MECHANISMS OF PULMONARY-EDEMA INDUCED BY TUMOR NECROSIS FACTOR-ALPHA

We tested the hypothesis that human recombinant tumor necrosis factor-α (TNF) promotes pulmonary edema by neutrophil-dependent effects on the pulmonary vasculature. The isolated guinea pig lung was perfused with phosphate-buffered Ringer's solution with or without human neutrophils. The infusion of neutrophils (9 x 106 total) into lungs isolated after the in vivo administration of TNF (3.2 x 105 units/kg) resulted in weight gain (+1.951 ± 0.311 g versus -0.053 ± 0.053 g in control) and an increase in the lung (wet-dry)-to-dry weight ratio (8.3 ± 0.5 versus 6.0 ± 0.2 in control), indicating the formation of pulmonary edema. The neutrophil-dependent pulmonary edema induced by TNF was associated with a combination of increased capillary permeability (capillary filtration coefficient [K(f,c)], and 0.170 ± 0.048 g/min/cm H2O/g at 30 minutes versus 0.118 ± 0.008 g/min/cm H2O/g at baseline) and increased pulmonary capillary pressure (P(pc), 12.8 ± 0.8 cm H2O at 60 minutes versus 6.0 ± 0.3 cm H2O at baseline). The P(pc) increase was mediated by thromboxane A2 (TXA2) because the TXA2 synthetase inhibitor Dazoxiben (0.5 mM) prevented the effect (P(pc), 6.7 ± 0.6 cmH2O at 60 minutes with Dazoxiben), and thromboxane B2 (TXB2) levels were increased in the pulmonary venous effluent (5,244 ± 599 pg/ml at 60 minutes versus 60 ± 13 pg/ml at baseline). Studies using WEB-2086 (37 μM), a platelet activating factor (PAF) receptor antagonist, indicated that PAF mediated the increased vascular permeability (K(f,c), 0.107 ± 0.014 g/min/cm H2O/g at 30 minutes using WEB-2086) and, in part, the increased P(pc) (P(pc), 84. ± 0.7 cm H2O at 60 minutes using WEB-2086). In addition, alterations of endothelial peripheral actin bands were noted after TNF administration. The data indicate that TNF induces neutrophil-dependent pulmonary edema associated with increased P(pc) (mediated by TXA2 and PAF), increased K(f,c) (mediated by PAF), and changes in endothelial peripheral actin bands.