The Role of Nitric Oxide in Apoptosis and Autophagy: Biochemical and Computational Studies

Publisher Summary This chapter focuses on the regulation and function of nitric oxide (NO)/inducible NOS (iNOS) in the liver in settings of acute inflammation. It also helps in understanding the factors that govern the consequence of sustained NO production in tissues and investigates the mechanisms of cytotoxicity, such as necrosis and autophagy. In the liver, iNOS limits cell death in acute settings of endotoxemia, liver regeneration, and exposure to cell death ligands, while conversely creating hepatic damage under settings of ischemia/reperfusion and hemorrhagic shock. Organ physiology and the pathophysiological response to nitric oxide (NO) vary across a range of acute inflammatory stresses such as trauma, hemorrhage, ischemia/reperfusion injury, endotoxemia, and sepsis, in part reflected by the amount, duration, cell type, and source of NO. The liver is a primary site of response to acute inflammatory stress, in which NO generated by the inducible NO synthase may impact cell/tissue/organ function either positively or negatively. These divergent outcomes appear to depend on the context and milieu in which NO is produced, including the levels of antioxidants or conversely the generation of reactive oxygen species, which trigger cell protection or cell death. Specifically, the fate of the primary liver cell type, the hepatocyte, is controlled by the NO downstream activation of soluble guanylate cyclase and production of cyclic guanosine monophosphate, or the S-nitrosative inhibition of active site cysteine within the enzymes that architect apoptosis, the caspases. NO can modulate a complex variety of processes including signaling, modification of proteins, and gene expression to affect apoptosis and the related process of autophagy in a cell-specific manner. The switch between positive and negative impact of NO on the fate of cells, tissues, and organs will be discussed with special attention to the use of experimental data and mathematical models to identify likely mechanisms of actions and future therapeutic directions.