Chest
Volume 89, Issue 5, May 1986, Pages 709-716
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Clinical Investigations
Leukotriene-associated Toxic Oxygen Metabolites Induce Airway Hyperreactivity

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The effect of toxic oxygen metabolite scavengers was examined in a guinea pig trachealis model of leukotriene (LTD4)-induced synergism upon histamine contractures. Under both physiologic (2.5 mM) and low (OmM) extracellular calcium conditions, LTD4 (10−7 to 10−9 M) potentiated histamine isometric tension responses. This LTD4-induced histamine hyperresponse was inhibited by pretreatment with Superoxide dismutase. Inhibition of LTD4 receptor binding by FPL 55712 (10−5 M) also aborted this interaction. Actual trachealis superoxide anion (O2) generation by LTD4 was observed with a maximal release of 15 nM O2/CPK unit × 10−2 over 60 min. Phorbol myristate acetate (PMA) also generated O 2 in this preparation. Trachealis muscle hyperreactivity to histamine induced by 10−8 M LTD4 assayed in OmM (Ca++)E was not induced by PMA. It is concluded that exogenous LTD4 activates toxic oxygen metabolites which interact to induce an acquired hyperreactivity to agonist histamine in trachealis smooth muscle.

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Materials and Methods

Isometric tension of guinea pig trachealis to agonists was obtained after equilibration at a resting tension of 2.0 g for 60 min at 37°C in Krebs-Henseleit (KH) buffer gassed with 95 percent O2-5 percent CO2. KH contained either physiologic extracellular calcium (2.5 mM)E or was calcium-free/low calcium (OmM). Isometric tension methods and KH composition have been recently detailed.4 Cumulative histamine concentration-response curves by successive microliter increments were acquired in a paired

Results

Cumulative histamine concentration-tension responses in 2.5 mM (Ca++)E following LTD4 (10−9 to 10−7M) incubation were hyperresponsive, exhibiting an increase in both maximal tension and a leftward shift of the EC50 (Fig 1; Table 1). The maximal mg isometric tension values for histamine alone and for histamine with LTD4 (10−7M) were 1,710 ± 195 and 2,308 ± 305, respectively (p<0.01). Although acetylcholine alone (10−5M) increased the isometric tension baseline by 53 percent (Fig 1), the maximal

Discussion

This study confirms an enhancement of histamine contractures upon guinea pig airways smooth muscle induced by leukotriene-D4. The sulfidopeptide leukotrienes are spasmogenic upon airways smooth muscle with effects upon both small and central airways. In human airways they are 200 to 3,000 times more potent than histamine, with several studies indicating their extremely potent bronchoconstrictor activity.2, 10, 11, 12, 13

It is currently not clear whether leukotrienes per se cause hyperreactivity

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  • Cited by (0)

    Supported in part by a grant from the Foundation for Research in Bronchial Asthma and Related Disorders.

    Manuscript received June 27; revision accepted November 4.

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