Effects of ONO-5046, a specific neutrophil elastase inhibitor, on endotoxin-induced lung injury in sheep.
The purpose of the present study was to assess the role of polymorphonuclear leukocyte (neutrophil) elastase in endotoxin-induced acute lung injury in sheep with lung lymph fistula. We studied the effects of ONO-5046, a specific inhibitor of neutrophil elastase, on the lung dysfunction induced by the intravenous infusion of 1 microgram/kg of Escherichia coli endotoxin. Endotoxin alone produced a biphasic response as previously reported. Early (0.5-1 h) after endotoxin, pulmonary arterial pressure increased from 19.5 +/- 0.9 cmH2O at baseline to a peak of 46.8 +/- 2.4 cmH2O (P < 0.05). Pulmonary vascular resistance increased from 3.03 +/- 0.17 cmH2O.l-1.min at baseline to a peak of 9.77 +/- 0.70 cmH2O.l-1.min (P < 0.05). Circulating neutrophils decreased from 7,355 +/- 434/mm3 at baseline to a nadir of 1,762 +/- 32/mm3 (P < 0.05). Thromboxane B2 and 6-ketoprostaglandin F1 alpha concentrations in plasma and lung lymph were significantly increased. Late (3-5 h) after endotoxin, pulmonary arterial pressure and pulmonary vascular resistance returned to baseline levels, but lung lymph flow remained increased from 4.2 +/- 0.3 ml/0.5 h at baseline to 7.3 +/- 0.7 ml/0.5 h (P < 0.05), with a slight increase in lung lymph-to-plasma protein concentration ratio, suggesting increased pulmonary vascular permeability. The histopathological features of the lungs during the early period in sheep treated with endotoxin alone revealed a large increase in neutrophils per 100 alveoli and changes of pulmonary edema such as thickening of the interstitium of the lung and alveolar flooding.(ABSTRACT TRUNCATED AT 250 WORDS)
Kubo
K
K
Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
Kobayashi
T
T
Hayano
T
T
Koizumi
T
T
Honda
T
T
Sekiguchi
M
M
Sakai
A
A
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D016470:Bacteremia / Q000473:pathology / Q000503:physiopathology*; D001784:Blood Gas Analysis; D004731:Endotoxins / Q000097:blood; D004927:Escherichia coli Infections / Q000473:pathology / Q000503:physiopathology*; D004950:Esterases / Q000037:antagonists & inhibitors* / Q000097:blood; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D007962:Leukocytes / Q000187:drug effects; D008171:Lung Diseases / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology* / Q000503:physiopathology*; D008196:Lymph / Q000502:physiology; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology*; D011652:Pulmonary Circulation / Q000187:drug effects; D012756:Sheep; D013449:Sulfonamides / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000378:metabolism
D004731:Endotoxins; D013449:Sulfonamides; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C069195:sivelestat; D004950:Esterases; D005998:Glycine