The endogenous negative regulators:potential drug target for treatment of septic shock

PAN Zhi－xing

(Department of Medical Microbiology and Immunology，University of Toledo Health Sciences Campus，3035 Arlington Avenue，Toledo，OH 43614，USA)

Bacteria－ induced sepsis and septic shock is characterized by cardiovascular collapse following microbial invasion of the body.The progressive hypotension，hyporeactivity to vasopressor agents and vascular leak lead to circulatory failure with multiple organ dysfunction and death.Transcription factor NF － κB and inflammatory cytokines(e.g.TNF － α and IL －1β)play critical roles in the pathogenesis of sepsis and septic shock.During the last decade，we have focused on investigating the key positive signaling pathways involved in the activation of NF－κB and the resultant inflammatory response.Interestingly，we have recently discovered that MKP－1，a MAP kinase phosphatase，negatively regulates the NF－κB－dependent inflammatory response.It would appear that this endogenous negative feedback regulation may be an interesting and effective therapeutic strategy to combat an overactive inflammatory response，without serious adverse effects.In addition，we have found that rolipram，which is already in late phase III clinical trials for COPD，is a potent anti－sepsis agent in vitro and in vivo by enhancing expression of MKP－1.Therefore，rolipram may act as an anti－sepsis agent for treatment of sepsis and septic shock.Our studies should provide useful signal mechanisms and preclinical information that will allow us to initiate clinical studies for rolip ram in victims with sepsis and septic shock.