Yonago Acta medica 1998;41:45–52
The Relevance of Leukotriene B4 to the Development of Acute Lung Injury Induced by Lipopolysaccharide
Kozo Hidaka and Yuichi Ishibe
Department of Anesthesiology and Reanimatology, Faculty of Medicine, Tottori University, Yonago 683-0826 Japan
Acute lung injury (ALI) induced by lipopolysaccharide (LPS) develops by the
activation of leukocytes via various mediators. Leukotriene B4 (LTB4)
has a strong effect on activation and migration of leukocytes. We investigated the
role of LTB4 in the chain leading to the development of ALI induced by
LPS, by observing how an LTB4 receptor antagonist, ONO-4057, suppresses
or mitigates leukocyte activation and migration. The 36 rabbits used in the experiment
were divided into 3 groups: C group (control group of 12 rabbits treated with physiological
saline solution only); L group (of 12 rabbits treated with 20 µg/kg LPS) and L-O
group (of 12 rabbits treated with, first, 10 mg/kg ONO-4057, then LPS). Blood samples
were taken before, 3 h after and 6 h after the injection of drugs; then the rabbits
were exsanguinated. The right and left lungs were removed for wet/dry weight ratio
and bronchoalveolar lavage fluid (BALF) measurements, respectively. We measured:
the leukocyte counts in the peripheral blood, the chemiluminescence (CL) intensity
to measure the amount of oxygen free radical species (active oxygen species) production,
the LTB4 concentration in the blood, the complement activity levels (CH50),
the polymorphonuclear neutrophil elastase (PMN-E) and myeloperoxidase (MPO) levels
in BALF, and the wet/dry weight ratio of the right lung. The leukocyte counts in
L and L-O rabbits decreased significantly 3 h after LPS injection, then were regained
by the 6th h. Regarding CL (with and without zymosan stimulation), there was no significant
difference over time for C group. For L group, the zymosan-stimulated CL showed a
significant increase at the 6th h, whereas the non-stimulated CL showed significant
increases at the 3rd and 6th h. For L-O group, the zymosan-stimulated CL showed a
significant increase at the 6th h, whereas the non-stimulated CL increased after
3 h, then slightly decreased after 6 h. The LTB4 levels showed significant
increases at the 6th h for both L and L-O groups. The CH50 showed significant decreases
at 6th h for both L and L-O groups. The MPO activity in the BALF was significantly
high for both the L and L-O groups. There was a tendency for a high PMN-E level in
the BALF for L group. The mean wet/dry weight ratio of the right lung was significantly
high for L group, compared to both C and L-O groups. Although an inhibitory effect
on LTB4 receptors by ONO-4057 failed to prevent leukocyte migration, it
successfully suppressed the activity of non-stimulated CL, MPO and PMN-E, and, as
a result, prevented the wet/dry weight ratio from increasing.
Key words: ALI; LPS; LTB4; LTB4 receptor antagonist
