Allergen challenge of lung tissue from asthmatics elicits bronchial contraction that correlates with the release of leukotrienes C4, D4, and E4.

Abstract

The leukotrienes C4, D4, and E4, previously referred to as slow reacting substance of anaphylaxis, elicited longlasting contractions of bronchi isolated from two birch pollen-sensitive asthmatics. The leukotrienes were 1,000 times more potent on a molar basis than was histamine or prostaglandin F2a. Moreover, allergen released leukotrienes C4, D4, and E4 from the lung tissue of the asthmatics in amounts that appeared to correlate well to the anaphylactic bronchial contraction. Irrespectively of whether the lung was stimulated with specific allergen, the ionophore A23187 or "4C-labeled arachidonic acid, 15-hydroxyicosatetraenoic acid, and other lipoxygenase-derived monohydroxy acids were the major metabolites of arachidonic acid in the lung, and thromboxane A2 and prostaglandin 12 were the predominant cyclooxygenase products identified. However, cyclooxygenase inhibition with indomethacin had no effect on the contraction response to antigen in the bronchi, whereas, in the presence of U-60257, an inhibitor of leukotriene biosynthesis, the allergen neither released leukotrienes from the lung nor caused bronchial contraction. These findings indicate that leukotrienes C4, D4, and E4 are major mediators of allergic bronchoconstriction in man.

Antigen‐induced contraction of guinea‐pig isolated trachea: studies with novel inhibitors and antagonists of arachidonic acid metabolites

“…Similarly, contraction to antigen can be elicited in passively (Dunlop & Smith, 1975;Dunlop et al, 1977;Adams & Lichtenstein, 1979;Davis et al, 1982) and intrinsically sensitized human tracheobronchial smooth muscle (Davis et al, 1982;Dahlen et al, 1983). The nature of the mediators and mechanisms involved in ' Author for correspondence.…”

“…this response have been the subject of extensive biochemical and pharmacological investigation over the years (Chand & Eyre, 1978;Adams & Lichtenstein, 1979;Hand & Buckner, 1979;Burka & Paterson, 1980;1981ab;Saad et al, 1983;De Nucci et al, 1986). Conclusions about the precise contribution of various mediators to the contractile response vary depending on the species studied (Dunlop & Smith, 1975;Dunlop et al, 1977;Dahlen et al, 1983;Jones et al, 1987), the type of antibody mediating the response (Andersson, 1980;Regal, 1984;Undem et al, 1985) the nature of the experiment (biochemical or functional response) and the experimental conditions such as the presence or absence of additional blocking drugs (Hand et al, 1986).…”

Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells

“…Human tracheal epithelial cells, chopped human bronchi, and human lung homogenates convert arachidonic acid mainly to 15-HETE (5,12). Lung specimens from asthmatic subjects produce more 15-HETE than specimens from nonasthmatic subjects (13)(14)(15). Increased amounts of 15-HETE have been found in bronchoalveolar lavage fluid (BALF) of antigenchallenged atopic asthmatic patients (16), in sputum samples from asthmatic subjects (17), and in nasal secretions from healthy control subjects (18).…”

The effects of low dose leukotriene receptor antagonist therapy on airway remodeling and cysteinyl leukotriene expression in a mouse asthma model

“…The CysLTs are released from human lung due to allergic subjects in response to challenge with allergen (Dahlen et al, 1983). Hanazawa et al (2000) showed significant increases in CysLTs in breath condensates of patients with moderate and severe asthma, compared with normal subjects.…”