Abstract
Cystathionine-γ-lyase (CSE) is a hydrogen sulfide (H2S)-synthesizing enzyme that promotes inflammation by upregulating H2S in sepsis. Liver sinusoidal endothelial cells (LSECs) are fenestrated endothelial cells (liver sieve) that undergo alteration during sepsis and H2S plays a role in this process. Substance P (SP) is encoded by the preprotachykinin A (PPTA) gene, and promotes inflammation in sepsis; however, its regulation by H2S is poorly understood. Furthermore, the interaction between H2S and SP in modulating LSEC fenestrations following sepsis remains unclear. This study aimed to investigate whether CSE/H2S regulates SP and the neurokinin-1 receptor (NK-1R) and modulates fenestrations in LSECs following caecal ligation and puncture (CLP)-induced sepsis. Here we report that the absence of either CSE or H2S protects against liver sieve defenestration and gaps formation in LSECs in sepsis by decreased SP-NK-1R signaling. Following sepsis, there is an increased expression of liver CSE and H2S synthesis, and plasma H2S levels, which were aligned with higher SP levels in the liver, lungs and plasma and NK-1R in the liver and lungs. The genetic deletion of CSE led to decreased sepsis-induced SP and NK-1R in the liver, lungs and plasma SP suggesting H2S synthesized through CSE regulates the SP-NK-1R pathway in sepsis. Further, mice deficient in the SP-encoding gene (PPTA) preserved sepsis-induced LSEC defenestration and gaps formation, as seen by maintenance of patent fenestrations and fewer gaps. In conclusion, CSE/H2S regulates SP-NK-1R and modulates LSEC fenestrations in sepsis.
Highlights
Hydrogen sulfide (H2S) is an endogenous gasotransmitter and plays a role in inflammation
Densitometry analysis of western blots showed that liver and lung neurokinin-1 receptor (NK-1R) protein expression increased significantly following sepsis (* p < 0.05 vs. WT sham)
Statistical significance was assigned as p < 0.05 (* p < 0.05 vs. WT sham). This is the first study demonstrating that H2S synthesized through CSE enzyme regulates Substance P (SP) and NK-1R, suggesting that SP plays a key role in promoting H2S-mediated Liver sinusoidal endothelial cells (LSECs) damage in sepsis
Summary
Hydrogen sulfide (H2S) is an endogenous gasotransmitter and plays a role in inflammation. Treatment with a CSE inhibitor (PAG) [5,6], silencing of the CSE gene with siRNA [4] and mice deficient in the CSE gene [7] conferred protection against H2S-mediated inflammatory response and organ injury in sepsis. These studies suggest that H2S has an important role in modulating the inflammatory process during sepsis
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