Inducible nitric oxide synthase (iNOS) and regulation of leucocyte/endothelial cell interactions: studies in iNOS-deficient mice.
It is well established that constitutive production of nitric oxide is central to numerous processes in the microvasculature, including controlling the trafficking of inflammatory leucocytes. However, during many inflammatory responses induction of inducible nitric oxide synthase (iNOS) increases nitric oxide production. The role of iNOS-derived nitric oxide in modulating leucocyte recruitment is less well understood, although recent studies using iNOS-deficient mice have begun to examine this issue. This article describes much of the work that implicates iNOS as having a role in controlling leucocyte recruitment, including the intravital microscopy studies which revealed that iNOS-deficient mice have elevated leucocyte-endothelial cell interactions during endotoxaemia. Furthermore in additional studies, we compared expression of endothelial adhesion molecules in wild-type and iNOS-deficient mice, under conditions in which iNOS was expressed. Adhesion molecule expression was measured using an in vivo dual radiolabel immunoassay. To induce iNOS, mice were treated with either 1 or 50 microg of bacterial lipopolysaccharide (LPS), and 4 h later expression of P-selectin, E-selectin and vascular cell adhesion molecule-1 was determined in eight different tissues. In nearly all cases, adhesion molecule expression did not differ between the two types of mice, either in the absence of an inflammatory stimulus, or following LPS treatment. These findings indicate that iNOS does not regulate expression of endothelial adhesion molecules either under basal conditions, or during the endotoxaemic response. This further suggests that alterations in leucocyte function may mediate the modulating effect of iNOS on leucocyte recruitment.
Hickey
M J
MJ
Baker Medical Research Institute, Melbourne, Victoria, Australia.
Granger
D N
DN
Kubes
P
P
D000818:Animals; D002450:Cell Communication / Q000276:immunology; D004730:Endothelium, Vascular / Q000166:cytology*; D007962:Leukocytes / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II
D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse