Effects of thromboxane synthase inhibition on tumor necrosis factor-induced lung injury in sheep.
To examine the role of thromboxane (Tx) A2 in the pathogenesis of acute lung injury caused by tumor necrosis factor alpha (TNF), we tested the effects of OKY-046, a selective thromboxane synthase inhibitor, on pulmonary hemodynamics, lung lymph balance, circulating leukocytes, arterial blood gas analysis, and TxA2 (as TxB2) and prostacyclin (as 6-keto-prostaglandin F1 alpha) levels in plasma and lung lymph after TNF infusion in awake sheep. Infusion of human recombinant TNF (3.5 micrograms/kg) into a chronically instrumented awake sheep caused a transient increase in pulmonary arterial pressure (Ppa). The Ppa peaked within 15 min of the start of TNF infusion from 23.3 +/- 1.1 (SE) cmH2O of baseline to 42.3 +/- 2.3 cmH2O and then decreased toward baseline. The pulmonary hypertension was accompanied by transient hypoxemia, peripheral leukopenia, and the increases in TxB2 in plasma and lung lymph. These changes were followed by an increase in flow of protein-rich lung lymph, consistent with an increase in pulmonary microvascular permeability. OKY-046 significantly prevented the rises of Ppa and TxB2 concentrations in plasma and lung lymph during early phase after TNF infusion. OKY-046, however, did not attenuate the increase of lung lymph flow, transient hypoxemia, and leukopenia. From these data, and by comparison with our previous studies of OKY-046-pretreated sheep during endotoxemia, we conclude that TxA2 has an important role of the increase in the early pulmonary hypertension, but it is not related to the early hypoxemia, leukopenia, and lung lymph balances in TNF-induced lung injury.(ABSTRACT TRUNCATED AT 250 WORDS)
Koizumi
T
T
First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
Kubo
K
K
Kobayashi
T
T
Sekiguchi
M
M
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D001784:Blood Gas Analysis; D006439:Hemodynamics / Q000187:drug effects; D007958:Leukocyte Count; D008168:Lung / Q000502:physiology; D008171:Lung Diseases / Q000139:chemically induced* / Q000503:physiopathology; D008208:Lymphatic System / Q000502:physiology; D008689:Methacrylates / Q000494:pharmacology; D012756:Sheep; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha
D008689:Methacrylates; D014409:Tumor Necrosis Factor-alpha; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D013930:Thromboxane-A Synthase; C034364:ozagrel