| First Author | Manandhar S | Year | 2023 |
| Journal | Int J Mol Sci | Volume | 24 |
| Issue | 17 | PubMed ID | 37686458 |
| Mgi Jnum | J:340533 | Mgi Id | MGI:7527681 |
| Doi | 10.3390/ijms241713650 | Citation | Manandhar S, et al. (2023) 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. Int J Mol Sci 24(17) |
| abstractText | Hydrogen sulfide (H(2)S), synthesized by cystathionine gamma-lyase (Cth), contributes to the inflammatory response observed in sepsis. This study examines the effect of Cth-derived H(2)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(2)S-synthesizing activity (via Cth) in both Cth(-/-) 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-2alpha), adhesion molecules (ICAM-1 and VCAM-1), ERK1/2 phosphorylation, and NF-kappaB in the liver and lung compared with in CLP-WT mice. Additionally, we found that PAG treatment in Cth(-/-) mice had no additional effect on the expression of ERK1/2 phosphorylation, NF-kappaB, or the production of chemokines and adhesion molecules in the liver and lung compared to Cth(-/-) 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(-/-), PAG-treated WT, and Cth(-/-) groups of mice showed decreased immunoreactivity of adhesion molecules on endothelial cells in the liver and lung following sepsis. Inhibition of H(2)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(2)S has an important role in the pathogenesis of sepsis and validates PAG use as a suited tool for investigating the Cth/H(2)S-signalling axis in sepsis. |
