Hyperoxic lung damage in mice: appearance and bioconversion of peptide leukotrienes.
High concentrations of oxygen damage the lung and increase bronchoalveolar lavage (BAL) fluid levels of leukotrienes. We sought to identify the specific leukotrienes produced and their relationship to the severity of the lung damage and the inflammatory cell populations by exposing mice to 100% oxygen for up to 4 days. Leukotrienes were not detected in BAL fluid from air-exposed mice. Leukotriene D4 (LTD4) was found after 2 days of exposure to 100% oxygen, increased with longer periods of exposure, and then decreased while LTE4 appeared when the lung damage became severe. LTB4 and LTC4 were not found at any time. Neutropenic mice had identical results, indicating that neutrophils were not the source of the leukotrienes. To determine why LTC4 was not found and why LTD4 decreased and LTE4 increased on day 4, we measured the metabolic capacity of BAL supernatant for leukotrienes. Incubation of LTD4 in BAL supernatant from air-exposed mice resulted in the conversion of LTD4 to LTE4, which was blocked by L-cysteine, a dipeptidase inhibitor. Faster conversion occurred after exposure to 100% oxygen for 3 and 4 days. The rate of bioconversion correlated with the BAL protein concentration (r = 0.756, P less than 0.001), and it was similar in neutropenic and nonneutropenic mice. Little LTC4 and no LTE4 were converted in BAL supernatant from air- or oxygen-exposed mice. The early and progressive increase in LTD4 suggests that sulfidopeptide leukotrienes may play a role in the pathogenesis of hyperoxic lung damage. The increased dipeptidase activity during hyperoxic exposure may serve a protective role by converting the more potent LTD4 to the less potent LTE4.
Smith
L J
LJ
Department of Medicine, Northwestern University Medical School, Chicago, Illinois.
Shamsuddin
M
M
Anderson
J
J
Hsueh
W
W
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000032:analysis*; D002851:Chromatography, High Pressure Liquid; D011464:Epoprostenol / Q000032:analysis; D007975:Leukotriene B4 / Q000032:analysis / Q000378:metabolism*; D017999:Leukotriene E4; D008168:Lung / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000378:metabolism; D010100:Oxygen / Q000633:toxicity*; D011863:Radioimmunoassay; D013189:SRS-A / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism*; D013928:Thromboxane A2 / Q000032:analysis
D013189:SRS-A; D007975:Leukotriene B4; D013928:Thromboxane A2; D017999:Leukotriene E4; D011464:Epoprostenol; D010100:Oxygen