Primary cultures of adult rat hepatocytes were treated in the presence or absence of extracellular calcium with ten different membrane-active toxins. In all cases more than half the cells were killed in 1 to 6 hours in the presence but not in the absence of extracellular calcium. An effect of calcium on the primary mechanism of membrane injury by any of the agents cannot be implicated. Viability, as determined by trypan blue exclusion correlated well with other indices of viability such as plating efficiency and the hydrolysis of fluorescein diacetate. It is concluded that the cells are killed by processes that involve at least two steps. In each type of injury, disruption of the integrity of the plasma membrane by widely differing mechanisms is followed by a common functional consequence involving extracellular calcium, and most likely representing an influx of calcium across the damaged plasma membrane and down a steep concentration gradient. This later step represents, or at least initiates, a final common pathway for the toxic death of these cells.

No abstract

Cyclophilin D (which is encoded by the Ppif gene) is a mitochondrial matrix peptidyl-prolyl isomerase known to modulate opening of the mitochondrial permeability transition pore (MPTP). Apart from regulating necrotic cell death, the physiologic function of the MPTP is largely unknown. Here we have shown that Ppif -/-mice exhibit substantially greater cardiac hypertrophy, fibrosis, and reduction in myocardial function in response to pressure overload stimulation than control mice. In addition, Ppif -/-mice showed greater hypertrophy and lung edema as well as reduced survival in response to sustained exercise stimulation. Cardiomyocyte-specific transgene expression of cyclophilin D in Ppif -/-mice rescued the enhanced hypertrophy, reduction in cardiac function, and rapid onset of heart failure following pressure overload stimulation. Mechanistically, the maladaptive phenotype in the hearts of Ppif -/-mice was associated with an alteration in MPTP-mediated Ca 2+ efflux resulting in elevated levels of mitochondrial matrix Ca 2+ and enhanced activation of Ca 2+ -dependent dehydrogenases. Elevated matrix Ca 2+ led to increased glucose oxidation relative to fatty acids, thereby limiting the metabolic flexibility of the heart that is critically involved in compensation during stress. These findings suggest that the MPTP maintains homeostatic mitochondrial Ca 2+ levels to match metabolism with alterations in myocardial workload, thereby suggesting a physiologic function for the MPTP.

Vancomycin use is often associated with nephrotoxicity. It remains uncertain, however, to what extent vancomycin is directly responsible, as numerous potential risk factors for acute kidney injury frequently coexist. Herein, we critically examine available data in adult patients pertinent to this question. We review the pharmacokinetics/pharmacodynamics of vancomycin metabolism. Efficacy and safety data are discussed. The pathophysiology of vancomycin nephrotoxicity is considered. Risk factors for nephrotoxicity are enumerated, including the potential synergistic nephrotoxicity of vancomycin and piperacillin‐tazobactam. Suggestions for clinical practice and future research are given.

Current evidence suggests that O2 and H2O2 injure cells as a result of the generation of a more potent oxidizing species. In addition to O2 and H2O2 the third essential component of the complex that mediates the lethal cell injury is a cellular source of ferric iron. The hypothesis most consistent with all the available data suggests that O2 reduces a cellular source of ferric to ferrous iron, and the latter then reacts with H2O2 to produce a more potent oxidizing species, like the *OH or an equivalently reactive species. In turn, *OH initiates the peroxidative decomposition of the phospholipids of cellular membranes. "OH also damages the inner mitochondrial membrane. Upon mitochondrial deenergization, a sequence of events is initiated that similarly leads to the loss of viability of the cell. DNA represents a third cellular target of *OH. Depending on the cell type, oxidative DNA damage can be coupled to cell killing through a mechanism related to the activation of poly (ADP-ribose) polymerase. -Environ Health Perspect 102(Suppl 10): 1 7-24 (1994)