Leukocyte-endothelial cell interactions are linked to vascular permeability via ICAM-1-mediated signaling.
Two key characteristics of the inflammatory response are the recruitment of leukocytes to inflamed tissue as well as changes in vessel permeability. We explored the relationship between these two processes using intravital confocal microscopy in cremasters of anesthetized (65 mg/kg Nembutal ip) mice. We provide direct evidence that intercellular adhesion molecule-1 (ICAM-1) links leukocyte-endothelial cell interactions and changes in solute permeability (Ps). Importantly, we show that arterioles, not just venules, respond to proinflammatory stimuli, thus contributing to microvascular exchange. We identified two independent, ICAM-1-mediated pathways regulating Ps. Under control conditions in wild-type (WT) mice, there is a constitutive PKC-dependent pathway (Ps = 1.0 +/- 0.10 and 2.2 +/- 0.46 x 10(-6) cm/s in arterioles and venules, respectively), which was significantly reduced in ICAM-1 knockout (KO) mice (Ps = 0.54 +/- 0.07 and 0.77 +/- 0.11 x 10(-6) cm/s). The PKC inhibitor bisindolylmaleimid l (1 micromol/l in 0.01% DMSO) decreased P(s) in WT mice to levels similar to those in ICAM-1 KO mice. Likewise, a PKC activator (phorbol-12-myristate-acetate; 1 micromol/l in 0.01% DMSO) successfully restored Ps in ICAM-1 KO vessels to be not different from that of the WT controls. On the other hand, during TNF-alpha-induced inflammation, Ps in WT mice was significantly increased (2-fold in venules and 2.5-fold in arterioles) in a Src-dependent and PKC-independent manner. The blockade of Src (PP2; 2 micromol/l in 0.01% DMSO) but not PKC significantly reduced the TNF-alpha-dependent increase in Ps. We conclude that ICAM-1 plays an essential role in the regulation of Ps in microvessels and that there are two separate (constitutive and inducible) signaling pathways that regulate permeability under normal and inflamed conditions.
Sumagin
Ronen
R
Department of Biomedical Engineering, University of Rochester, Rochester, NY 14642, USA.
Lomakina
Elena
E
Sarelius
Ingrid H
IH
D000818:Animals; D018821:CD18 Antigens / Q000502:physiology; D002196:Capillaries / Q000473:pathology; D002199:Capillary Permeability / Q000502:physiology*; D042783:Endothelial Cells / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007249:Inflammation / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology*; D007962:Leukocytes / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000502:physiology
D018821:CD18 Antigens; D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D019061:src-Family Kinases; D011493:Protein Kinase C