Suppression of fluid pumping in isolated bovine mesenteric lymphatics by Interleukin-1: Interaction with prostaglandin E 2

Abstract

In addition to local physiological forces, the modulation of lymphatic pumping by chemical mediators may play an important role in the regulation of extravascular water in inflammation and shock. Since Interleukin-1 (IL-1) appears to be of major importance in the host's response to infection by mediating many inflammatory events, we thought it important to determine if this cytokine could affect the lymphatic circulation and in particular to ask whether IL-1 was capable of altering lymphatic pumping in response to changes in transmural pressure. Bovine lymphatic segments (6 to 8 cm in length) were cannulated at both ends and suspended in an organ bath preparation. The vessels were provided with Krebs solution from a reservoir. With no net driving pressure, a transmural pressure applied to the ducts elicited contractile activity and fluid pumping with increases in pumping up to 8 cm H 2O and reductions in flow above this level of distension. Human recombinant IL-1α (10 −7 to 10 −9 M) administered into the lumina of the vessels depressed pumping activity approximately 5–30% at transmural pressures between 2 and 16 cm H 2O. With limited supplies, we could only assess the effects of human recombinant IL-1β at 10 −8 M. However, it was more potent than IL-1α, inhibiting pumping at all transmural pressures with maximum suppression in the range of 70% at peak flows. The ability of IL-1 to induce prostaglandin synthesis may be one of its most important biologic functions. It is likely therefore that IL-1 and PGE 2 are closely linked and are probably present together in inflammatory lesions. With this in mind, we investigated the effects of PGE 2 alone and in combination with IL-1α. PGE 2 by itself reduced pumping at concentrations between 10 −6 and 10 −9 M. When mixed with IL-1α (both agents at a final concentration of 10 −9 M), the mixture had a marked inhibitory effect on flow, reducing pumping 50 to 70% at peak flows. The effect of the mixture of IL-1α and PGE 2 compared with the two agents administered separately was greater than the predicted additive effect at transmural pressures above 6 cm H 2O. At lower transmural pressures, however, the level of real inhibition was less than the predicted additive effect. Measurements of outflow pressures from the isolated vessels revealed only subtle changes with IL-1α or PGE 2 alone, but the administration of the two agents together produced very irregular pressure patterns illustrating a marked effect on contractile activity. We conclude that IL-1 alone or in combination with PGE 2 reduces the sensitivity of the vessels to pressure changes and decreases the maximum pumping capabilities of the vessel. We speculate that this may have an impact on the ability of the lymphatics to remove extravasated fluid and protein from the tissue spaces in inflammatory and shock states.