Cystathionine-Gamma-Lyase Gene Deletion Protects Mice against Inflammation and Liver Sieve Injury following Polymicrobial Sepsis

Abstract

BackgroundHydrogen 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.MethodsSepsis 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.ResultsAn 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.ConclusionsMice 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.

Hydrogen sulfide dysregulates the immune response by suppressing central carbon metabolism to promote tuberculosis

“…This modulation of immunity is also supported by decreased levels of cytokines responsible for controlling bacterial infections, such as IL-1β, IL-6, IL-9, IL-12, TNF-α, IL-17, and IFN-γ (29,39), observed in the serum of the WT mice. The data point to H 2 S as a regulator of innate and adaptive immunity during Mtb infection and our findings agree with studies showing that CSE-deficient mice are resistant to sepsis and associated inflammatory responses (16).…”

“…The strong CSE and MPST signals within the TB lungs raises the provocative idea that H 2 S could also function as an in vivo fuel source for Mtb. Not surprisingly, as was demonstrated in this study, overproduction of H 2 S is also associated with several other clinicopathological manifestations, including sepsis and associated inflammation (12)(13)(14)(15)(16). As was previously demonstrated in different inflammatory models, increased levels of H 2 S inhibit production of proinflammatory mediators, such as IL-1β, IL-6, TNF-α, NO, and mitochondrial ROI, but stimulate production of the antiinflammatory cytokine IL-10 in a dose-dependent manner (57)(58)(59), which supports our observations in Mtb-infected WT mice.…”

“…During septic shock, H 2 S synthesizing activity, neutrophil infiltration, and proinflammatory cytokine levels increase significantly (13)(14)(15). Notably, CSE-deletion mice had significantly reduced inflammation following sepsis (16), suggesting that CSE exacerbates inflammation in this model system. H 2 S is also an endogenous potentiator of T cell activation (17), which is essential for the control of Mtb infection.…”

H2S-Induced Sulfhydration: Biological Function and Detection Methodology

“…On the other hand, Bhatia et al (2005) demonstrated that the treatment with DL-propargylglycine, a CSE inhibitor, significantly reduced the severity of pancreatitis and lung injury induced by caerulein. Similarly, in caecal-ligation and puncture-induced sepsis mice model, CSE gene deletion alleviated the liver and lung injury and reduced inflammation along with the activation of ERK1/2 and NF-κB pathway ( Gaddam et al, 2016 ). Those results suggested that H 2 S played a role as pro-inflammatory cytokines.…”

H2S attenuates acute lung inflammation induced by administration of lipopolysaccharide in adult male rats

“…Several studies reported that H 2 S gives protection against ALI (Campos et al 2016;Zhang et al 2016). But, Qu et al (2014); Gaddam et al (2016) have found the reverse. Due to these antagonistic results, the present research was done to evaluate the effect of NaHS that serves as a donor of H 2 S and PAG which is an irreversible inhibitor of the H 2 S synthesizing enzyme CSE on ALI produced by LPS.…”