leukotriene-b4 and Bronchial-Spasm

The sheep model of allergic airway disease shares many pathophysiological similarities with allergic airway disease in humans. Studies performed in this animal model present strong evidence that the release of arachidonic acid metabolites plays an important role in the development of late bronchial responses to antigen challenge. The release of leukotrienes through the lipoxygenase pathway during the acute bronchial obstruction after inhalation of Ascaris suum antigen represents the key factor for the initiation of the subsequent events, namely the late phase response and the bronchial hyperreactivity. If this hypothesis can be substantiated in patients with bronchial asthma then pharmacologic modification of the lipoxygenase pathway and/or products may be important in the treatment of asthma.

Topics: Animals; Arachidonic Acids; Ascaris; Bronchial Provocation Tests; Bronchial Spasm; Disease Models, Animal; Hypersensitivity, Delayed; Leukotriene B4; Sheep; SRS-A

Evidence has been presented that lipoxygenase products of arachidonic acid metabolism released during the early stages of allergic reactions play an important role in the subsequent development of late bronchial responses. Moreover, because of this, the activity of the lipoxygenase pathway and sensitivity to the products generated may be important factors that distinguish between dual and acute responders. We recognize that these studies were performed in an experimental animal model of allergic airway disease. If the same mechanisms that are active in sheep are proven active in humans, then pharmacologic modification of the lipoxygenase pathway or its products (or both) may be important for the treatment of some forms of asthma.

Topics: Allergens; Animals; Arachidonate 5-Lipoxygenase; Arachidonic Acid; Arachidonic Acids; Asthma; Bronchial Spasm; Disease Models, Animal; Hypersensitivity, Delayed; Hypersensitivity, Immediate; Leukotriene B4; Models, Biological; Platelet Activating Factor; Prostaglandin-Endoperoxide Synthases; Sheep; SRS-A

Topics: Acetophenones; Allergens; Animals; Asthma; Bronchial Provocation Tests; Bronchial Spasm; Dogs; Humans; Leukotriene B4; Leukotriene E4; Sheep; SRS-A; Tetrazoles

In conclusion, we have described a novel series of acetohydroxamic acids that are potent and selective inhibitors of arachidonate 5-lipoxygenase in vitro and in vivo. In addition, we have shown that these compounds attenuate "leukotriene-dependent" anaphylactic bronchospasm, the accumulation of inflammatory leukocytes, and the development of fever in experimental models. It now remains to be determined if these compounds have any therapeutic value in man.

Topics: 5,8,11,14-Eicosatetraynoic Acid; Anaphylaxis; Animals; Arachidonate 5-Lipoxygenase; Arachidonate Lipoxygenases; Arachidonic Acid; Arachidonic Acids; Bronchial Provocation Tests; Bronchial Spasm; Fever; Gastric Mucosa; Guinea Pigs; Humans; Hydroxamic Acids; Inflammation; Leukocytes; Leukotriene B4; Lipoxygenase Inhibitors; Masoprocol; Rats; SRS-A

The complement anaphylatoxin peptides, C3a and C5a, are potential mediators of immediate hypersensitivity reactions, eliciting many of the same actions on isolated tissue and cell preparations as specific antigen. Instilled intratracheally in experimental animals, the peptides induce acute bronchospasms and are sometimes lethal. In vitro, they cause dose-dependent contraction of isolated lung tissue preparations, a response which correlates well with bronchospasms observed in vivo, and our current understanding of the cellular and molecular mechanisms of this action are reviewed here. C5a and its catabolic derivative, C5ades Arg, stimulate contraction of isolated guinea pig lung parenchymal strips in part by production of leukotrienes that constitute SRS-A, and by release of histamine. Leukotrienes in turn release thromboxane from lung tissue, and evidence indicates that at least part of the spasmogenic activity of these peptidolipids is mediated by this effect. C3a is considerably less potent than C5a in contracting lung tissues and appears to act primarily by causing the release of spasmogenic cyclooxygenase metabolites. Both peptides may additionally have direct action on contractile cells within the tissue. Platelet-activating factor (PAF), an unusual phospholipid mediator released from inflammatory cells stimulated with C5a and other agents, also contracts isolated lung parenchymal tissues. PAF stimulates release of significant quantities of thromboxane from guinea pig lung; however, indomethacin does not block contractile responses of the tissue. Recent evidence indicates that PAF may act on parasympathetic neurons in lung to release endogenous acetylcholine, and this action may be a major component of tissue responses to this mediator. Thus the complement anaphylatoxins stimulate release of many of the same mediators from lung tissues as are released by antigen challenge of sensitized tissue, and may, therefore, play an important role in the pathogenesis of allergic bronchospasms.

Topics: Anaphylatoxins; Animals; Bronchi; Bronchial Spasm; Complement Activation; Complement C3; Complement C3a; Complement C5; Complement C5a; Dose-Response Relationship, Drug; Inflammation; Leukotriene B4; Lung; Mice; Muscle Contraction; Peptides; Platelet Activating Factor; SRS-A

The likelihood that the leukotriene products derived from the 5-lipoxygenase pathway mediate aspects of obstructive airways diseases is strongly suggested by their documented capacities to effect airway spasmogenicity, airway hyperreactivity, tissue edema formation, mucus secretion, and tissue infiltration by leukocytes. That the various leukotriene components of SRS-A have unique receptors on responding tissues and are recoverable from airway surfaces in several inflammatory lung diseases and that several resident and infiltrating cell types have significant potential for leukotriene biosynthesis lend further support to their postulated pathobiologic roles. To fulfill Koch's postulates for proof of leukotrienes' etiologic role, it remains to be shown that inhibition of their biosynthesis or specific antagonism at their end-organ receptors can greatly ameliorate these disease states.

Topics: Animals; Arachidonate Lipoxygenases; Bronchial Spasm; Dose-Response Relationship, Drug; Humans; Hydroxyeicosatetraenoic Acids; In Vitro Techniques; Leukotriene B4; Lipoxygenase; Lung; Lung Diseases, Obstructive; Macrophages; Mast Cells; Monocytes; Pulmonary Alveoli; Pulmonary Ventilation; Receptors, Leukotriene; Receptors, Prostaglandin; SRS-A; Vital Capacity

Topics: 5,8,11,14-Eicosatetraynoic Acid; Anaphylaxis; Asthma; Bronchi; Bronchial Spasm; Fatty Acids, Unsaturated; Humans; Leukotriene B4; Lipoxygenase; Muscle, Smooth; SRS-A

Recent evidence suggests that leukotrienes may have a causative role in exercise-induced asthma. Twenty-four subjects with exercise-induced asthma received either 600 mg zileuton, a 5-lipoxygenase inhibitor, or a placebo four times daily for 2 d prior to exercise challenge (a total of nine doses). The last dose was administered in the laboratory 2 h before the exercise challenge. There was no bronchodilation after nine doses of the 5-lipoxygenase inhibitor (p=0.95). The administration of zileuton inhibited bronchospasm after exercise challenge by 40.75% as compared with placebo. Five minutes after the completion of exercise, the zileuton group's FEV1 was 85.76% of the preexercise value, compared with 73.92% of the preexercise value in the placebo group (p<0.01). The maximum percent change in baseline FEV1 after zileuton was a 15.58% decrement from the preexercise level, as compared with a 28.1% decrease after placebo (p<0.001). Five minutes after exercise, the FVC after zileuton was 92.76% of the preexercise value, as compared with 86.26% after placebo (p<0.05). This is the first study in which a 5-lipoxygenase inhibitor has been shown to attenuate exercise-induced asthma. These results suggest that leukotrienes are important biochemical mediators in the development of exercise-induced bronchospasm, and that leukotriene inhibit may have a role in the treatment of this disorder.

Topics: Adult; Albuterol; Anti-Asthmatic Agents; Asthma, Exercise-Induced; Bronchial Spasm; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Forced Expiratory Volume; Humans; Hydroxyurea; Inflammation Mediators; Leukotriene Antagonists; Leukotriene B4; Leukotriene C4; Leukotrienes; Lipoxygenase Inhibitors; Vital Capacity

The importance of leukotrienes as mediators of inflammation and bronchoconstriction was examined with two recently described 5-lipoxygenase inhibitors, zileuton and A-78773. Preclinical evaluation of these two molecules indicates that they are potent, selective, direct, reversible inhibitors of 5-lipoxygenase with activity in a variety of purified cells and in more complex biological systems such as whole blood, lung fragments, and tracheal tissues. In various animals models of inflammation and allergy, the molecules inhibited edema, inflammatory cell influx, and bronchospasm. These observations are consistent with the recent clinical success of zileuton in treating asthma and inflammatory bowel disease. In all preclinical systems tested thus far, A-78773 is more potent and longer acting than zileuton, indicating that the molecule could be even more effective in the clinic than zileuton and that both molecules are useful tools in defining the role of leukotrienes in preclinical and clinical settings.

Topics: Animals; Bronchial Spasm; Guinea Pigs; Hydroxyurea; Inflammation; Leukotriene B4; Lipoxygenase Inhibitors; Lung; Male; Rats

Aspirin and nonsteroidal antiinflammatory drugs induce bronchospastic reactions in patients with aspirin-sensitive respiratory disease. Although the mechanism of this reaction is unknown, all drugs that induce the respiratory reaction also inhibit the cyclooxygenase enzyme. The ensuing changes in arachidonate metabolism are presumed to play a role in the pathogenesis of the reaction. We measured generation of leukotrienes and thromboxane by calcium ionophore stimulated blood monocytes. Before aspirin challenge, monocytes released significantly more thromboxane B2 in patients with aspirin sensitivity than in patients without aspirin sensitivity or in healthy control subjects (p < 0.02). During aspirin-induced bronchospasm, release of leukotriene B4 increased significantly (45.5%, p = 0.018), whereas release of thromboxane B2 decreased (-46.9%, p = 0.028). Two hours after ingestion of 60 mg aspirin, normal monocyte release of thromboxane B2 did not drop, whereas leukotriene B4 release increased. Monocytes formed only minimal amounts of leukotriene C4. We conclude that the profile of released eicosanoids from aspirin-sensitive monocytes is distinct from non-aspirin-sensitive subjects, and that these differences could contribute to the development of bronchospasm after aspirin ingestion.

Topics: Administration, Oral; Adult; Arachidonic Acid; Aspirin; Asthma; Bronchial Spasm; Calcimycin; Eicosanoids; Female; Humans; Leukotriene B4; Male; Middle Aged; Monocytes; Thromboxane B2

6-Hydroxy-2-(4-sulfamoylbenzylamino)-4,5,7-trimethylbenzothiazo le hydrochloride (E6080), an orally active and selective 5-lipoxygenase inhibitor, dose-dependently inhibited the bronchospasm induced by antigen (ovalbumin) inhalation in sensitized conscious guinea pigs. The inhibitory effect of E6080 was more potent than that of a typical 5-lipoxygenase inhibitor, AA861, but less than that of a leukotriene (LT) antagonist, LY171883. When airway infiltration of neutrophils and eosinophils was measured in bronchoalveolar lavage fluid (BALF) at 6 h after antigen inhalation by passively sensitized guinea pigs, the inhibitory effect of E6080 on neutrophil infiltration was more marked than that on eosinophil infiltration. The inhibitory effect of E6080 on bronchoalveolar cellular infiltration and bronchoepithelial damage was confirmed by examination of photomicrographs of the lung. In addition to the above pharmacological effects, E6080 inhibited the increase in BALF levels of both i-LTC4 and i-LTB4. These results suggest that E6080 may prove to be effective for the treatment of asthma, in which large amounts of leukotrienes (LTs) are elaborated.

Topics: Acetophenones; Animals; Autacoids; Benzoquinones; Bronchial Spasm; Bronchoalveolar Lavage Fluid; Eosinophils; Guinea Pigs; Leukotriene B4; Leukotrienes; Lipoxygenase Inhibitors; Male; Neutrophils; SRS-A; Tetrazoles; Thiazoles

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

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Bronchial Spasm; Dogs; In Vitro Techniques; Leukotriene B4; Muscle, Smooth; Ozone; Platelet Activating Factor; Prostaglandin Endoperoxides, Synthetic; SRS-A; Synaptic Transmission; Thromboxane A2; Trachea

To explore the mechanisms of grain dust-induced acute bronchoconstriction, extracts of grain dust were incubated with chopped human lung fragments. The supernatants of the incubation media were examined for the presence of leukotrienes and histamine with high-performance liquid chromatographic techniques. Human lung fragments responded to the extract of grain dust by releasing histamine in a dose-dependent manner. Moreover, leukotrienes (B4, D4, and E4 were also found to be released. The action of grain dust appeared to be independent of the complement pathway or cell cytotoxicity since the lung tissue released the chemical mediators in the absence of plasma and responded to further reaction with compound 48/80 after interaction with grain dust. These data demonstrate that grain-dust extract may induce the release of mediators of anaphylaxis by a nonimmunologic process. This may explain the occurrence of acute bronchoconstriction in some of the grain workers.

Topics: Allergens; Bronchial Spasm; Chromatography, High Pressure Liquid; Dust; Edible Grain; Histamine Release; Humans; In Vitro Techniques; Leukotriene B4; Lung; SRS-A

Amoxanox inhibited immunologically stimulated and LTD4-induced bronchoconstriction in laboratory animals. Amoxanox, like DSCG, inhibited rat IgE-mediated PCA and histamine release from rat peritoneal mast cells, and suppressed immunologically stimulated or calcium ionophore A23187-induced SRS-A generation in rat peritoneal cavity and guinea pig lung fragments. This compound also reduced the contractile response of guinea pig lung parenchymal and ileal strips to LTD4, but did not significantly affect the response of the ileum to either histamine or acetylcholine. Therefore, the antiallergic action of amoxanox seems to be associated with inhibition of chemical mediator release and antagonistic activity on SRS-A.

Topics: Aminopyridines; Animals; Bronchial Spasm; Female; Guinea Pigs; Histamine Release; Immunoglobulin E; Ionophores; Leukotriene B4; Lung; Male; Mast Cells; p-Methoxy-N-methylphenethylamine; Passive Cutaneous Anaphylaxis; Rats; 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 mechanism of action of ketotifen in the prevention of bronchial asthma is discussed, the pathogenesis of the disease itself being taken as a starting point. The following biological effects of ketotifen may be relevant to its therapeutic activity: the inhibition of release of myotonic mediators, leukotrienes in particular, the inhibition of slow reacting substances-induced bronchoconstriction in vivo, calcium antagonistic properties, and the prevention or reversal of decreased beta-adrenoceptor sensitivity. In asthmatic patients the prevention of bronchospasm due to mediator release and a progressive reduction of bronchial hyperreactivity are the major consequences of these properties.

Topics: Animals; Asthma; Bronchial Spasm; Guinea Pigs; Histamine Release; Humans; In Vitro Techniques; Ketotifen; Leukocytes; Leukotriene B4; Mast Cells; Peritoneum; Rats; SRS-A

Leukotrienes and prostaglandins possess properties which are central in the asthmatic reaction. They are bronchoconstrictors, they inhibit the mucociliary clearance, increase blood flow and permeability and thereby induce edema formation, and they attract and activate leukocytes. They are formed partly by allergic reactions and partly by a large number of other more non-specific reactions. Finally, the concentration of prostanoids has been found increased in the asthmatic reaction in vivo. The leukotrienes have not been traced in vivo in asthmatic attacks so far, but have been found in vivo in man in a specific type I allergic conjunctival reaction. Much evidence suggests that these mediators are relevant in asthmatic diseases, even though prostaglandin inhibitors have no effect in asthma. There still remains the need to investigate the influence on asthmatic diseases by as yet unavailable leukotriene blocking agents. Even though leukotrienes are judged today to be important mediators in asthma, it does not seem reasonable to expect that a single mediator is responsible for asthmatic diseases. Rather, it seems quite likely that asthma is caused by a complex interplay of a large number of mediators, circulating hormones, nervous mechanisms, receptor abnormalities, intracellular metabolic defects, etc. Despite this complexity, investigations in recent years have increased the knowledge of the biochemistry and human physiological effects of leukotrienes and prostaglandins which has created an improved understanding of the asthmatic reaction's pathophysiology, contributed a pharmacological rationale for previously used therapy, and stimulated new perspectives for specific pharmacological research.

Topics: Anti-Inflammatory Agents; Arachidonic Acid; Arachidonic Acids; Asthma; Autacoids; Bronchial Spasm; Ciliary Motility Disorders; Cyclooxygenase Inhibitors; Edema; Enzyme Inhibitors; Histamine Release; Humans; Leukotriene B4; Leukotrienes; Mast Cells; Prostaglandins