Release of leukotrienes, induced by the Ca++ ionophore A23187, from human lung parenchyma in vitro.
When chopped human lung is stimulated with the Ca++ ionophore A23187 (0.25-10 microM) leukotriene (LT) B4, LTD4 and LTE4 are found in the incubation medium according to different patterns. LTD4 is released promptly and its levels increase up to 45 min after the stimulus (A23187, 10 microM) and decline later (120 min); LTE4 formation follows a sigmoidal shape and continues to accumulate even 2 hr after the challenge; LTB4 levels reach a plateau at 45 min. LTC4 was undetectable in most experiments but it was found to accumulate when reduced glutathione (10 mM) was added. Addition of exogenous LTC4 to unstimulated fragments of human lung shows that an effective interconversion to LTD4 and LTE4 takes place: A23187 stimulates formation of LT and cyclo-oxygenase products dose dependently; a statistically significant formation of LT occurs at A23187 concentration of 1 microM whereas thromboxane B2 (TXB2) and 6-K-prostaglandin F1 alpha levels increased significantly only at 2.5 microM A23187. Pretreatment with U-60257 (100 microM) prevented formation of LT without a concomitant increase of TXB2 levels. Indomethacin (1.5 microM) blocked the release of 6-K-prostaglandin F1 alpha and TXB2 without a shift of arachidonic acid towards LT-like activity. Addition of exogenous LTC4 did not trigger synthesis of TXB2 or 6-K-prostaglandin F1 alpha. Our results indicate that reduced glutathione levels and the activity of the enzymes involved in LT biosynthesis and/or metabolism play an important role in controlling the pattern of LT release from human lung.
Sautebin
L
L
Viganò
T
T
Grassi
E
E
Crivellari
M T
MT
Galli
G
G
Berti
F
F
Mezzetti
M
M
Folco
G
G
D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D007975:Leukotriene B4 / Q000378:metabolism*; D017999:Leukotriene E4; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D013189:SRS-A / Q000031:analogs & derivatives / Q000378:metabolism*
D001095:Arachidonic Acids; D013189:SRS-A; D007975:Leukotriene B4; D016718:Arachidonic Acid; D000001:Calcimycin; D017999:Leukotriene E4; D005978:Glutathione