Mechanisms of Pulmonary Edema Induced by Tumor Necrosis Factor-α

• Published in: Circulation research 1990-07, Vol.67 (1), p.68-77
• Main Authors: Hocking, Denise C, Phillips, Patricia G, Ferro, Thomas J, Johnson, Arnold
• Format: Article
• Language: English
• Subjects: Actins - metabolism; Animals; Arachidonic Acid; Arachidonic Acids - metabolism; Biological and medical sciences; Biomechanical Phenomena; Capillary Permeability; Cardiology. Vascular system; Chronic cor pulmonale; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Guinea Pigs; Heart; In Vitro Techniques; Lung - metabolism; Lung - pathology; Lung - physiopathology; Medical sciences; Neutrophils - physiology; Organ Size; Pneumology; Pulmonary Circulation; Pulmonary Edema - chemically induced; Pulmonary Edema - metabolism; Pulmonary Edema - physiopathology; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Tumor Necrosis Factor-alpha; Vascular Resistance
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.67.1.68

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 Ringerʼs solution with or without human neutrophils. The infusion of neutrophils (9 × 10 total) into lungs isolated after the in vivo administration of TNF (3.2 × 10 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 [Kt,c] 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 (Ppc, 12.8±0.8 cm H2O at 60 minutes versus 6.0±0.3 cm H2O at baseline). The Ppc increase was mediated by thromboxane A2 (TXA2) because the TXA2 synthetase inhibitor Dazoxiben (0.5 mM) prevented the effect (Ppc, 6.7±0.6 cm H2O 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 (Kt,c, 0.107±0.014 g/min/cm H2O/g at 30 minutes using WEB-2086) and, in part, the increased Ppc (Ppc, 8.4±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 Ppc (mediated by TXA2 and PAF), increased Kt,c (mediated by PAF), and changes in endothelial peripheral actin bands.