title: Hydrogen sulfide donor NaHS reduces organ injury in a rat model of pneumococcal pneumosepsis, associated with improved bio-energetic status.
abstract: Sepsis is characterized by a generalized inflammatory response and organ failure, associated with mitochondrial dysfunction. Hydrogen sulfide donor NaHS has anti-inflammatory properties, is able to reduce metabolism and can preserve mitochondrial morphology and function. Rats were challenged with live Streptococcus pneumonia or saline and infused with NaHS (36 µmol/kg/h) or vehicle. Lung and kidney injury markers were measured as well as mitochondrial function, viability and biogenesis. Infusion of NaHS reduced heart rate and body temperature, indicative of a hypo-metabolic state. NaHS infusion reduced sepsis-related lung and kidney injury, while host defense remained intact, as reflected by unchanged bacterial outgrowth. The reduction in organ injury was associated with a reversal of a fall in active oxidative phosphorylation with a concomitant decrease in ATP levels and ATP/ADP ratio. Preservation of mitochondrial respiration was associated with increased mitochondrial expression of α-tubulin and protein kinase C-ε, which acts as regulators of respiration. Mitochondrial damage was decreased by NaHS, as suggested by a reduction in mitochondrial DNA leakage in the lung. Also, NaHS treatment was associated with upregulation of peroxisome proliferator-activated receptor-γ coactivator 1α, with a subsequent increase in transcription of mitochondrial respiratory subunits. These findings indicate that NaHS reduces organ injury in pneumosepsis, possibly via preservation of oxidative phosphorylation and thereby ATP synthesis as well as by promoting mitochondrial biogenesis. Further studies on the involvement of mitochondria in sepsis are required.
authors.affiliation: Laboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Center, Amsterdam, The Netherlands. h.aslami@amc.uva.nl
authors.forename: Hamid
authors.initials: H
authors.lastname: Aslami
authors.forename: Wilco P
authors.initials: WP
authors.lastname: Pulskens
authors.forename: Maria T
authors.initials: MT
authors.lastname: Kuipers
authors.forename: Aafkeline P
authors.initials: AP
authors.lastname: Bos
authors.forename: André B P
authors.initials: AB
authors.lastname: van Kuilenburg
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Jeroen
authors.initials: J
authors.lastname: Roelofsen
authors.forename: Joris J T H
authors.initials: JJ
authors.lastname: Roelofs
authors.forename: Raphaela P
authors.initials: RP
authors.lastname: Kerindongo
authors.forename: Charlotte J P
authors.initials: CJ
authors.lastname: Beurskens
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Schultz
authors.forename: Wim
authors.initials: W
authors.lastname: Kulik
authors.forename: Nina C
authors.initials: NC
authors.lastname: Weber
authors.forename: Nicole P
authors.initials: NP
authors.lastname: Juffermans
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000378:metabolism; D004734:Energy Metabolism; D006339:Heart Rate / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D055370:Lung Injury / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control*; D008928:Mitochondria / Q000378:metabolism; D063269:Mitochondrial Turnover / Q000187:drug effects; D010084:Oxidation-Reduction; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis; D013440:Sulfides / Q000494:pharmacology* / Q000627:therapeutic use; D014404:Tubulin / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000893:Anti-Inflammatory Agents; D013440:Sulfides; D014404:Tubulin; C497257:Prkce protein, rat; D051744:Protein Kinase C-epsilon; D042967:Electron Transport Complex I; C025451:sodium bisulfide