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Calcium Regulation and Cell Injury: A Heuristic Hypothesis a

A number of years ago, a series of systematic studies on the progession of the pathogenesis of lethal and sublethal cell injury was begun in our laboratories,’ the results of which led us to investigate the relationship between sodium and calcium regulation and cell volume control and its role in injury? Our data showed that membrane phenomena were involved and that not only was there a strong link between the above events but that this link involved the cytoskeleton.3 We therefore began to formulate a hypothesis3” concerning the role of ion deregulation in the pathogenesis of diverse types of injury including acute lethal injury resulting in necrosis (i.e., myocardial infarction or heavy-metal toxicity), as well as chronic injury including abnormalities of growth such as hyperplasia, preneoplastic lesions, atherosclerotic plaques, and neoplasia. Our data suggest that alterations of [Ca2+Ii constitute a nodal point involved in both types of injury (FIG. l), implying that modification of such deregulation could accelerate or retard the pathogenesis of either. Injuries that deregulate [Caz+ji involve those conditions that interfere with ATP synthesis resulting in ATP deficiency and interference with mitochondria1 calcium-accumulating ability and those that alter plasma membrane permeability leading to changes of Ca2+ influx through specific or nonspecific channels. Such deregulation could also result from interactions that modify calcium sequestration by the endoplasmic reticulum. Na+ and Ca2+ regulation are also intertwined because of Na+Ca2+ exchange, important in excitable tissues. Note that the phosphoinositol (PI) pathway also articulates with [Caz+ji in several interactions including calciummediated activation of phospholipase C (PLC), redistribution of calcium from intracellular compartments such as the endoplasmic reticulum, and activation of protein kinase C. Also, several growth factors, some of which are oncogene products, feed into that part of the PI pathway mechanism! As [Caz+Ii increases, a number of effects that occur after cell injury are initiated, some mediated through calcium-calmodulin complexes and some apparently independent of calmodulin. Activation of phospholipase appears to be in the latter category and results in activation of phospholipase C and phospholipase A, which mediates membrane damage through hydrolysis of phospholipids and activates a number of other mediators including the prostanoid pathway. Cytoskeletal changes, on the other hand, appear to involve calcium-calmodulin and include microtubule depolymerization and actin filament modification resulting in such phenomena as autophagocytosis and protein catabolism, blebbing at the cell surface, and changes in intermediate