Cystathionine-γ-
lyase (CSE) isa
hydrogen sulfide (H2S)-synthesizing
enzyme that promotesinflammation 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) andmodulates fenestrations in LSECs following caecalligation and
puncture (CLP)-induced
sepsis. Here we report thatthe absence of either CSE or H2S protects against liver sieve defenestration and gaps formation in LSECsin
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) preservedsepsis-induced LSEC defenestrationand 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.