Effect of tumor necrosis factor-alpha, IL-1beta, and IL-6 on interstitial fluid pressure in rat skin

Interstitial fluid pressure (P(if)) decreases in several experimental models of acute inflammation, enhancing edema formation. The present study was designed to determine the effect of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and IL-1beta as well as lipopolysaccharides (LPS) on P(if) in a model of gram-negative sepsis. P(if) was measured in the paw skin of anesthetized rats (pentobarbital sodium, 50 mg/kg ip) using micropipettes (3-7 micrometer) and servo-controlled counterpressure technique. Test substances were injected intra-arterially (ia), intravenously (iv), or subdermally (sd). After intra-arterial or intravenous administration, the test substances were circulated for 1 min before circulatory arrest was induced with an intravenous injection of KCl while the rats were under pentobarbital anesthesia. Circulatory arrest was induced to avoid edema formation, which would raise interstitial fluid volume to cause a more positive P(if). Administration of 0.5 ml of LPS (5 mg/ml ia) lowered P(if) significantly from control values of -0.2 +/- 0.3 to -2.0 +/- 0.3 mmHg (P < 0.05) within 1 h. Corresponding values for TNF-alpha (500 ng/ml iv) were -0.4 +/- 0.2 to -2.3 +/- 0.1 mmHg (P < 0.05). Administration of 5 microliter (5 mg/ml sd) of LPS did not affect P(if) significantly (P > 0.05), but TNF-alpha, IL-1beta, and IL-6 had a significant effect on P(if) when given subdermally. IL-6 (50 ng/ml) caused a decrease in P(if) from control values of -1.2 +/- 0.3 to -2. 8 +/- 0.5 mmHg (P < 0.05) within 1 h. The experiments demonstrate that LPS, TNF-alpha, IL-1beta, and IL-6 induce lowering of P(if) when given intravenously or intra-arterially, whereas only TNF-alpha, IL-1beta, and IL-6 induce lowering of P(if) when given subdermally. We therefore suggest that the lowering of P(if) in this experimental model of sepsis is related to the release of and a local effect in skin of TNF-alpha, IL-1beta, and IL-6.