Involvement of thromboxane in injury to isolated rat lungs perfused with phorbol myristate acetate in the presence and absence of neutrophils.
In a previous study, we demonstrated that a non-toxic concentration of phorbol myristate acetate (PMA) produced edema in isolated rat lungs which were coperfused with neutrophils (PMN). In this study, we examined whether prostaglandins or thromboxane were responsible for increases in pressure and/or edema in this preparation. In lungs perfused with PMA (14 ng/ml) and PMN (1 X 10(8], significantly greater amounts of thromboxane B2 (TxB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were produced than in controls. Relative lung weights and increases in perfusion pressure correlated with concentrations of TxB2 and 6-keto-PGF1 alpha that were produced. Indomethacin (10 microM) or Dazmegrel (10 microM) retarded the increase in perfusion pressure and prevented the increase in relative lung weight induced by PMA and PMN. When lungs were perfused with a high concentration of PMA (57 ng/ml) in the absence of added PMN, lungs also become edematous. Compared to controls, concentrations of TxB2 and 6-keto-PGF1 alpha were elevated in media collected from this preparation. As with lungs perfused with PMN and PMA, increases in pressure and relative weights of lungs perfused with PMA (57 ng/ml) correlated with the concentrations of TxB2 that were detected in perfusion media. Although indomethacin (10 microM) and Dazmegrel (50 microM) retarded the increase in perfusion pressure in this preparation, they only partially attenuated the increase in lung weight. These results suggest that, depending on the concentration, PMA can produce lung injury via different mechanisms. Thromboxane does not seem to be required for the genesis of edema induced by a high concentration of PMA in the absence of perfused neutrophils; however, it appears to play an obligatory role in the pathogenesis of edema induced by a low concentration of PMA in the presence of PMN.
Carpenter
L J
LJ
Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824.
Roth
R A
RA
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism*; D000818:Animals; D007093:Imidazoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009504:Neutrophils / Q000502:physiology*; D009929:Organ Size; D010477:Perfusion; D011312:Pressure; D011654:Pulmonary Edema / Q000139:chemically induced; D051381:Rats; D011919:Rats, Inbred Strains; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*; D013929:Thromboxane B2 / Q000378:metabolism*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
D007093:Imidazoles; C039242:dazmegrel; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D013930:Thromboxane-A Synthase; D013755:Tetradecanoylphorbol Acetate; D007213:Indomethacin