Nasal Obstruction; Nasal Provocation Tests; Neutrophils; Plants; Pollen; Rhinitis, Allergic, Seasonal; Time Factors

To investigate the function of prostaglandin H synthase-1 and synthase-2 (PGHS-1 and PGHS-2) in the normal lung and in allergic lung responses, we examined allergen-induced pulmonary inflammation and airway hyperresponsiveness in wild-type mice and in PGHS-1(-/-) and PGHS-2(-/-) mice. Among nonimmunized saline-exposed groups, we found no significant differences in lung function or histopathology, although PGE(2) was dramatically reduced in bronchoalveolar lavage (BAL) fluid from PGHS-1(-/-) mice, relative to wild-type or PGHS-2(-/-) mice. After ovalbumin sensitization and challenge, lung inflammatory indices (BAL cells, proteins, IgE, lung histopathology) were significantly greater in PGHS-1(-/-) mice compared with PGHS-2(-/-) mice, and both were far greater than in wild-type mice, as illustrated by the ratio of eosinophils in BAL fluid (8:5:1, respectively). Both allergic PGHS-1(-/-) and PGHS-2(-/-) mice exhibited decreased baseline respiratory system compliance, whereas only allergic PGHS-1(-/-) mice showed increased baseline resistance and responsiveness to methacholine. Ovalbumin exposure caused a modest increase in lung PGHS-2 protein and a corresponding increase in BAL fluid PGE(2) in wild-type mice. We conclude that (a) PGHS-1 is the predominant enzyme that biosynthesizes PGE(2) in the normal mouse lung; (b) PGHS-1 and PGHS-2 products limit allergic lung inflammation and IgE secretion and promote normal lung function; and (c) airway inflammation can be dissociated from the development of airway hyperresponsiveness in PGHS-2(-/-) mice.

Topics: Allergens; Animals; Bronchoalveolar Lavage Fluid; Dinoprostone; Female; Hypersensitivity; Immunoglobulin E; Isoenzymes; Leukotriene B4; Lung; Lung Compliance; Lysosomes; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Prostaglandin-Endoperoxide Synthases

Previous studies have shown that antihistamines provide little or no protection against the recruitment of leucocytes in allergic inflammation.. We wanted to examine if threshold doses of histamine can potentiate chemoattractant-induced leukocyte adhesion and if complete inhibition of histamine-induced microvascular effects is necessary to reduce allergic leucocyte recruitment.. The role of histamine in allergic leucocyte recruitment was examined by use of intravital microscopy of the hamster cheek pouch microcirculation.. We found that topical administration of histamine caused a concentration-dependent increase in microvascular permeability in the cheek pouch; i.e. 0.3 microM histamine caused no detectable plasma leakage, while 1 microM and 10 microM histamine resulted in 29 +/- 9.3 and 356 +/- 47 leakage sites/cm2 cheek pouch area, respectively. The percentage of postcapillary venules with more than five adherent leucocytes (an index of early leucocyte recruitment) was 1.1 +/- 0.51% in the control situation, and did not increase significantly after stimulation with histamine alone (0.3-10 microM) or with 1 nM leukotriene B4 (LTB4). On the other hand, coapplication of 10 microM histamine and 1 nM LTB4 increased leucocyte adhesion 24-fold. In fact, the 10 times lower dose of histamine (1 microM) together with 1 nM LTB4 increased leucocyte adhesion to a similar extent (20 fold). The increase in vascular permeability evoked by exogenous 10 microM histamine (with or without LTB4), or by histamine released from activated mast cells (antigen challenge), was completely reversed by local pretreatment with the H1-receptor antagonist mepyramine. This mepyramine treatment also abolished the enhanced leucocyte adhesion in response to coapplication of histamine and LTB4. Moreover, mepyramine, which had no effect on leucocyte recruitment evoked by 3 nM LTB4 per se, reduced antigen-induced recruitment of leucocytes to the extravascular tissue by 79.5 +/- 14.8%.. We conclude that threshold concentrations of histamine can strikingly potentiate chemoattractant-induced leucocyte responses, and that in order to reduce allergic leucocyte recruitment it may be necessary to use antihistamines in doses high enough to abolish the microvascular actions of histamine.

Topics: Animals; Capillary Permeability; Cell Adhesion; Cheek; Cricetinae; Drug Synergism; Histamine; Hypersensitivity; Leukocytes; Leukotriene B4; Male; Mesocricetus; Microcirculation

Neutrophils from allergic subjects were hypersensitive to stimulation by low calcium ionophore concentration (0.15 microM), resulting in an increased formation of leukotriene B4 (LTB4), 5S-hydroxy-6,8,11,14-(E,Z,Z,Z)-eicosatetraenoic acid (5-HETE), and other arachidonic acid metabolites through the 5-lipoxygenase pathway. In parallel, luminol-dependent chemiluminescence was also higher in neutrophils from allergic patients at the basal state and after stimulation by calcium ionophore, revealing an enhancement of radical oxygen species and peroxide production. The activity of glutathione peroxidase, the main enzyme responsible for hydroperoxide reduction, was lowered in these cells. Diethyl-dithiocarbamate (DTC) induced a concentration-dependent decrease in chemiluminescence and arachidonic acid metabolism after neutrophil stimulation. These data show that the elevation of arachidonic acid metabolism in neutrophils from allergic patients is strongly correlated with oxidative status. This elevation may be the consequence of an increased cellular hydroperoxide known to activate 5-lipoxygenase (5-LOX) activity and/or an increased arachidonic acid availability, due either to phospholipase A2 (PLA2) activation or inhibition of arachidonate reesterification into phospholipids. Lowering this oxidative status was associated with a concomitant decrease of this metabolism. Our results suggest that the effect of DTC may be the consequence of an inhibition of peroxyl radical and cellular lipid hydroperoxide production. Thus, DTC may modulate arachidonic acid metabolism in neutrophils by modulating the cellular hydroperoxide level.

Topics: Adult; Arachidonic Acid; Ditiocarb; Female; Humans; Hypersensitivity; Leukotriene B4; Luminescent Measurements; Luminol; Male; Middle Aged; Neutrophils; Oxidation-Reduction

Selective eosinophil recruitment into tissues is a characteristic feature of allergic diseases. Chemokines are effective leukocyte chemoattractants and may play an important role in mediating eosinophil recruitment in various allergic conditions in man. Here, we describe a novel mouse model of eosinophil recruitment in which we have compared the in vivo chemoattractant activity of different C-C chemokines. Furthermore, we describe the use of antibodies to chemokines and receptor blockade to address the endogenous mechanisms involved in eosinophil recruitment in a late-phase allergic reaction in mouse skin. Intradermal injection of mEotaxin and mMIP-1alpha, but not mMCP-1, mRANTES, mMCP-5, or mMIP-1beta, induced significant 111In-eosinophil recruitment in mouse skin. Significant 111In-eosinophil recruitment was also observed in an active cutaneous anaphylactic reaction. Pretreatment of skin sites with antieotaxin antiserum, but not an antiMIP-1alpha antibody, suppressed 111In-eosinophil recruitment in this delayed-onset allergic reaction. Similarly, desensitization of the eosinophil eotaxin receptor CCR3 with mEotaxin, or blockade of the receptor with metRANTES, significantly inhibited 111In-eosinophil recruitment in the allergic reaction. These results demonstrate an important role for endogenous eotaxin in mediating the 111In-eosinophil recruitment in allergic inflammation, and suggest that blockade of the CCR3 receptor is a valid strategy to inhibit eosinophil migration in vivo.

Topics: Anaphylaxis; Animals; Chemokine CCL11; Chemokines, CC; Chemotactic Factors, Eosinophil; Chemotaxis, Leukocyte; Complement C5a; Cytokines; Eosinophils; Female; Hypersensitivity; Hypersensitivity, Delayed; Leukotriene B4; Mice; Mice, Inbred CBA; Platelet Activating Factor; Receptors, CCR3; Receptors, Chemokine; Skin

The peptidoleukotrienes and leukotriene B4, formed from arachidonic acid through the action of 5-lipoxygenase (5-LO), exert a spectrum of biological effects. It has been proposed that potent and selective 5-LO inhibitors will be effective therapy in diseases in which the peptidoleukotrienes and leukotriene B4 have been implicated, such as asthma and arthritis. The novel compound (S)-N-hydroxy-N-(2,3-dihydro-6-phenylmethoxy-3-benzyofuranyl )urea (SB 202235) was evaluated as a selective inhibitor of 5-LO in a cell-free system as well as in various cellular assays. In addition, the potential therapeutic value of SB 202235 was assessed in preclinical models of allergic asthma. The activity of the 5-LO enzyme isolated from rat basophilic leukemia-1 cells was inhibited by SB 202235 in a concentration-dependent manner with an IC50 value of 1.9 microM. Consistent with its ability to inhibit 5-LO, SB 202235 inhibited the production of leukotriene B4 by human monocytes and in human whole blood (IC50 values of 1.5 microM and 1.1 microM, respectively). The selectivity of SB 202235 was confirmed by its lack of effect against several other enzymes and receptors. SB 202235 potently and effectively inhibited the contraction produced by a single concentration of ovalbumin in guinea pig trachea (IC50 = 20 microM) and of anti-IgE in human bronchus (IC50 = 2 microM). SB 202235 (3-30 microM) also inhibited the contraction of guinea pig trachea in response to increasing concentration of ovalbumin. When administered orally (30 mg/kg) to conscious guinea pigs, SB 202235 attenuated antigen-induced broncho-constriction and the subsequent eosinophil influx.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antigens; Asthma; Benzofurans; Bronchoconstriction; Disease Models, Animal; Eosinophils; Guinea Pigs; Humans; Hypersensitivity; In Vitro Techniques; Leukotriene B4; Lipoxygenase Inhibitors; Trachea; Urea

Nedocromil sodium, a disodium salt of a pyroquinolinedicarboxylic acid, raises the bronchial hyperresponsiveness threshold, because it inhibits the mediators released by the various cells, and reduces the involvement and activation of inflammatory cells. The aim of this study was to evaluate the state of activation of the immunocompetent cells and the main chemical mediators present in the bronchoalveolar lavage (BAL) fluid from 10 atopic asthmatic patients, before and after treatment with nedocromil sodium. The following examinations were performed before treatment and after 120 days of therapy with nedocromil sodium at 16 mg/day (two 2-mg puffs x 4): the level of chemical mediators and the state of activation of immunocompetent cells in BAL fluid; immunological analytes in activation of immunocompetent cells in BAL fluid; immunological analytes in peripheral blood; aspecific bronchial challenge test with ultrasonicated bidistilled H2O fog to evaluate variations in the hyperreactivity threshold; questionnaire to determine any adverse effects of treatment (cough, breathlessness, sleep disorders). Our findings demonstrate that nedocromil sodium prevents the release of chemotactic and inflammatory mediators by the effector cells and thus stabilizes microvascular permeability and epithelial damage, so raising the threshold of response to bronchoconstriction stimuli. Lastly, nedocromil sodium is associated with a better preventive therapeutic efficacy and good tolerance and can therefore be suggested as a valid drug to be used in the long-term treatment of bronchial asthma.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Albumins; Asthma; Blood Proteins; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Dinoprostone; Eosinophil Granule Proteins; Humans; Hypersensitivity; Immunoglobulins; Immunologic Factors; Leukocytes; Leukotriene B4; Lymphocytes; Macrophages; Male; Nedocromil; Peptide Hydrolases; Ribonucleases; Thromboxane B2

Effects of R[+]-8-([1-[3,4-dimethoxyphenyl]-2-hydroxyethyl]amino) -3,7-dihydro-7-[2-methoxyethyl]-1,3-dimethyl-1H-purine-2,6-dione (MKS-492), a reported type III isozyme inhibitor of cyclic nucleotide phosphodiesterase, on antigen- or platelet activating factor (PAF)-induced bronchoconstriction and allergic reactions in guinea pigs and rats were investigated. 1) MKS-492 inhibited antigen-induced bronchoconstriction in guinea pigs. Aminophylline also inhibited the reaction. 2) MKS-492 inhibited PAF-induced bronchoconstriction and inhibited the increase in airway responsiveness to histamine in guinea pigs, although aminophylline failed to affect these reactions. 3) MKS-492 relaxed guinea pig tracheal muscle in vitro more potently than aminophylline. 4) MKS-492 inhibited leukotriene B4 (LTB4)-induced airway eosinophilia in guinea pigs. 5) MKS-492 inhibited passive cutaneous anaphylaxis and mediator-induced skin reactions in rats more potently than aminophylline. Both drugs inhibited antigen- and phospholipase A2-induced histamine release from guinea pig lung tissue. 6) MKS-492 inhibited PAF-induced O2- generation from guinea pig alveolar macrophages. These results indicate that MKS-492 is a more potent inhibitor of allergic bronchoconstriction and PAF- or LTB4-induced inflammatory reactions in guinea pigs and the allergic cutaneous reactions in rats when compared to aminophylline.

Topics: Aminophylline; Animals; Antigens; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Female; Guinea Pigs; Histamine; Histamine Release; Hypersensitivity; Leukocyte Count; Leukotriene B4; Male; Muscle Relaxation; Muscle, Smooth; Passive Cutaneous Anaphylaxis; Phosphodiesterase Inhibitors; Platelet Activating Factor; Purinones; Rats; Rats, Wistar; Superoxides; Trachea

In allergic and nonallergic asthma, eosinophils play an important effector role. However, because the pathogenesis of these types of asthma seems different, the mechanisms responsible for the tissue mobilization of those cells may be different. The in vivo and in vitro migratory response of eosinophils from patients with allergic and nonallergic asthma toward 20-hydroxy-leukotriene B4 (20-OH-LTB4), which is reported here, illustrates this.. By means of the Rebuck skin window technique the in vivo skin mobilizing capacity of intracutaneously applied buffer, LTB4, and 20-hydroxy (OH)-LTB4 was evaluated in healthy subjects (n = 6), subjects with allergic asthma (n = 14), and subjects with nonallergic asthma (n = 17). Also the in vitro chemotactic responsiveness of eosinophils from the circulation of both patient groups (both n = 8) toward buffer, LTB4, and 20-OH-LTB4 were tested by use of a microchemotaxis chamber technique.. Although none of the substances were capable of inducing macroscopic observable skin reactions, intracutaneously applied 20-OH-LTB4 had an almost similar capacity to mobilize eosinophils in the skin of the subjects with nonallergic asthma as allergens had in subjects with allergic asthma. In 92% of the tested subjects with nonallergic asthma significant skin eosinophilia was observed. By contrast, LTB4 did not induce significant skin eosinophilia in both patient groups compared with buffer solution. This in vivo eosinophil mobilizing capacity of 20-OH-LTB4 in subjects with nonallergic asthma was confirmed by in vitro chemotaxis studies. Dose ranges of both LTB4 and 20-OH-LTB4 proved to be potent chemoattractants for eosinophils from patients with nonallergic asthma, but not for those of healthy subjects and those with allergic asthma.. Our results indicate that 20-OH-LTB4 may be involved in the tissue mobilization of eosinophils in nonallergic asthma and that in vitro 20-OH-LTB4 (and LTB4) may act as potent chemotactic factors on eosinophils from those patients.

Topics: Adult; Asthma; Chemotaxis, Leukocyte; Eosinophils; Female; Humans; Hypersensitivity; Leukotriene B4; Male; Reference Values; Skin; Skin Window Technique

Eosinophil infiltration is the hallmark of allergic inflammatory events. However, the mechanisms governing the influx of eosinophils into the tissue at a site of an allergic reaction remains unclear. We have examined the interactions of eosinophils and neutrophils isolated from the same atopic donor with cultured human umbilical vein endothelial cell (EC) monolayers in the search for a mechanism for this selective eosinophil recruitment. First, the adherence of eosinophils and neutrophils to ECs stimulated with lipopolysaccharide, interleukin (IL)-1 alpha, and tumor necrosis factor-alpha were compared. Each mediator induced a similar dose-dependent enhancement of eosinophil adhesiveness for both eosinophils and neutrophils. Thus, although cytokine activation of ECs in the vasculature adjacent to an inflammatory site probably serves as an important focusing mechanism for the extravasation of inflammatory cells at this site, there does not appear to be any selective EC-dependent mechanism for eosinophil recruitment. Little or no effect on eosinophil and neutrophil adherence was observed with IL-3, IL-5, granulocyte/macrophage colony-stimulating factor, platelet-activating factor (PAF), leukotriene B4, or histamine. Second, the migration of eosinophils and neutrophils through an EC monolayer in response to chemoattractants was examined. PAF was found to selectively enhance eosinophil transendothelial migration at doses of 10(-7) to 10(-10) M, with optimal effect at 10(-8) M. This effect was gradient dependent and could be inhibited by WEB 2086, a specific PAF inhibitor. These results suggest that localized production of PAF may be a prime factor in the events leading to eosinophil accumulation at allergic inflammatory sites, and that selectivity for eosinophil recruitment occurs at the stage of transendothelial cell migration under the influence of cell-specific chemoattractants.

Topics: Amitrole; Cell Adhesion; Cell Movement; Cytokines; Endothelium, Vascular; Eosinophils; Humans; Hypersensitivity; In Vitro Techniques; Interleukin-1; Leukotriene B4; Lipopolysaccharides; Microscopy, Electron; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Peroxidases; Platelet Activating Factor; Tumor Necrosis Factor-alpha

Fundamental studies were conducted to examine the release of histamine and leukotriene (LT) C4 from lung fragments of guinea pigs and the effects of E6080 on the release of LTB4 and LTC4 from lung fragments or inflammatory cells. The release of histamine and LTs showed large interindividual variations and a marked dependence on experimental conditions. Addition of 10 mM L-cysteine significantly increased LTC4 release compared with that in its absence (about 1.7 times, in terms of mean value). E6080 inhibited antigen-stimulated LTB4 and LTC4 release from passively sensitized human (IC50: LTB4 0.08 microM, LTC4 0.2 microM) and guinea-pig lung fragments (IC50: LTC4 1.1 microM). The LTB4 and LTC4 releases from healthy human polymorphonuclear leukocytes (calcium ionophore A23187) and from allergic patients' leukocytes (basophils, antigen) were inhibited by E6080 with IC50 values of below 1.0 microM. Furthermore, the LTC4 release from rat alveolar macrophages (silica particles) was inhibited by E6080 with an IC50 of 0.2 microM. The potent inhibition by E6080 might be a result of the inhibition of 5-lipoxygenase, since 5-lipoxygenase in rat basophilic leukemia cell was inhibited by E6080 with an IC50 of 0.2 microM. The results confirm the potent inhibitory effects of E6080 on the release of LTs.

Topics: Animals; Arachidonate 5-Lipoxygenase; Basophils; Benzoquinones; Dose-Response Relationship, Drug; Guinea Pigs; Histamine Release; Humans; Hypersensitivity; In Vitro Techniques; Leukotriene B4; Leukotrienes; Lipoxygenase Inhibitors; Lung; Male; Neutrophils; SRS-A; Thiazoles

To investigate the role of neuropeptides in allergic inflammation, we examined the effect of peptides on eosinophil chemotaxis. Eosinophils were purified from the blood of allergic and normal subjects using a discontinuous Percoll density gradients. Chemotaxis was induced by platelet-activating factor (PAF) and leukotriene B4, and was assayed by a modified Boyden's chamber technique. Four neuropeptides were examined in this study: substance P (SP), neurokinin A, calcitonin gene-related peptide (CGRP), and cholecystokinin octapeptide. Peptides alone (10 nM to 10 microM) were not chemotactic for eosinophils. However, when eosinophils were pre-treated with peptides (100 nM) at 37 degrees C for 30 min, chemotactic response to PAF (10 nM) was significantly enhanced (p < 0.01) in allergic subjects; % control by SP, neurokinin A, CGRP and cholecystokinin octapeptide was 269 +/- 42, 243 +/- 32, 227 +/- 21, and 251 +/- 42, respectively (n = 8). Similar results were obtained in leukotriene B4-induced eosinophil chemotaxis. In contrast, no enhancement was observed in normal subjects. Potentiating effect of SP and CGRP on PAF-induced eosinophil chemotaxis in allergic subjects was significantly attenuated by SP antagonist [D-Pro2,D-Trp7,9]-SP and human CGRP (8-37) receptor antagonist, respectively. Neutral endopeptidase inhibitors (phosphoramidon, leupeptin, and bestatin) failed to significantly augment the PAF-induced eosinophil chemotaxis when the cells were pretreated with various peptides and neutral endopeptidase inhibitors. The C-terminal fragment of SP (SP6-11) had an effect similar to that of the intact SP molecule, whereas no potentiating effect by the N-terminal of SP (SP1-9) was observed. These results suggest that neuropeptides may play a significant role in eosinophil infiltration by priming cells in allergic inflammation.

Topics: Chemotaxis, Leukocyte; Dose-Response Relationship, Drug; Eosinophils; Humans; Hypersensitivity; In Vitro Techniques; Leukotriene B4; Neuropeptides; Peptide Fragments; Platelet Activating Factor; Protease Inhibitors; Receptors, Calcitonin; Receptors, Cell Surface; Receptors, Neurokinin-1; Receptors, Neurotransmitter; Substance P

We tested the hypothesis that allergic sheep that develop both early and late airway responses to inhaled Ascaris suum antigen (late responders) have an increased capacity to generate leukotrienes (LTs) compared with allergic sheep that show only early responses to inhaled antigen (acute responders). To test this hypothesis, we measured LTB4 production, in vitro, by granulocytes isolated from peripheral blood and by macrophages isolated from bronchoalveolar lavage (BAL) from both groups of sheep greater than or equal to 2 wk after the animal's last antigen challenge; LTB4 production by granulocytes isolated from BAL from both groups of sheep 6 and 48 h after local airway challenge with A. suum antigen was also measured. LTB4 production was induced by incubating cells (i.e., either granulocytes or macrophages) with calcium ionophore (A23187, 2 microM) and arachidonic acid (30 microM). LTB4 production was quantitated by high-performance liquid chromatography and verified by radioimmunoassay (RIA). On stimulation peripheral blood granulocytes from late responders (n = 7) produced (means +/- SD/10(6) cells) 13.3 +/- 5.2 ng LTB4 compared with 5.3 +/- 1.5 ng LTB4 (P less than 0.05) for acute responders (n = 7). This increased LTB4 production did not result from variations in granulocyte differential or cyclooxygenase activity (as indicated by RIA measurements of prostaglandin E2 production).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antigens, Helminth; Arachidonic Acid; Arachidonic Acids; Ascaris; Calcimycin; Cell Adhesion; Granulocytes; Hypersensitivity; In Vitro Techniques; Leukotriene B4; Lung; Macrophages; Reference Values; Sheep; Therapeutic Irrigation

Topics: Animals; Chemotaxis, Leukocyte; Complement System Proteins; Fever; Humans; Hypersensitivity; Inflammation; Leukotriene B4; Neutrophils; Nociceptors; Prostaglandins

To study the contribution of leukotriene C4 (LTC4), leukotriene D4 (LTD4), leukotriene B4 (LTB4), and inflammation to the antigen-induced late bronchial response, these leukotrienes, histamine, and cell differentials were evaluated in bronchoalveolar lavage fluid (BALF). Immediate and late responses were induced by Ascaris suum antigen inhalation in 11 conscious sheep. Bronchoalveolar lavage was performed on 3 separate test days, before challenge (control), during the immediate response, and during the late response. Leukotrienes were measured by radioimmunoassay after purification by reverse-phase high-performance liquid chromatography. LTB4 and LTC4 were detected in control BALF, but LTD4 was not. LTC4 and LTB4 were increased in the late response (p less than 0.05 compared with each control). The percent neutrophils recovered by bronchoalveolar lavage was increased during the late response, and this was significantly correlated with pulmonary resistance (p less than 0.01). Histamine levels in BALF were elevated during the immediate response but not during the late response. Our results suggest that histamine and LTC4 may contribute to the contraction of bronchial smooth muscle in the immediate and the late response, respectively. The increase in LTB4, a neutrophil chemotactic factor, during the late response may be responsible for the increase in the percent neutrophils.

Topics: Administration, Inhalation; Animals; Antigens; Ascaris; Bronchial Spasm; Bronchoalveolar Lavage Fluid; Chromatography, High Pressure Liquid; Histamine Release; Humans; Hypersensitivity; Hypersensitivity, Delayed; Leukocyte Count; Leukotriene B4; Neutrophils; Radioimmunoassay; Sheep; SRS-A

1. Inflammatory cells such as eosinophils and neutrophils are thought to contribute actively to the pathogenesis of asthma by the release of bronchoconstrictor mediators including leukotrienes. Previous studies have revealed the almost exclusive synthesis of leukotriene C4 (LTC4) by human eosinophils and of leukotriene B4 (LTB4), 20-OH-LTB4 and the non-enzymatically formed LTB4-isomers by neutrophils when stimulated in vitro with the calcium ionophore A23187 or opsonized zymosan (OZ). In this study we have investigated whether nedocromil sodium, a new anti-asthma drug, was capable of inhibiting A23187- and OZ-induced leukotriene formation by these cells. 2. Nedocromil sodium inhibited A23187- and OZ-induced LTC4 formation by eosinophils in a concentration-dependent manner (mean IC30 for A23187: 5.6 X 10(-5) M; mean IC30 for OZ: 6.3 X 10(-5) M), whereas it did not inhibit A23187- and OZ-induced LTB4 formation by neutrophils. 3. Extension of the preincubation time of the cells with the drug did not alter the observed inhibitory capacity. The optimal preincubation time was 5 min. 4. The in vitro inhibition of LTC4 formation by eosinophils by nedocromil sodium may be a valuable property of this drug in the treatment of asthma.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Asthma; Calcimycin; Eosinophils; Humans; Hypersensitivity; In Vitro Techniques; Leukotriene B4; Nedocromil; Neutrophils; Quinolones; Zymosan

The effect of glucocorticosteroid (GCS) treatment on ovalbumine-induced IgE-mediated immediate and late allergic response was studied in sensitized guinea pigs. The results show that the GCS budesonide (BUD) inhibits the allergen-induced IgE-mediated immediate and late bronchial obstruction. The effect on the early reaction is correlated to the inhibition of leukotrienes and histamine release. The importance of mediator release inhibition for the antianaphylactic effect of GCS is discussed. In examining the effect on the late reaction, it was found that BUD had to be present during the early reaction but did not inhibit the early reaction. Furthermore, the effect on the late reaction was correlated to the inhibition of vascular leakage but not to the infiltration of inflammatory cells as examined in bronchoalveolar lavage. The results indicate that some triggering factors important for the development of the late reaction are released during the early reaction. Inhibition of the release of that factor or the activation of inflammatory cells by that factor might be the mechanism behind the antiinflammatory activities of GCS.

Topics: Anaphylaxis; Animals; Antigens; Bronchi; Bronchial Provocation Tests; Budesonide; Cromolyn Sodium; Dimercaprol; Guinea Pigs; Histamine Release; Hypersensitivity; Hypersensitivity, Delayed; Immunoglobulin E; Leukotriene B4; Lung; Ovalbumin; Peptide Hydrolases; Pregnenediones; SRS-A

In an attempt to understand the relationship between viral upper respiratory tract infection and the underlying virological and immunological mechanisms, thirty-four volunteers were inoculated intranasally with coronavirus 229E; subsequent virus shedding and/or antibody rises, indicating active infection, were observed in twenty-nine. There was a greater increase in independently measured scores of clinical severity, e.g. cold symptoms, in those with detectable IgE in nasal secretions (P less than 0.01). A similar association was found between clinical scores and serum IgE concentrations greater than or equal to 150 IU/ml, but the relationship with systemic atopy, as assessed by skin-prick tests to common allergens, was less marked. A more detailed study of twelve of the infected volunteers failed to explain these findings on the basis of mast cell mediator release, as concentrations of leukotriene B4, the sulphidopeptide leukotriene C4, and histamine, were not appreciably elevated in the nasal secretions following virus inoculation. Similarly, there was no evidence that circulating coronavirus specific IgE was produced. Thus, this study suggest that atopy may be related to the severity of cold symptoms produced by coronavirus 229E, although the exact connection has yet to be determined.

Topics: Adolescent; Adult; Antibodies, Viral; Coronaviridae Infections; Female; Histamine; Humans; Hypersensitivity; Immunoglobulin E; Leukotriene B4; Male; Middle Aged; Skin Tests; SRS-A

The mechanism of the anti-inflammatory effect of proglumetacin maleate, a novel indomethacin derivative, was examined in vivo in an allergic air pouch inflammation model in rats. Proglumetacin maleate did not affect the volume of pouch exudate 6 h after immunological challenge, irrespective of whether it was administered orally or locally, but it caused dose-dependent inhibition 24 h after challenge. It also caused dose-dependent reduction of leukocyte migration into the pouch exudate both 6 and 24 h after challenge. It markedly decreased the prostaglandin E2 content of the pouch exudate, but tended to increase the leukotriene B4 content. The main metabolites of proglumetacin maleate, desproglumideproglumetacin maleate and indomethacin, had effects similar to those of proglumetacin maleate on these four parameters on an equimolar dose basis. Unlike these three drugs, dexamethasone decreased the leukotriene B4 content of the pouch exudate. These results suggest that the action of proglumetacin maleate is qualitatively the same as that of indomethacin in vivo; that is, it inhibits cyclo-oxygenase in inflammatory sites.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Dexamethasone; Dinoprostone; Exudates and Transudates; Hypersensitivity; Indoleacetic Acids; Indomethacin; Inflammation; Injections, Subcutaneous; Leukotriene B4; Male; Prostaglandins E; Rats; Rats, Inbred Strains

Topics: Animals; Anti-Inflammatory Agents; Bronchial Provocation Tests; Colchicine; Humans; Hypersensitivity; Immunoglobulin E; In Vitro Techniques; Leukotriene B4; Prednisone

Amoxanox has potent antiallergic activity because it inhibits the release of chemical mediators such as histamine and leukotrienes. We studied the in vitro effect of amoxanox on arachidonic acid metabolism, including the lipoxygenase and cyclooxygenase pathways. Amoxanox inhibited calcium ionophore A23187-induced formation of 5-HETE, LTB4, SRS-A (LTC4, LTD4 and LTE4), and 12-HETE in rat peritoneal resident monocytes. These results indicate that amoxanox inhibits 5- and 12-lipoxygenases. The compound, however, did not affect the formation of TXB2 or 6-keto-PGF1 alpha in guinea pig lung fragments and PGE2 or PGF2 alpha in bovine seminal vesicles, suggesting that it did not inhibit cyclooxygenase. These results show that the antiallergic action of amoxanox is associated, at least in part, with the reduction of leukotrienes due to the inhibition of lipoxygenases.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; 5,8,11,14-Eicosatetraynoic Acid; Aminopyridines; Animals; Asthma; Calcimycin; Cattle; Guinea Pigs; Histamine H1 Antagonists; Hydroxyeicosatetraenoic Acids; Hypersensitivity; In Vitro Techniques; Leukotriene B4; Lipoxygenase Inhibitors; Lung; Male; Monocytes; Prostaglandins; Rats; Rats, Inbred Strains; SRS-A; Thromboxane B2

Antigen-induced contractions of passively sensitized preparations of human bronchi and lung parenchymal strips were studied. Mepyramine did not affect the magnitude or time course of the contractile responses of either preparation. Indomethacin potentiated the responses of lung parenchymal strips, but inhibited those of bronchial preparations. Responses of both tissues were inhibited by the leukotriene antagonist FPL 55712, by the lipoxygenase inhibitor BW 755C, and by the anti-allergic compound disodium cromoglycate Disodium cromoglycate and BW 755C inhibited histamine release from lung parenchymal strips. The results indicate an important role for leukotrienes in allergic contraction of both large and small human airways, while histamine is of little importance. Bronchoconstrictor prostaglandins may also contribute to the response of large airways.

Topics: Bronchi; Chromones; Cromolyn Sodium; Histamine; Humans; Hypersensitivity; In Vitro Techniques; Indomethacin; Leukotriene B4; Lung; Muscle, Smooth; Prostaglandins; SRS-A

Topics: Chemical Phenomena; Chemistry; Humans; Hypersensitivity; Leukotriene B4; SRS-A

Topics: Animals; Anti-Inflammatory Agents; Arachidonic Acid; Arachidonic Acids; Cyclooxygenase Inhibitors; Humans; Hypersensitivity; Inflammation; Leukotriene B4; Phospholipases A; Prostaglandin Endoperoxides; Prostaglandin-Endoperoxide Synthases; Prostaglandins; SRS-A; Thromboxane-A Synthase

Topics: Humans; Hypersensitivity; Inflammation; Leukotriene B4; SRS-A

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

The production of leukotrienes has been monitored in tear fluids from subjects following a conjunctival provocation test, and skin blister fluids following initiation of a Prausnitz-Kustner reaction. In tear fluids elevated levels of leukotriene C4 (LTC4)-immunoreactive material were measured following allergen challenge as compared to control tear fluid obtained by mechanical or reflex stimulation. Analysis by high performance liquid chromatography indicated the presence of LTC4, LTD4 and LTE4. In the skin, significantly elevated levels of LTC4-immunoreactive material were measured following allergen challenge in the Prausnitz-Kustner reaction. HPLC analysis indicated the presence of both LTC4 and LTD4. LTB4 immunoreactive material was detected both in the tear fluid and the skin tissue fluid. However, no significant increase occurred in either tissue after the allergic reactions. These results indicate that the SRS-A leukotrienes are released in vivo in man following allergen challenge, and indicate these mediators may be important in human allergic diseases.

Topics: Adolescent; Adult; Conjunctiva; Female; Humans; Hypersensitivity; Leukotriene B4; Male; Radioimmunoassay; Skin; SRS-A; Tears

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

Topics: Animals; Anti-Inflammatory Agents; Calcium Channel Blockers; Cardiovascular System; Digestive System; Glucocorticoids; Humans; Hypersensitivity; Leukotriene B4; Muscle Contraction; Respiratory System; SRS-A

Topics: Adolescent; Adult; Aged; Burns; Female; Humans; Hypersensitivity; Leukocytes; Leukotriene B4; Lymphocytes; Male; Middle Aged; Time Factors

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: Chemotaxis, Leukocyte; Granulocytes; Histamine; Humans; Hypersensitivity; Immunoglobulin E; Inflammation; Leukotriene B4; Lipoxygenase; Mast Cells; Neutrophils; Prostaglandins; SRS-A

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