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

Interstitial fluid pressure (P-if) decreases in several experimental models of acute inflammation, enhancing edema formation. The present study was de signed to determine the effect of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and IL-1 beta 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 pm) and servo-controlled counterpressure technique. Test substances we re injected intra-arterially (ia), intravenously (iv), or subdermally (sd). After intra-arterial or intravenous administration, the test substances we re circulated for 1 min before circulatory arrest was induced with an intra venous 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 v alues for TNF-alpha (500 ng/ml iv) were -0.4 +/- 0.2 to -2.3 +/- 0.1 mmHg ( P < 0.05). Administration of 5 pi (5 mg/ml sd) of LPS did not affect P-if s ignificantly (P > 0.05), but TNF-alpha, IL-1 beta, and IL-6 had a significa nt effect on P-if when given subdermally. IL-6 (50 ng/ml) caused a decrease in Pif 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-1 beta, an d IL-6 induce lowering of P-if when given intravenously or intra-arterially , whereas only TNF-alpha, IL-1 beta, and IL-6 induce lowering of Pif when g iven subdermally. We therefore suggest that the lowering of Pif in this exp erimental model of sepsis is related to the release of and a local effect i n skin of TNF-alpha, IL-1 beta, and IL-6.