Endothelin1 potentiates leukotoxin-induced edematous lung
injury.
Ishizaki, Takeshi, Kazuo Shigemori, Tsuguhiko Nakai, Susumu Miyabo,
Mika Hayakawa, Takayuki Ozawa, Norbert F. Voelkel, Shih-Wen Chang.
Dept. of Internal Medicine, Fukui Medical School, Fukui, Japan,
910-11, Dept. of Biomedical Chemistry, University of Nagoya, Nagoya,
Japan 466, Pulmonary Hypertension Center, Div. of Pulmonary Sciences
and Critical Care Medicine, Univ. of Colorado Health Sciences Center,
Denver, Co 80262., Pulmonary Section, Dept. of Medicine, Northwestern
Univ. Medical School, Chicago, IL 60611
APStracts 2:0232A, 1995.
We tested the hypothesis that Leukotoxin (Lx), a cytochrome P450
-dependent linoleate product of leukocytes, can stimulate the release
of endothelin 1 (ET1) from the lung and further that exogenous ET1
synergizes with Lx, to produce edematous lung injury. In isolated rat
lungs perfused with Earle's balanced salt solution Lx (10 [mu]mol)
alone caused lung edema and increased the perfusate and lung tissue
ET1 levels. The combination of ET1 (5 nM) and Lx (5 [mu]mol), at
concentrations which by themselves did not increase wet lung weight
(WLW), significantly increased WLW, wet to dry lung weight (WLW/DLW)
as well as the lung effluent lactate dehydrogenase activity (LDH).
Pretreatment with BQ123 (5x10-6 M), an ETA receptor antagonist, which
significantly attenuated the ET1 (5 nM)-induced increase in Ppa and
Pc, suppressed the edematous lung injury generated by the combination
of ET1 and Lx, suggesting that the edema-enhancing effect of ET1 in
Lx-treated lungs occurred through ETA-receptor-dependent elevation of
Ppa and Pc. Elevation of the pulmonary venous pressure in Lx-treated
lungs (13.5 cm H2O), mimicked the effect of ET1 on Ppa and Pc and
produced a degree of lung edema which was comparable to that after
combined ET1 + Lx treatment, but without increase in the perfusate
LDH. These data support the idea that ET1 and Lx promote lung edema
in a synergistic fashion.
Received 13 February 1995; accepted in final form 24 May 1995.
APS Manuscript Number A164-5.
Article publication pending Journal of Applied Physiology.
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 8 June 1995.