Tumor Necrosis Factor Causes Increased Pulmonary Permeability and Edema: Comparison to Septic Acute Lung Injury

Abstract

Tumor necrosis factor .alpha. (TNF), a monokine produced by mononuclear cells in response to bacterial endotoxin (LPS), creates a syndrome similar to septic shock in animal models. To study whether TNF could induce acute lung injury similar to that seen in gram-negative sepsis, we injected recombinant human TNF (rHuTNF.alpha.) into the guinea pigs and monitored arterial blood gases, leukocyte counts, and left atrial (Pla), pulmonary artery (Ppa), and mean arterial pressures (MAP) serially for 8 h. Pulmonary histopathology was assessed microscopically, and cell counts and 125I-labeled albumin (125I-albumin) in bronchoalveolar lavage (BAL) fluid and lung wet/dry weight ratios were determined. Five groups of animals were studied; the 2 TNF groups received high (1.4 .times. 104 U/kg) or low (1.0 .times. 106 U/kg) doses of rHuTNF.alpha., the sepsis group received 2 .times. 109 Echerichia coli/kg intravenously, and the control group received saline. An LPS control group receiving 40 ng/kg E. coli LPS was also included because the rHuTNF.alpha. contained a small amount of LPS as a contaminant. Pulmonary permeability was assessed by studying the Pla and the BAL fluid/plasma 125I-albumin ratio (permeability index). The permeability index was significantly increased in the high-dose TNF (0.0408 .+-. 0.0041, p < 0.05) and sepsis groups (0.0466 .+-. 0.0068, p < 0.01) relative to controls (0.0215 .+-. 0.0028). The wet/dry lung weight ratios were also significantly increased in the high-dose TNF (6.07 .+-. 0.29, p < 0.05), and sepsis groups (6.22 .+-. 0.30, p < 0.05) relative to the control group (5.18 .+-. 0.20). The mean Pla was not elevated in these groups, demonstrating that the increased albumin flux was due to increased permeability and not hemodynamic changes. The permeability index in the LPS (0.307 .+-. 0.0068) and low-dose TNF (0.0245 .+-. 0.0033) groups wre not significantly different from that of controls. These results demonstrate that injection of a single mediator, rHuTNF.alpha., can produce increased pulmonary permeability and edema, and suggest that TNF could contribute to the pathogenesis of septic acute lung injury.