Molecular mechanisms in the early phase of hemorrhagic shock.
Hemorrhagic shock (HS) results in the initiation of an inflammatory cascade that is critical for survival following successful resuscitation. We identified a complex sequence of molecular events including shock-dependent and reperfusion-dependent responses that offer a new comprehensive approach for consequences of HS. Shock-dependent initializing mechanisms include the induction of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, and CD14 and play a catalyzing role for subsequent phenotypic changes following resuscitation. The early immediate response genes iNOS and COX-2 promote the inflammatory response by the rapid and excessive production of nitric oxide (NO) and prostaglandins. The transcription factor hypoxia-inducible factor-1 (HIF-1) may regulate the induction of iNOS during the ischemic phase of shock. NO is an important signaling molecule which is involved in redox-sensitive mechanisms including the downstream activation of nuclear factor (NF)-kappaB. NO-dependent NF-kappaB activation promotes the induction of inflammatory cytokine expression during the reperfusion phase. Peroxynitrite-mediated direct toxicity and NO-mediated inflammatory toxicity contribute to organ injury. Patients suffering consequences of severe HS are susceptible to systemic inflammation, organ injury, and mortality if physiologic and therapeutic mechanisms are ineffective in limiting the activation of the inflammatory cascade.
Hierholzer
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Chirurgische Klinik der Technischen Universität München, Klinikum Rechts der Isar, Ismaningerstr. 22, 81675 München. hierholzer@nt1.chir.med.tu-muenchen.de
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D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000378:metabolism / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
D016207:Cytokines; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018950:Lipopolysaccharide Receptors; D009687:Nuclear Proteins; D014157:Transcription Factors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases