The rat acute-phase protein α2-macroglobulin plays a central role in amifostine-mediated radioprotection

Abstract

Previously we reported that elevated circulating concentrations of the acute-phase (AP) proteinα2-macroglobulin(α2M), either as typically occurring in pregnant female rats or after administrationto male rats, provides radioprotection, displayed as 100% survival ofexperimental animals exposed to total-body irradiation with 6.7 Gy (LD50/30) x-rays, that is as effective as that afforded by the synthetic radioprotectoramifostine. The finding that amifostine administration induces a 45-fold increase inα2M in the circulation ledus to hypothesise that α2M assumes an essential role in both natural and amifostine-mediated radioprotection inthe rat. In the present work we examined the activation of cytoprotectivemechanisms in rat hepatocytes after the exogenous administration ofα2M and amifostine. Our results showed that the IL6/JAK/STAT3 hepatoprotectivesignal pathway, described in a variety of liver-injury models, upregulated theα2M gene in amifostine-pretreated animals. In bothα2M- and amifostine-pretreated rats we observed the activation of the Akt signalling pathwaysthat mediate cellular survival. At the cellular level this was reflected as a significantreduction of irradiation-induced DNA damage that allowed for the rapid and completerestoration of liver mass and ultimately at the level of the whole organism thecomplete restoration of body weight. We conclude that the selective upregulation ofα2M plays a central role in amifostine-provided radioprotection.