Journal of Applied Physiology
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J Appl Physiol 73: 2493-2498, 1992;
8750-7587/92 $5.00
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Journal of Applied Physiology, Vol 73, Issue 6 2493-2498, Copyright © 1992 by American Physiological Society

ARTICLES

OKY-046 prevents increases in LTB4 and pulmonary edema in phorbol ester-induced lung injury in dogs

R. S. Sprague, A. H. Stephenson and A. J. Lonigro
Department of Medicine, Saint Louis University School of Medicine, Missouri 63104.

Thromboxanes (Txs) were implicated as possible participants in the altered microvascular permeability of acute lung injury when the Tx synthase inhibitor, OKY-046, was reported to prevent pulmonary edema induced by phorbol myristate acetate (PMA). Recently, however, we found that OKY-046, at a dose just sufficient to block Tx synthesis in intact dogs, did not prevent PMA-induced pulmonary edema but rather merely reduced it modestly. The present study was designed to explore other mechanisms whereby OKY-046 might prevent PMA-induced pulmonary edema. The finding that 5-lipoxygenase (5-LO) metabolites of arachidonic acid were increased within the lung after PMA administration, coupled with the report that OKY-046 inhibited slow-reacting substance of anaphylaxis formation, permitted formulation of the hypothesis that OKY-046, at a dose in excess of that required to inhibit Tx synthesis, inhibits the formation of a product(s) of 5-LO and, thereby, prevents edema formation. In vehicle-pretreated pentobarbital-anesthetized male mongrel dogs (n = 4), PMA (20 micrograms/kg i.v.) increased pulmonary vascular resistance (PVR) from 4.4 +/- 0.3 to 26.3 +/- 8.8 mmHg.l-1 x min (P < 0.01) and extravascular lung water from 6.7 +/- 0.5 to 19.1 +/- 6.2 ml/kg body wt (P < 0.05). Concomitantly, both TxB2 and leukotriene B4 (LTB4) were significantly increased in the lung. Pretreatment with OKY-046 (100 mg/kg i.v., n = 8) prevented PMA-induced increases in TxB2, LTB4, and pulmonary edema formation but did not prevent the increase in PVR.(ABSTRACT TRUNCATED AT 250 WORDS)


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Y. Kim, R. Y. Imdad, A. H. Stephenson, R. S. Sprague, and A. J. Lonigro
Vascular Endothelial Growth Factor mRNA in Pericytes Is Upregulated by Phorbol Myristate Acetate
Hypertension, January 1, 1998; 31(1): 511 - 515.
[Abstract] [Full Text] [PDF]


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