Pharmacological Inhibition and Genetic Deletion of Cystathionine Gamma-Lyase in Mice Protects against Organ Injury in Sepsis: A Key Role of Adhesion Molecules on Endothelial Cells
Hydrogen sulfide (H<sub>2</sub>S), synthesized by cystathionine gamma-lyase (Cth), contributes to the inflammatory response observed in sepsis. This study examines the effect of Cth-derived H<sub>2</sub>S in adhesion molecules on endothelial cells of vital organs in mice in a...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-09-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/17/13650 |
| _version_ | 1797582325528133632 |
|---|---|
| author | Sumeet Manandhar Stephen Chambers Andrew Miller Isao Ishii Madhav Bhatia |
| author_facet | Sumeet Manandhar Stephen Chambers Andrew Miller Isao Ishii Madhav Bhatia |
| author_sort | Sumeet Manandhar |
| collection | DOAJ |
| description | Hydrogen sulfide (H<sub>2</sub>S), synthesized by cystathionine gamma-lyase (Cth), contributes to the inflammatory response observed in sepsis. This study examines the effect of Cth-derived H<sub>2</sub>S in adhesion molecules on endothelial cells of vital organs in mice in a cecal ligation puncture (CLP)-induced model of sepsis, using two different and complementary approaches: Cth gene deletion and pharmacological inhibition. Our findings revealed a decreased level of H<sub>2</sub>S-synthesizing activity (via Cth) in both Cth<sup>−/−</sup> mice and PAG-treated wild-type (WT) mice following CLP-induced sepsis. Both treatment groups had reduced MPO activity and expression of chemokines (MCP-1 and MIP-2α), adhesion molecules (ICAM-1 and VCAM-1), ERK1/2 phosphorylation, and NF-κB in the liver and lung compared with in CLP-WT mice. Additionally, we found that PAG treatment in Cth<sup>−/−</sup> mice had no additional effect on the expression of ERK1/2 phosphorylation, NF-κB, or the production of chemokines and adhesion molecules in the liver and lung compared to Cth<sup>−/−</sup> mice following CLP-induced sepsis. The WT group with sepsis had an increased immunoreactivity of adhesion molecules on endothelial cells in the liver and lung than the WT sham-operated control. The Cth<sup>−/−</sup>, PAG-treated WT, and Cth<sup>−/−</sup> groups of mice showed decreased immunoreactivity of adhesion molecules on endothelial cells in the liver and lung following sepsis. Inhibition of H<sub>2</sub>S production via both approaches reduced adhesion molecule expression on endothelial cells and reduced liver and lung injury in mice with sepsis. In conclusion, this study demonstrates that H<sub>2</sub>S has an important role in the pathogenesis of sepsis and validates PAG use as a suited tool for investigating the Cth/H<sub>2</sub>S-signalling axis in sepsis. |
| first_indexed | 2024-03-10T23:20:28Z |
| format | Article |
| id | doaj.art-67c33a2e43414fccb79485ef48e2ece4 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T23:20:28Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-67c33a2e43414fccb79485ef48e2ece42023-11-19T08:20:23ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-09-0124171365010.3390/ijms241713650Pharmacological Inhibition and Genetic Deletion of Cystathionine Gamma-Lyase in Mice Protects against Organ Injury in Sepsis: A Key Role of Adhesion Molecules on Endothelial CellsSumeet Manandhar0Stephen Chambers1Andrew Miller2Isao Ishii3Madhav Bhatia4Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New ZealandDepartment of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New ZealandDepartment of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New ZealandDepartment of Health Chemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, JapanDepartment of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New ZealandHydrogen sulfide (H<sub>2</sub>S), synthesized by cystathionine gamma-lyase (Cth), contributes to the inflammatory response observed in sepsis. This study examines the effect of Cth-derived H<sub>2</sub>S in adhesion molecules on endothelial cells of vital organs in mice in a cecal ligation puncture (CLP)-induced model of sepsis, using two different and complementary approaches: Cth gene deletion and pharmacological inhibition. Our findings revealed a decreased level of H<sub>2</sub>S-synthesizing activity (via Cth) in both Cth<sup>−/−</sup> mice and PAG-treated wild-type (WT) mice following CLP-induced sepsis. Both treatment groups had reduced MPO activity and expression of chemokines (MCP-1 and MIP-2α), adhesion molecules (ICAM-1 and VCAM-1), ERK1/2 phosphorylation, and NF-κB in the liver and lung compared with in CLP-WT mice. Additionally, we found that PAG treatment in Cth<sup>−/−</sup> mice had no additional effect on the expression of ERK1/2 phosphorylation, NF-κB, or the production of chemokines and adhesion molecules in the liver and lung compared to Cth<sup>−/−</sup> mice following CLP-induced sepsis. The WT group with sepsis had an increased immunoreactivity of adhesion molecules on endothelial cells in the liver and lung than the WT sham-operated control. The Cth<sup>−/−</sup>, PAG-treated WT, and Cth<sup>−/−</sup> groups of mice showed decreased immunoreactivity of adhesion molecules on endothelial cells in the liver and lung following sepsis. Inhibition of H<sub>2</sub>S production via both approaches reduced adhesion molecule expression on endothelial cells and reduced liver and lung injury in mice with sepsis. In conclusion, this study demonstrates that H<sub>2</sub>S has an important role in the pathogenesis of sepsis and validates PAG use as a suited tool for investigating the Cth/H<sub>2</sub>S-signalling axis in sepsis.https://www.mdpi.com/1422-0067/24/17/13650hydrogen sulfidecystathionine gamma-lyasesepsisadhesion moleculesendothelial cells |
| spellingShingle | Sumeet Manandhar Stephen Chambers Andrew Miller Isao Ishii Madhav Bhatia Pharmacological Inhibition and Genetic Deletion of Cystathionine Gamma-Lyase in Mice Protects against Organ Injury in Sepsis: A Key Role of Adhesion Molecules on Endothelial Cells International Journal of Molecular Sciences hydrogen sulfide cystathionine gamma-lyase sepsis adhesion molecules endothelial cells |
| title | Pharmacological Inhibition and Genetic Deletion of Cystathionine Gamma-Lyase in Mice Protects against Organ Injury in Sepsis: A Key Role of Adhesion Molecules on Endothelial Cells |
| title_full | Pharmacological Inhibition and Genetic Deletion of Cystathionine Gamma-Lyase in Mice Protects against Organ Injury in Sepsis: A Key Role of Adhesion Molecules on Endothelial Cells |
| title_fullStr | Pharmacological Inhibition and Genetic Deletion of Cystathionine Gamma-Lyase in Mice Protects against Organ Injury in Sepsis: A Key Role of Adhesion Molecules on Endothelial Cells |
| title_full_unstemmed | Pharmacological Inhibition and Genetic Deletion of Cystathionine Gamma-Lyase in Mice Protects against Organ Injury in Sepsis: A Key Role of Adhesion Molecules on Endothelial Cells |
| title_short | Pharmacological Inhibition and Genetic Deletion of Cystathionine Gamma-Lyase in Mice Protects against Organ Injury in Sepsis: A Key Role of Adhesion Molecules on Endothelial Cells |
| title_sort | pharmacological inhibition and genetic deletion of cystathionine gamma lyase in mice protects against organ injury in sepsis a key role of adhesion molecules on endothelial cells |
| topic | hydrogen sulfide cystathionine gamma-lyase sepsis adhesion molecules endothelial cells |
| url | https://www.mdpi.com/1422-0067/24/17/13650 |
| work_keys_str_mv | AT sumeetmanandhar pharmacologicalinhibitionandgeneticdeletionofcystathioninegammalyaseinmiceprotectsagainstorganinjuryinsepsisakeyroleofadhesionmoleculesonendothelialcells AT stephenchambers pharmacologicalinhibitionandgeneticdeletionofcystathioninegammalyaseinmiceprotectsagainstorganinjuryinsepsisakeyroleofadhesionmoleculesonendothelialcells AT andrewmiller pharmacologicalinhibitionandgeneticdeletionofcystathioninegammalyaseinmiceprotectsagainstorganinjuryinsepsisakeyroleofadhesionmoleculesonendothelialcells AT isaoishii pharmacologicalinhibitionandgeneticdeletionofcystathioninegammalyaseinmiceprotectsagainstorganinjuryinsepsisakeyroleofadhesionmoleculesonendothelialcells AT madhavbhatia pharmacologicalinhibitionandgeneticdeletionofcystathioninegammalyaseinmiceprotectsagainstorganinjuryinsepsisakeyroleofadhesionmoleculesonendothelialcells |