Heat shock proteins (Hsps) and protection from hepatotoxicity

Cells respond to adverse environmental conditions by the highly regulated expression of a set of proteins referred to as heat shock proteins (Hsps). Much of the interest in Hsps stems from numerous reports that correlate the general induction of Hsps with the development of resistance to a variety of cytotoxic insults. The overall objective of this research was to examine more specifically the role of Hsp upregulation in cytoprotection. Various hypotheses were tested as to whether increased expression of Hsps in general, or of specific Hsps, provided protection against selective toxicants. Studies in HepG2 cells transfected with adenovirus containing gene for a constitutively active heat shock factor (HSF) found that general upregulation of Hsps significantly reduced toxicity from all toxicants tested. Transfection to achieve selective induction of either Hsp70i or Hsp27 offered protection against differing subsets of toxicants, suggesting some specificity in terms of the kinds of toxicity diminished by individual Hsps. Adenoviral vectors were also used to successfully transfect the same genes into the livers of mice, but inflammatory reactions to the vectors precluded hypothesis testing regarding cytoprotection in these animals.;The model hepatotoxicant acetaminophen was used to evaluate protective roles for Hsp70i and Hsp27 in transgenic animals. Transgenic mice lacking an inducible Hsp70 response (Hsp70 knockouts) experienced increased liver injury from acetaminophen, suggesting that Hsp70i is important in modulating toxicity from acetaminophen in vivo. In contrast, acetaminophen hepatotoxicity was unchanged in transgenic mice overexpressing Hsp27, suggesting that, at least in this model for this toxicant, Hsp27 is not protective. Auxiliary studies in rats treated with the nephrotoxic chemical uranyl acetate showed that even when Hsp upregulation is correlated with a protected state, it is not necessarily responsible. Additionally, studies in mice found that Hsp upregulation preceded toxicity from the model hepatotoxicant bromobenzene but not carbon tetrachloride. Insight into the role of Hsp in moderating toxicity for studies such as these may lead to novel therapeutic approaches to human disease.