Cytopathic Hypoxia in Circulatory Shock: The Role of Poly (ADP-Ribose) Synthetase Activation

Abstract

Generally, three classical forms of tissue hypoxia — induced by hypoxemia, anemia, or inadequate perfusion — are considered as causative factors in relationship to the suppressed tissue metabolism associated with various disease states including circulatory shock. However, recently, a fourth mechanism, termed ‘cytopathic hypoxia’, has also been proposed [1]. This term is used to denote diminished production of adenosine triphosphate (ATP) despite normal (or even supranormal) PO2 values in the vicinity of mitochondria within cells. A number of pathogenic mechanisms have been proposed, including diminished delivery of a key substrate (e.g., pyruvate) into the mitochondrial tricarboxylic acid (TCA) cycle, inhibition of key mitochondrial enzymes involved in either the TCA cycle or the electron transport chain, or collapse of the protonic gradient across the inner mitochondrial membrane leading to uncoupling of oxidation (of NADH and FADH) from phosphorylation of ADP to form ATP. It is likely that cytopathic hypoxia occurs in both animals and patients with sepsis or endotoxemia, and that some, or possibly all, of the above listed mechanisms are relevant for its pathogenesis. Recent studies have suggested, that, in addition to the above listed mechanisms, activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS), also known as poly (ADP-ribose) polymerase (PARP) — an enzyme traditionally associated with DNA repair [2, 3, 4], chromatin relaxation [5], cell differentiation [6], DNA replication [7], transcriptional regulation [8], control of cell cycle [9], p53 expression and apoptosis [10], and transformation [11] — also plays a pathogenetic role in the pathogenesis of cytopathic hypoxia in circulatory shock. This chapter overviews some of the evidence in favor of this latter notion.