Hydrogen sulfide [corrected] increases survival during sepsis: protective effect of CHOP inhibition.

TitleHydrogen sulfide [corrected] increases survival during sepsis: protective effect of CHOP inhibition.
Publication TypeJournal Article
Year of Publication2014
AuthorsFerlito M, Wang Q, Fulton WB, Colombani PM, Marchionni L, Fox-Talbot K, Paolocci N, Steenbergen C
JournalJ Immunol
Volume192
Issue4
Pagination1806-14
Date Published2014 Feb 15
ISSN1550-6606
KeywordsAnimals, Apoptosis, Bacteria, Caspase 3, Cecum, Cytokines, Endoplasmic Reticulum Stress, Enzyme Activation, Hydrogen Sulfide, Lipopolysaccharides, Macrophages, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-E2-Related Factor 2, Sepsis, Spleen, Survival, Transcription Factor CHOP
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.

DOI10.4049/jimmunol.1300835
Alternate JournalJ Immunol
PubMed ID24403532
Grant List5R01HL039752 / HL / NHLBI NIH HHS / United States
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Luigi Marchionni, M.D., Ph.D.

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