title: Hydrogen sulfide [corrected] increases survival during sepsis: protective effect of CHOP inhibition.
abstract: Sepsis is a major cause of mortality, and dysregulation of the immune response plays a central role in this syndrome. H2S, a recently discovered gaso-transmitter, is endogenously generated by many cell types, regulating a number of physiologic processes and pathophysiologic conditions. We report that H2S increased survival after experimental sepsis induced by cecal ligation and puncture (CLP) in mice. Exogenous H2S decreased the systemic inflammatory response, reduced apoptosis in the spleen, and accelerated bacterial eradication. We found that C/EBP homologous protein 10 (CHOP), a mediator of the endoplasmic reticulum stress response, was elevated in several organs after CLP, and its expression was inhibited by H2S treatment. Using CHOP-knockout (KO) mice, we demonstrated for the first time, to our knowledge, that genetic deletion of Chop increased survival after LPS injection or CLP. CHOP-KO mice displayed diminished splenic caspase-3 activation and apoptosis, decreased cytokine production, and augmented bacterial clearance. Furthermore, septic CHOP-KO mice treated with H2S showed no additive survival benefit compared with septic CHOP-KO mice. Finally, we showed that H2S inhibited CHOP expression in macrophages by a mechanism involving Nrf2 activation. In conclusion, our findings show a protective effect of H2S treatment afforded, at least partially, by inhibition of CHOP expression. The data reveal a major negative role for the transcription factor CHOP in overall survival during sepsis and suggest a new target for clinical intervention, as well potential strategies for treatment.
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: Marcella
authors.initials: M
authors.lastname: Ferlito
authors.forename: Qihong
authors.initials: Q
authors.lastname: Wang
authors.forename: William B
authors.initials: WB
authors.lastname: Fulton
authors.forename: Paul M
authors.initials: PM
authors.lastname: Colombani
authors.forename: Luigi
authors.initials: L
authors.lastname: Marchionni
authors.forename: Karen
authors.initials: K
authors.lastname: Fox-Talbot
authors.forename: Nazareno
authors.initials: N
authors.lastname: Paolocci
authors.forename: Charles
authors.initials: C
authors.lastname: Steenbergen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001419:Bacteria / Q000276:immunology*; D053148:Caspase 3 / Q000378:metabolism; D002432:Cecum / Q000601:surgery; D016207:Cytokines / Q000096:biosynthesis; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004789:Enzyme Activation; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008070:Lipopolysaccharides; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy / Q000378:metabolism*; D013154:Spleen / Q000187:drug effects; D013534:Survival; D051742:Transcription Factor CHOP / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
chemical_list: D016207:Cytokines; C497250:Ddit3 protein, mouse; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D051742:Transcription Factor CHOP; D053148:Caspase 3; D006862:Hydrogen Sulfide