Studies on the release of leukotrienes and histamine by human lung parenchymal and bronchial fragments upon immunologic and nonimmunologic stimulation. Effects of nordihydroguaiaretic acid, aspirin, and sodium cromoglycate.
Fragments of human lung parenchyma or bronchi were studied by high performance liquid chromatography, gas chromatography-mass spectrometry, and bioassay for the biosynthesis of 5-lipoxygenase metabolites of arachidonic acid, and by radioenzymatic assay for the release of histamine, upon immunologic and nonimmunologic stimulation. Human lung parenchyma were passively sensitized with serum from timothy-positive allergic patients (radioallergosorbent test, 30-40%) and challenged with 0.5 microgram/ml of timothy allergen. Analysis of the incubation media showed the presence of LTB4, LTC4, LTD4, LTE4, and histamine. Maximum release of LTB4 and LTD4 was observed after 15 min of challenge (92.8 +/- 21, and 67.8 +/- 14 pmol/g tissue wet weight, respectively; mean +/- SEM) whereas maximum release of LTC4 was observed after 5 min of challenge (25 +/- 7.1 pmol). In parallel to leukotriene formation, histamine was released rapidly and reached a maximum after approximately 15 min of challenge (2.85 +/- 0.76 nmol/g tissue). When fragments of human lung parenchyma were stimulated with ionophore A23187 (4 microM), we observed a profile of leukotriene and histamine release similar to that seen in response to the allergen. Ionophore A23187 stimulated the release of two- to fivefold greater amounts of leukotrienes and histamine than did the allergen. Release of LTC4 and histamine was maximal after 5 min of stimulation (83 +/- 22.2 and 5.2 +/- 0.95 nmol/g tissue, respectively), whereas LTB4 and LTD4 release reached a maximum after 15 min (438 +/- 66.6 and 205 +/- 68 nmol/g tissue, respectively). In addition, human lung parenchyma metabolized LTB4 into omega-OH-LTB4 and omega-COOH-LTB4. This tissue also released 5-hydroxy-eicosatetraenoic acid (5-Hete), 12-Hete, and 15-Hete. Fragments of human lung bronchi also released a similar profile of leukotrienes (except LTC4) and histamine when challenged with the allergen or ionophore A23187. Maximum release of LTB4 and LTD4 by allergen or ionophore stimulation was observed after approximately 15 min (40 +/- 7.5 and 21 +/- 8 pmol/g tissue, respectively, upon allergen challenge; 100 +/- 13 and 47 +/- 10.6 pmol/g tissue, respectively, upon ionophore stimulation). The maximum release of histamine by bronchi was observed after approximately 15 min of allergen challenge and 5 min of ionophore stimulation (2.25 +/- 0.65 and 3.15 +/- 0.9 nmol/g tissue, respectively). The release of leukotrienes but not of histamine by human lung parenchyma upon both allergen and ionophore challenge was inhibited by nordihydroguaiaretic acid (NDGA) (ID50, 2 X 10(-6)M).(ABSTRACT TRUNCATED AT 400 WORDS)
Salari
H
H
Borgeat
P
P
Fournier
M
M
Hebert
J
J
Pelletier
G
G
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D001091:Arachidonate Lipoxygenases; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D001241:Aspirin / Q000494:pharmacology; D001980:Bronchi / Q000276:immunology / Q000378:metabolism; D002396:Catechols / Q000494:pharmacology; D004205:Cromolyn Sodium / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D007975:Leukotriene B4 / Q000378:metabolism; D008084:Lipoxygenase / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors; D008168:Lung / Q000276:immunology / Q000378:metabolism*; D009637:Masoprocol; D013189:SRS-A / Q000378:metabolism
D000276:Adjuvants, Immunologic; D001095:Arachidonic Acids; D002396:Catechols; D016859:Lipoxygenase Inhibitors; D013189:SRS-A; D007975:Leukotriene B4; D016718:Arachidonic Acid; D009637:Masoprocol; D001091:Arachidonate Lipoxygenases; D008084:Lipoxygenase; D004205:Cromolyn Sodium; D001241:Aspirin