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 · l^-1 · min) and microvascular filtration coefficient (K(f), 0.024 ± 0.002 to 0.040 ± 0.006 g · min^-1 · cmH₂O^-1) in isolated blood-perfused rabbit lungs. ADO (5 μmol/min) blocked the increases in PVR (257 ± 9 to 283 ± 26) and K(f) (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 K(f) (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.