ENDOGENOUS INTERLEUKIN-10 REGULATES HEMODYNAMIC PARAMETERS, LEUKOCYTE-ENDOTHELIAL CELL-INTERACTIONS, AND MICROVASCULAR PERMEABILITY DURING ENDOTOXEMIA

The objective of this study was to determine whether endogenous IL-10 is capable of regulating hemodynamic parameters, leukocyte recruitment , and microvascular permeability in response to endotoxin. Intravital microscopy was used to examine hemodynamic parameters, leukocyte rolli ng and adhesion, and microvascular permeability in cremasteric postcap illary venules in wild-type mice and in IL-10-deficient (IL-10(-/-)) m ice exposed to lipopolysaccharide (LPS). Doses of LPS (3 or 30 mu g/kg , IV), which did not reduce blood pressure and minimally altered micro vascular hemodynamic factors in wild-type mice, caused significant red uctions in these parameters in IL-10(-/-) mice, demonstrating at least a 10-fold increased sensitivity in IL-10(-/-) mice to LPS-induced hem odynamic alterations. Furthermore, in response to LPS (30 mu g/kg, IV) , leukocyte rolling, adhesion, and fluorescein isothiocyanate-albumin extravasation were increased in the IL-10(-/-) mice. Antibody blockade experiments showed that in both types of mice, leukocyte rolling was mediated by E-selectin and P-selectin. Leukocyte accumulation into oth er tissues, such as lung, also was enhanced greatly in IL-10(-/-) mice . This was specific to endotoxin, because acute chemotactic stimuli in cluding N-formyl-methionyl-leucyl-phenylalanine elicited similar respo nses in IL-10(-/-) and wild-type mice. These results suggest that endo genous IL-10 may be a homeostatic regulator of hemodynamic parameters, leukocyte-endothelial cell interactions, and microvascular dysfunctio n in response to endotoxin and provide potential mechanisms to explain the protective effect of IL-10 against LPS-induced mortality.