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Mechanisms of cell protection by adaptation to chronic and acute hypoxia: molecular biology and clinical practice.

Several experimental and clinical studies have shown that specific biochemical and molecular pathways are involved in the myocardial and skeletal muscle cell tolerance to acute and/or chronic hypoxic injury. A number of different factors were proposed to play a role in the preservation of tissue viability, but to a few of them a pivotal role in the adaptive mechanisms to hypoxic stimuli could be ascribed. Starting from the observation that mitochondrial electron transport chain (ETC) enzymic complexes are the targets of oxygen reduced availability, most of data are compatible with a mechanism of enzymic adaptation in which the nitric oxide (NO) generation plays the major role. If the partial and reversible NO-induced inhibition of ETC enzymic complexes represents the most rapid and prominent adaptive mechanism in counteracting the damaging effects of hypoxia, the sarcolemmal and mitochondrial K+(ATP) channels activation results to be closely involved in cytoprotection. This process is depending on protein kinase C (PKC) isoform activation triggered by reactive oxygen species (ROS) generation, adenosine triphosphate (ATP) depletion and Ca++ overload. It is well known that all these factors are present in hypoxia-induced oxidative damage and mitochondrial Ca++ altered pools represent powerful stimuli in the damaging processes. The activation of mitochondrial K+(ATP) channels leads to a significant reduction of Ca++ influx and attenuation of mitochondrial Ca++ overload. Closely linked to these adaptive changes signal transduction pathways are involved in the nuclear DNA damage and repair mechanisms. On this context, an essential role is played by the hypoxia-induced factor-1alpha (HIF-1alpha) in terms of key transcription factor involved in oxygen-dependent gene regulation. The knowledge of the biochemical and molecular sequences involved in these adaptive processes call for a re-evaluation of the therapeutic approach to hypoxia-induced pathologies. On this light, some specific aspects of the therapeutic management of critically ill patients are taken into consideration and discussed in relation to the cellular biodynamics.