POTENTIAL PROTECTIVE ROLE OF THE HEAT-SHOCK RESPONSE IN SEPSIS

The heat shock response, a primitive and highly conserved cellular def ense mechanism, has broad protective effects against sepsis-induced in jury. In various models of sepsis, induction of the heat shock respons e protects against sepsis-induced mortality, organ injury, cardiovascu lar dysfunction, and apoptosis, The mechanisms by which the heat shock response protects against sepsis-induced injury are currently under i nvestigation. One potential mechanism involves the ability of the heat shock response to inhibit proinflammatory responses, The heat shock r esponse has been demonstrated to inhibit expression of the cytokines t umor necrosis factor (TNF)-alpha and interleukin (IL)-1 beta, The heat shock response has also been demonstrated to inhibit cytokine-mediate d expression of inducible nitric oxide synthase, Recent studies demons trated that the heat shock response inhibits nuclear translocation of nuclear factor-kappa B (NF-kappa B), a transcription factor involved i n the regulation of many proinflammatory responses. Heat shock respons e-mediated inhibition of NF-kappa B nuclear translocation involves sta bilization of an NF-kappa B inhibitory protein called I-kappa B alpha. The heat shock response also increases expression of I-kappa B alpha, thus providing another potential mechanism by which the heat shock re sponse can modulate proinflammatory responses. Future studies designed to further understand the protective role of the heat shock response against sepsis-induced injury may allow for the development of rationa l pharmacologic agents or gene therapy methods to safely induce the he at shock response as a strategy to treat patients with sepsis.