Role of inducible nitric oxide synthase in the regulation of leucocyte recruitment

Constitutively produced nitric oxide released by endothelial cells has been shown to act as an endogenous agent which inhibits the rolling and adhesio n of leucocytes in the microcirculation. However, during various types of i nflammation, expression of the inducible form of nitric oxide synthase (iNO S) can dramatically increase the amount of nitric oxide present in tissues. Furthermore, as iNOS can be expressed by a wide variety of cell types, the distribution of nitric oxide is likely to be altered relative to that in u nstimulated tissue. Under these conditions, it is less well understood whet her iNOS-derived nitric oxide retains the anti-adhesive capabilities of con stitutively produced nitric oxide. This review summarizes work done to exam ine this issue. Three main approaches have been used. In vitro studies have examined the role of iNOS in adhesive interactions between stimulated endo thelial cells and leucocytes, providing evidence of an anti-adhesive effect of iNOS. In addition, the role of iNOS has been examined in vivo in animal models of inflammation using pharmacological iNOS inhibitors. These experi ments were extended by the advent of the iNOS-deficient (iNOS(-/-)) mouse. Intravital microscopy studies of these mice have indicated that, under cond itions of low-dose endotoxaemia, iNOS-derived nitric oxide can inhibit leuc ocyte rolling and adhesion. The potential mechanisms for these effects are discussed. In contrast, several other stud ies have observed either no effe ct or an enhancing effect of iNOS on inflammatory leucocyte recruitment. Ta ken together, these studies suggest that the importance of iNOS in modulati ng leucocyte recruitment can vary according to the type of inflammatory res ponse.