Hyperthermia Promotes and Prevents Respiratory Epithelial Apoptosis through Distinct Mechanisms

Abstract

Hyperthermia has been shown to confer cytoprotection and to augment apoptosis in different experimental models. We analyzed the mechanisms of both effects in the same mouse lung epithelial (MLE) cell line (MLE15). Exposing MLE15 cells to heat shock (HS; 42 8 C, 2 h) or febrile-range hyperthermia (39.5 8 C) concurrent with activation of the death receptors, TNF receptor 1 or Fas, greatly accelerated apoptosis, which was detectable within 30 minutes and was associated with accelerated activation of caspase-2, -8, and -10, and the proapoptotic protein, Bcl2-interacting domain (Bid). Caspase-3 activation and cell death were partially blocked by inhibitors targeting all three initiator caspases. Cells expressing the IkB superrepessor were more susceptible than wild-type cells to TNFa-induced apoptosis at 37 8 C, but HS and febrile-range hyperthermia still increased apoptosis in these cells. Delaying HS for 3 hours after TNF-a treatment abrogated its proapoptotic effect in wild-type cells, but not in IkB superrepressor-expression cells, suggesting that TNF-a stimulates delayed resistance to the proapoptotic effects of HS through an NF-kB-dependent mechanism. Pre-exposure to 2-hour HS beginning 6 to16 hours before TNF-a treatment or Fas activation reduced apoptosis in MLE15 cells. The antiapoptotic effects of HS pretreatment were reduced in TNF-a-treated embryonic fibroblasts from heat shock factor-1 (HSF1)-deficient mice, but the proapoptotic effects of concurrent HS were preserved. Thus, depending on the temperature and timing relative to death receptor activation, hyperthermia can exert pro-and antiapoptotic effects through distinct mechanisms.Keywords: heat shock; febrile-range hyperthermia; Fas; TNF; apoptosis Hyperthermia can either be cytoprotective or accelerate apoptosis (1-4). Exposure to nonlethal hyperthermia by itself stimulates coordinated expression of heat-inducible proteins that support cell survival in the face of cellular stress, facilitate repair of cellular damage, and confer resistance to subsequent injury (4). However, when preceded by a proinflammatory stimulus, exposure to similar or lesser hyperthermia can enhance cell death and tissue injury (3, 5-7), a phenomenon coined the "heat shock paradox." The opposing effects of hyperthermia on cell and tissue injury and repair are well documented in the injured lung. Pre-exposure to core temperatures between 41.5 8 C and 43 8 C for 15 to 30 minutes conferred protection against lung injury induced 6 to 18 hours later in response to various triggers, including systemic LPS administration (8, 9), cecal ligation and puncture (10), lower extremity ischemiareperfusion (11), hemorrhagic shock and resuscitation (12), and intratracheal instillation of phospholipase A2 (13). Protection in these models correlated with expression of heat shock (HS) protein (HSP) 70 in lungs and other organs (9-11, 13, 14). Mouse embryonic fibroblasts (MEFs) lacking heat shock factor-1 (HSF1), the heat-inducible transcriptional activator of the HSP genes, exhibited increased susc...

A study of thermal dose-induced autophagy, apoptosis and necroptosis in colon cancer cells

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Fever Is Associated with Delayed Ventilator Liberation in Acute Lung Injury

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