Tumor necrosis factor α-induced pulmonary vascular endothelial injury

Tumor necrosis factor α (TNF-α) mediates components of the acute-phase response, stimulates granulocyte metabolism, and induces endothelial cell surface changes. We studied whether human recombinant TNF-α (rTNF-α) could increase pulmonary edema formation and pulmonary vascular permeability. Rabbits preinfused with ¹²⁵I-albumin were administered rTNF-α or saline. Animals were sacrificed, and lung wet/dry weight ratios as well as bronchoalveolar lavage fluid and plasma ¹²⁵I activities were determined. rTNF-α increased lung wet/dry weight ratios by 151% (P < 0.02) and bronchoalveolar lavage fluid plasma ¹²⁵I activity ratios by 376% (P < 0.01) compared with values for saline controls. Electron microscopy of lung sections demonstrated endothelial injury, perivascular edema, and extravasation of an ultrastructural permeability tracer. To demonstrate that rTNF-α could directly increase pulmonary vascular endothelial permeability in vitro, we studied albumin transfer across cultured porcine pulmonary artery endothelial cell monolayers. rTNF-α induced time-dependent dose-response increments in transendothelial albumin flux in the absence of granulocyte effector cells. These observations suggest that rTNF-α can provoke acute pulmonary vascular endothelial injury in vivo as well as in vitro.