Journal of Applied Physiology, Vol 64, Issue 3 944-951, Copyright © 1988 by American Physiological Society
Hyperoxic lung damage in mice: appearance and bioconversion of peptide leukotrienes
L. J. Smith, M. Shamsuddin, J. Anderson and W. Hsueh
Department of Medicine, Northwestern University Medical School, Chicago, Illinois.
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.
