Molecular biology of circulatory shock. Part III. Human hepatoblastoma (HepG2) cells demonstrate two patterns of shock-induced gene expression that are independent, exclusive, and prioritized.

Abstract

During shock and resuscitation, parenchymal cells of solid organs are exposed to a rapidly changing microenvironment, which may include a reduced oxygen tension and an increased concentration of certain cytokines including tumor necrosis factor alpha and interleukin-1. In vivo experiments that testedl iver biopsied from pigs undergoing cardiogenic shock and resuscitation demonstrated several patterns of gene expression. To study the independent and additive influences of hypoxia and of cytokines in vitro, human hepatoblastoma (HepG2) cells were perturbed by hypoxia/reoxygenation (H/R), by heat shock, and by the cytokines interleukin-1 and tumor necrosis factor alpha alone and in combination. H/R induces new patterns of protein synthesis and secretion that are indistinguishable from those induced by heat shock and independent of the acute-phase response mediated by the cytokines. The H/R (heat-shock) response has priority over and will extinguish gene expression supported by the cytokines. This previously unrecognized hierarchy of stress gene expression could well form the molecular basis of shock-related cell and organ failure.