title: Cystathionine-Gamma-Lyase Gene Deletion Protects Mice against Inflammation and Liver Sieve Injury following Polymicrobial Sepsis.
abstract: BACKGROUND
  Hydrogen sulfide (H2S), produced by the activity of cystathionine-gamma-lyase (CSE), is a key mediator of inflammation in sepsis. The liver sinusoidal endothelial cells (LSECs) are important target and mediator of sepsis. The aim of this study was to investigate the role of CSE-derived H2S on inflammation and LSECs fenestrae in caecal-ligation and puncture (CLP)-induced sepsis using CSE KO mice.
  
  
  METHODS
  Sepsis was induced by CLP, and mice (C57BL/6J, male) were sacrificed after 8 hours. Liver, lung, and blood were collected and processed to measure CSE expression, H2S synthesis, MPO activity, NF-κB p65, ERK1/2, and cytokines/chemokines levels. Diameter, frequency, porosity and gap area of the liver sieve were calculated from scanning electron micrographs of the LSECs.
  
  
  RESULTS
  An increased CSE expression and H2S synthesizing activity in the liver and lung of wild-type mice following CLP-induced sepsis. This was associated with an increased liver and lung MPO activity, and increased liver and lung and plasma levels of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β, and the chemokines MCP-1 and MIP-2α. Conversely, CSE KO mice had less liver and lung injury and reduced inflammation following CLP-induced sepsis as evidenced by decreased levels of H2S synthesizing activity, MPO activity, and pro-inflammatory cytokines/chemokines production. Extracellular-regulated kinase (ERK1/2) and nuclear factor-κB p65 (NF-κB) became significantly activated after the CLP in WT mice but not in CSE KO mice. In addition, CLP-induced damage to the LSECs, as indicated by increased defenestration and gaps formation in the LSECs compared to WT sham control. CSE KO mice showed decreased defenestration and gaps formation following sepsis.
  
  
  CONCLUSIONS
  Mice with CSE (an H2S synthesising enzyme) gene deletion are less susceptible to CLP-induced sepsis and associated inflammatory response through ERK1/2-NF-κB p65 pathway as evidenced by reduced inflammation, tissue damage, and LSECs defenestration and gaps formation.
authors: Department of Pathology, University of Otago, Christchurch, New Zealand.
authors: Ravinder Reddy
authors: RR
authors: Gaddam
authors: Department of Pathology, University of Otago, Christchurch, New Zealand.
authors: Robin
authors: R
authors: Fraser
authors: Department of Pathology, University of Otago, Christchurch, New Zealand.
authors: Alireza
authors: A
authors: Badiei
authors: Department of Pathology, University of Otago, Christchurch, New Zealand.
authors: Stephen
authors: S
authors: Chambers
authors: Centre for Education and Research on Ageing, Alzheimers and Ageing Institute, Biogerentology, ANZAC Research Institute, University of Sydney, Sydney and Concord Hospital, Sydney, Australia.
authors: Victoria C
authors: VC
authors: Cogger
authors: Centre for Education and Research on Ageing, Alzheimers and Ageing Institute, Biogerentology, ANZAC Research Institute, University of Sydney, Sydney and Concord Hospital, Sydney, Australia.
authors: David G
authors: DG
authors: Le Couteur
authors: Department of Biochemistry, Graduate School of Pharmaceutical Sciences, Keio University, Tokyo, Japan.
authors: Isao
authors: I
authors: Ishii
authors: Department of Pathology, University of Otago, Christchurch, New Zealand.
authors: Madhav
authors: M
authors: Bhatia
mesh_terms: D000818:Animals; D018925:Chemokines / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D017353:Gene Deletion; D008107:Liver Diseases / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D020011:Protective Agents / Q000378:metabolism*; D018805:Sepsis / Q000150:complications* / Q000382:microbiology
chemical_list: D018925:Chemokines; D016207:Cytokines; D020011:Protective Agents; D003542:Cystathionine gamma-Lyase