Inducible nitric oxide synthase: a little bit of good in all of us

The established dogma regarding the different isoforms of nitric oxide has been that constitutively expressed nitric oxide synthase is an extremely important homeostatic regulator of numerous important physiological processes whereas the inducible form of nitric oxide synthase underlies injury associated with intestinal inflammation. In this brief overview, I review some of the literature that clearly supports this contention, particularly the dramatically beneficial effects of oral L-NAME administration to animals with colitis induced by trinitrobenzene sulphonic acid (TNBS). However, I also highlight some of the gastrointestinal data that does not fit this simple tidy paradigm, particularly with respect to the inducible form of nitric oxide synthase (iNOS). For example, iNOS induced healing of skin and the intestinal mucosa, killing of certain bacteria, regulation of T cell proliferation and differentiation (Th1 v Th2), and control of leucocyte recruitment may mask or counter the toxic metabolites that are produced by iNOS. Perhaps it is not surprising that one does not always obtain benefit from inhibiting all iNOS either by gene deletion or by systemic NOS inhibition. I raise some potential flaws in our approaches to studying iNOS. For example, to date no attempts have been made to selectively inhibit iNOS in single cell types. Global inhibition of all iNOS assumes that the large variety of cell types that can produce iNOS have identical functions. Finally, I attempt to highlight areas that require additional investigation and issues that have not been explored.