期刊
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
卷 295, 期 3, 页码 H969-H977出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00400.2008
关键词
adhesion molecules; microvascular exchange
资金
- National Heart, Lung, and Blood Institute [RO1-HL75186, PO1-HL18208]
- American Heart Association [0615677T]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P01HL018208, R01HL075186] Funding Source: NIH RePORTER
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 (P-s). 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 (P-s = 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 (P-s = 0.54 +/- 0.07 and 0.77 +/- 0.11 x 10(-6) cm/s). The PKC inhibitor bisindolylmaleimid 1 (1 mu mol/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 mu mol/l in 0.01% DMSO) successfully restored P-s in ICAM-1 KO vessels to be not different from that of the WT controls. On the other hand, during TNF-alpha-induced inflammation, P-s 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 mu mol/l in 0.01% DMSO) but not PKC significantly reduced the TNF-alpha-dependent increase in P-s. We conclude that ICAM-1 plays an essential role in the regulation of P-s in microvessels and that there are two separate (constitutive and inducible) signaling pathways that regulate permeability under normal and inflamed conditions.
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