Cystathionine-Gamma-Lyase-Derived Hydrogen Sulfide-Regulated Substance P Modulates Liver Sieve Fenestrations in Caecal Ligation and Puncture-Induced Sepsis

Ravinder R Gaddam; Stephen Chambers; Robin Fraser; Victoria C Cogger; David G Le Couteur; Isao Ishii; Madhav Bhatia

doi:10.3390/ijms20133191

Back

Cystathionine-Gamma-Lyase-Derived Hydrogen Sulfide-Regulated Substance P Modulates Liver Sieve Fenestrations in Caecal Ligation and Puncture-Induced Sepsis

Journal article

Open access

Peer reviewed

Cystathionine-Gamma-Lyase-Derived Hydrogen Sulfide-Regulated Substance P Modulates Liver Sieve Fenestrations in Caecal Ligation and Puncture-Induced Sepsis

Ravinder R Gaddam, Stephen Chambers, Robin Fraser, Victoria C Cogger, David G Le Couteur, Isao Ishii and Madhav Bhatia

International journal of molecular sciences, Vol.20(13), p.3191

06/29/2019

DOI: 10.3390/ijms20133191

PMCID: PMC6651477

PMID: 31261857

Files and links (1)

url

https://doi.org/10.3390/ijms20133191View

Published (Version of record) Open Access

Abstract

Cystathionine-γ-lyase (CSE) isa hydrogen sulfide (H S)-synthesizing enzyme that promotesinflammation by upregulating H S in sepsis. Liver sinusoidal endothelial cells (LSECs) are fenestrated endothelial cells (liver sieve) that undergo alteration during sepsis and H S 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 H S is poorly understood. Furthermore, the interaction between H S and SP in modulating LSEC fenestrations following sepsis remains unclear. This study aimed to investigate whether CSE/H S 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 H S 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 H S synthesis, and plasma H S 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 H S 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/H S regulates SP-NK-1R and modulates LSEC fenestrations in sepsis.

cystathionine-gamma-lyase

neurokinin-1 receptor

hydrogen sulfide

substance P

liver sieve

Details

Title: Subtitle: Cystathionine-Gamma-Lyase-Derived Hydrogen Sulfide-Regulated Substance P Modulates Liver Sieve Fenestrations in Caecal Ligation and Puncture-Induced Sepsis
Creators: Ravinder R Gaddam - University of Otago
Stephen Chambers - University of Otago
Robin Fraser - University of Otago
Victoria C Cogger - Anzac Research Institute
David G Le Couteur - Anzac Research Institute
Isao Ishii - Showa Pharmaceutical University
Madhav Bhatia - University of Otago
Resource Type: Journal article
Publication Details: International journal of molecular sciences, Vol.20(13), p.3191
DOI: 10.3390/ijms20133191
PMID: 31261857
PMCID: PMC6651477
NLM abbreviation: Int J Mol Sci
ISSN: 1661-6596
eISSN: 1422-0067
Grant note: - / University of Otago 13/4 / Canterbury Medical Research Foundation - / ANZAC Research Institute
Language: English
Date published: 06/29/2019
Academic Unit: Internal Medicine
Record Identifier: 9984446546702771

Metrics

11 Record Views

15 Times Cited - Web of Science

See more details