The effect of tumor necrosis factor-α on microvascular permeability in an isolated, perfused lung

This study examines the hypotheses that TNF-alpha causes a dose-dependent increase in the microvascular permeability of ex vivo buffer perfused lungs that is quantitatively similar to that caused by lipopolysaccharide (LPS) or thromboxane A(2) (TxA(2)). We also postulated that TNF-alpha potentiates the effect of interleukin-1beta (IL-1beta) or TxA(2) receptor activation on pulmonary microvascular permeability. Lungs harvested from Wistar rats were perfused ex vivo with Krebs-Henseleit buffer containing 0, 10, 100, or 1000 ng/mL recombinant rat TNF-alpha. Twenty minutes later pulmonary microvascular permeability was determined by measuring the capillary filtration coefficient (K-f) using a gravimetric technique. The effect of TNF-alpha (100 ng/mL) on pulmonary Kf was compared with that of lungs exposed to LPS (400 mug/mL; E. coli 0111:B34) or a TxA(2) receptor agonist (U-46619; 7 x 10(-8)). In other experiments, perfused lungs were exposed to TNF-alpha plus IL-1beta (1 ng/mL) or TNF-alpha plus U-46619 after which K-f was measured. Exposure of ex vivo buffer perfused lungs to 10 - 1000 ng/mL TNF-a had no effect on K-f whereas LPS and U-46619 was associated with a two- and six-fold increase in K-f, respectively (P < 0.05). The K-f of lungs exposed to TNF-alpha plus IL-1 was similar to that of lungs exposed to TNF-alpha alone. Lastly, the K-f of lungs exposed to TNF-alpha plus U-46619 was not different than that of lungs exposed to U-46619 alone. In conclusion, TNF-alpha at least when administered for a relatively brief period of time does not affect microvascular permeability in an isolated, buffer-perfused lung model.