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 cent ral to numerous processes in the microvasculature, including controlling th e trafficking of inflammatory leucocytes. However, during many inflammatory responses induction of inducible nitric oxide synthase (iNOS) increases ni tric oxide production. The role of iNOS-derived nitric oxide in modulating leucocyte recruitment is less well understood, although recent studies usin g iNOS-deficient mice have begun to examine this issue. This article descri bes much of the work that implicates iNOS as having a role in controlling l eucocyte recruitment, including the intravital microscopy studies which rev ealed that iNOS-deficient mice have elevated leucocyte-endothelial cell int eractions during endotoxaemia. Furthermore in additional studies, we compar ed expression of endothelial adhesion molecules in wild-type and iNOS-defic ient mice, under conditions in which iNOS was expressed. Adhesion molecule expression was measured using an in vivo dual radiolabel immunoassay. To in duce iNOS, mice were treated with either 1 or 50 mug of bacterial lipopolys accharide (LIPS), and 4 h later expression of P-selectin, E-selectin and va scular cell adhesion molecule-1 was determined in eight different tissues. In nearly all cases, adhesion molecule expression did not differ between th e two types of mice, either in the absence of an inflammatory stimulus, or following LPS treatment. These findings indicate that iNOS does not regulat e expression of endothelial adhesion molecules either under basal condition s, or during the endotoxaemic response. This further suggests that alterati ons in leucocyte function may mediate the modulating effect of iNOS on leuc ocyte recruitment.