Cellular Protective Mechanisms Of Inducible Nitric Oxide Synthase

The inducible nitric oxide synthase (iNOS) is expressed constitutively but also induced in a number of epithelial cell types. iNOS regulates a number of cellular processes in these cell types without exerting toxicity. Among these functions is protection from cellular injury mediated by pro-apoptotic signals. We have had long-standing interest in the cell protective roles of iNOS in hepatocytes. We demonstrated that the upregulation of iNOS protects hepatocytes and the liver from TNF-mediated toxicity. This includes the inhibition of caspase activity through s-nitrosation. However, some of the effects are mediated through cGMP. Exploration into the mechanisms of the cGMP-mediated protection identified a role for the iNOS/NO/cGMP pathway in the activation of ADAM17 (TACE), which is a sheddase that cleaves a number of cell surface receptors including TNF receptor type 1 (TNFR1). The activation is associated with the phosphorylation of TACE. The iNOS/NO/cGMP/TACE pathway can be augmented by PDE5 inhibitors and reduce organ injury in the setting of sepsis. The implications go beyond acute pathophysiology and may be important to the mechanisms of iNOS in promoting aggressive cancers.