Low-dose cisplatin administration in murine  cecal ligation and puncture prevents the  systemic release of HMGB1 and attenuates  lethality.
Sepsis remains a major cause of morbidity and mortality worldwide. The systemic release of the nuclear protein HMGB1 is a late event in endotoxin-related lethality in mice. The platinating chemotherapeutic Cis induces DNA lesions that sequester HMGB1 within the nucleus of cells. We sought to determine if low, nontoxic doses of Cis could be an effective strategy in ameliorating sepsis-related mortality in a mouse model of CLP. In vitro studies with Cis prevented the LPS-induced release of HMGB1 from RAW264.7 cells, limited MAPK signaling, but had no effect on NF-kappaB activation or cytokine production. Low, nontoxic doses of Cis decreased mortality following CLP, whether delivered before or after puncture. Protection was associated with a decrease in the systemic release of HMGB1 and protection from end organ injury and in particular, less acute lung injury. Tissue-specific iNOS expression was markedly reduced. Low, nontoxic doses of Cis sequester HMGB1 effectively inside of the nucleus of LPS-stimulated immune cells and prevent its release in response to CLP. Platinating agents in general and Cis specifically may be a novel approach to the treatment of sepsis.
Pan
Pinhua
P
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Cardinal
Jon
J
Dhupar
Rajeev
R
Rosengart
Matthew R
MR
Lotze
Michael T
MT
Geller
David A
DA
Billiar
Timothy R
TR
Tsung
Allan
A
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002432:Cecum / Q000293:injuries; D002460:Cell Line; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D024243:HMGB1 Protein / Q000276:immunology / Q000378:metabolism*; D008026:Ligation; D008070:Lipopolysaccharides / Q000633:toxicity; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D018805:Sepsis / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality
D000970:Antineoplastic Agents; D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D002945:Cisplatin