Journal of Applied Physiology, Vol 56, Issue 4 999-1007, Copyright © 1984 by American Physiological Society
Cyclooxygenase inhibition during phorbol-induced granulocyte stimulation in awake sheep
J. H. Newman, J. E. Loyd, M. L. Ogletree, B. O. Meyrick and K. L. Brigham
In vitro, phorbol myristate acetate (PMA) causes sheep granulocytes to
release superoxide. Infused into sheep, PMA causes leukopenia, hypoxemia,
pulmonary hypertension, and increased flow of protein-rich lung lymph. Lung
lymph thromboxane B2 and 6-ketoprostaglandin F1 alpha levels rise markedly
after PMA infusion. To see whether cyclooxygenase products of arachidonic
acid mediate the lung vascular responses to PMA, we infused 5 micrograms/kg
PMA twice in each of six sheep, once in the presence of sodium
meclofenamate and once alone. We varied the order of paired experiments and
allowed 4-7 days between experiments. Meclofenamate (5 mg/kg loading dose +
3 mg X kg-1 X h-1 infusion) given alone had no effect on base-line
variables. Meclofenamate inhibited or delayed the initial pulmonary
hypertension and hypoxemia after PMA but exaggerated the later increase in
pulmonary arterial pressure; it prevented any increase in thromboxane B2
and 6-ketoprostaglandin F1 alpha after PMA. Meclofenamate did not affect
the degree of leukopenia or the severity of the later hypoxemia nor did it
prevent accumulation of granulocytes in the lung. Lung lymph flow was
higher with meclofenamate + PMA than with PMA alone, but lymph-to-plasma
protein concentration ratio was lower, suggesting that the main effect of
meclofenamate on lymph production after PMA was related to the degree of
pulmonary hypertension. We conclude that the early increase in pulmonary
arterial pressure caused by PMA is mediated by a cyclooxygenase product of
arachidonic acid, possibly thromboxane A2, but the later pulmonary
hypertension and the increase in pulmonary vascular permeability are not
the result of cyclooxygenase products.
