Adenosine prevents phorbol ester injury in rabbit lungs: role of leukotrienes and TNF.
The objective of this study was to determine whether adenosine (ADO) prevents phorbol myristate acetate- (PMA) induced lung injury by modulating peptidoleukotrienes (LT) and/or tumor necrosis factor (TNF) production. PMA significantly increased pulmonary vascular resistance (PVR, 275 +/- 4 to 447 +/- 30 cmH2O.1-1.min) and microvascular filtration coefficient.(Kf, 0.024 +/- 0.002 to 0.040 +/- 0.006 g.min-1.cmH2O-1) in isolated blood-perfused rabbit lungs. ADO (5 mumol/min) blocked the increases in PVR (257 +/- 9 to 283 +/- 26) and Kf (0.028 +/- 0.005 to 0.018 +/- 0.002). After PMA (30 min), perfusate levels of LTC4 + LTD4 increased by 15.3 +/- 2.1 pg/ml; LTE4 increased by 15.1 +/- 4.1 pg/ml. ADO reduced the increase in LTC4 + LTD4 to 2.7 +/- 6.1 pg/ml, but total LT increased by 31.9 +/- 16.6 pg/ml, implying that ADO enhanced the conversion of LTC4 and LTD4 to LTE4. MK-886 (L663,536), an LT synthesis inhibitor, blocked the increase in total LT (6.1 +/- 13.9 pg/ml) but did not reduce the PMA-induced increase in Kf (0.022 +/- 0.003 to 0.035 +/- 0.005) or PVR (238 +/- 11 to 495 +/- 21). After PMA administration, perfusate TNF levels were not different from the 10-fold increase observed in control experiments and were not reduced by ADO or MK-886. TNF production was independent of perfusate blood components and presumably due to low levels of endotoxin in the perfusate (70-90 ng/ml). These results indicate that ADO does not protect against PMA-induced acute lung injury by altering circulating levels of LT or TNF.
Bradley
J D
JD
Department of Anesthesiology, St. Louis University School of Medicine, Missouri 63110.
Zanaboni
P B
PB
Webster
R O
RO
Baudendistel
L J
LJ
Dahms
T E
TE
D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D020024:Leukotriene Antagonists; D015289:Leukotrienes / Q000096:biosynthesis; D008168:Lung / Q000187:drug effects* / Q000502:physiology; D055370:Lung Injury; D008297:Male; D010477:Perfusion; D011817:Rabbits; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014655:Vascular Resistance / Q000187:drug effects; D002722:Chlorobenzenes
D000241:Adenosine; D007211:Indoles; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D013755:Tetradecanoylphorbol Acetate; D014409:Tumor Necrosis Factor-alpha; C060893:MK-886; D002722:Chlorobenzenes