Mechanisms of pulmonary edema induced by tumor necrosis factor-alpha.
We tested the hypothesis that human recombinant tumor necrosis factor-alpha (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 10(6) total) into lungs isolated after the in vivo administration of TNF (3.2 x 10(5) 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 [Kf,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 microM), a platelet activating factor (PAF) receptor antagonist, indicated that PAF mediated the increased vascular permeability (Kf,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 Kf,c (mediated by PAF), and changes in endothelial peripheral actin bands.
Hocking
D C
DC
Research Service, Veterans Administration Medical Center, Albany, NY 12208.
Phillips
P G
PG
Ferro
T J
TJ
Johnson
A
A
D000199:Actins / Q000378:metabolism; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D001696:Biomechanical Phenomena; D002199:Capillary Permeability; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009504:Neutrophils / Q000502:physiology; D009929:Organ Size; D011652:Pulmonary Circulation; D011654:Pulmonary Edema / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha; D014655:Vascular Resistance
D000199:Actins; D001095:Arachidonic Acids; D014409:Tumor Necrosis Factor-alpha; D016718:Arachidonic Acid