targeting the ubiquitin proteasome pathway for the treatment of septic shock in patients针对泛素蛋白酶体途径治疗感染性休克的病人.pdfVIP

Available online /content/13/4/311 Viewpoint Targeting the ubiquitin proteasome pathway for the treatment of septic shock in patients Jan Brun1,2,3 and Douglas A Gray1,2 1Ottawa Health Research Institute, Ottawa, ON, Canada K1Y 4E9 2Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, Canada K1H 8M5 3Apoptosis Research Centre, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada K1H 8L1 Corresponding author: Douglas A Gray, dgray@ohri.ca Published: 14 August 2009 Critical Care 2009, 13:311 (doi:10.1186/cc7946) This article is online at /content/13/4/311 © 2009 BioMed Central Ltd Abstract Figure 1 Endotoxic shock is a serious systemic inflammatory response to an external biological stressor. The responsiveness of NF-κB is built upon rapid protein modification and degradation involving the ubiquitin proteasome pathway. Using transgenic mice, we have obtained in vivo evidence that interference with this pathway can alleviate the symptoms of toxic shock. We posit that administration of proteasome inhibitors may enhance the survival of patients with septic shock. Multiple myeloma, endotoxic shock and proteasome inhibitors Multiple myeloma (MM) provides an example of the functional importance of ubiquitin in the NF-κB pathway [1,2]. A drug that shows great promise against MM is Velcade (bortezomib, formerly PS-341), a specific reversible inhibitor of proteasome function and, hence, ubiquitin-mediated proteolysis (Figure 1). Velcade is thought to block the activation of NF-κB and thereby deprive MM cells of the signals that are otherwise constitutive. In cell culture and animal