Interestingly, sellckchem a recent study by Reis and colleagues  supports the notion of enhanced survival in a septic shock animal model with the use of proteasome inhibition combined with antibiotic treatment. This study at least is one of the first to demonstrate the safety of proteasome inhibition in acutely but invasively infected preclinical animal models. Although these results are encouraging, the animals were pretreated with proteasome inhibitors and antibiotics and, thus, experiments would need to be repeated in animals already undergoing septic shock. Overall, we believe that these results are at least encouraging with respect to safety and future use of proteasome inhibitors in septic shock patients with progressive infections.We still expect much to be learned from the in vivo 3X NF-��B luciferase model using Velcade.
Certainly, the 3X NF-��B luciferase mouse model alone or in combination with the CLP procedure will also be useful to test how conventional therapies compare to proteasome inhibitors, to optimize the pharmacological properties of such drugs for this application, and to determine if such agents should be used independently or in combination with current treatments.ConclusionConventional therapies to treat endotoxic shock improve the survival of some, but not all, patients; thus, additional novel treatments are required to treat this condition. Proteasome inhibitors effectively target the main signaling pathway(s) active during septic shock, and genetic experiments suggest that inhibition of this system should be advantageous for clinical interventions.
It would seem desirable, therefore, to evaluate the potential of existing or novel proteasome inhibitors to promote the survival of patients experiencing toxic shock.AbbreviationsCLP: cecal ligation and puncture; IKK: I��B kinase; IL: interleukin; LPS: lipolysaccharide; MM: multiple myeloma; NF: nuclear factor; TNF: tumor necrosis factor; TRAF: TNF-receptor-associated factor.Competing interestsThe authors declare that GSK-3 they have no competing interests.AcknowledgementsWe thank Dr R Chiu (University of Maastricht) for contributing Figure Figure22 of this manuscript.Clinical deterioration resulting in near or actual cardiopulmonary arrest in hospitalised children is common , associated with adverse outcome [2,3] and may be preventable [4-7]. Timely identification and referral of children may be facilitated by the application of calling criteria or severity of illness scores. The major limitation of available severity of illness scores for hospitalised patients is complexity [4,8,9].