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-.B 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 wildtype 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-alpha, IL-6, and IL-1 beta, and the chemokines MCP-1 and MIP-2 alpha. Conversely, CSE KO mice had less liver and lung injury and reduced inflammation following CLPinduced 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-kappa B p65 (NF-kappa B) 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 toWT 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 CLPinduced sepsis and associated inflammatory response through ERK1/ 2-NF-kappa B p65 pathway as evidenced by reduced inflammation, tissue damage, and LSECs defenestration and gaps formation.