The mechanisms of calcium-mediated cell injury and cell death [correcgted]

It has been known for some time that all pathophysiologic changes in shock and trauma have their basis at the cellular and molecular levels. These changes have been and continue to be studied in vivo in human patients and animal models and in vitro using a number of human and animal cell cultures. Cell injury and cell death have been studied in our laboratories for many years with reversible and irreversible cell responses having been characterized by functional, morphological, and biochemical methodologies. Recently, new technologies such as molecular biological experimentation for gene expression studies and digital imaging fluorescence microscopy to measure and localize ions, specifically the concentration of intracellular ionized calcium ([Ca2+i]), have been undertaken. Data from these studies have led us to propose a working hypothesis for a number of principle subcellular events that occur following a lethal injury. Dysregulation of [Ca2+i] is central to this hypothesis, since the effects of such dysregulation appear to affect many phenomena either positively or negatively. These phenomena are briefly discussed here. Much additional experimentation needs to be performed which should lead to further understanding of these events and to improved therapy, including modifiers of Ca(2+)-mediated events, new regulators of gene expression, and even gene therapy itself.