EFFECTS OF SODIUM THIOSULFATE DURING RESUSCITATION FROM TRAUMA-AND-HEMORRHAGE IN CYSTATHIONINE GAMMA LYASE (CSE) KNOCKOUT MICE

Background: Sodium thiosulfate (Na2S2O3) is a clinically established drug with antioxidant and sulphide-releasing properties. Na2S2O3 mediated neuro- and cardioprotective effects in ischemia/reperfusion models and anti-inflammatory effects in LPS-induced acute lung injury. Moreover, Na2S2O3 improved lung function during resuscitation from hemorrhagic shock in swine with pre-existing atherosclerosis, characterized by decreased expression of cystathionine gamma-lyase (CSE), a major source of hydrogen sulfide (H2S) synthesis in the vasculatu re. Based on these findings, we investigated the effects of Na2S2O3 administration during resuscitation from trauma-and-hemorrhage in mice under conditions of whole body CSE deficit. Methods: After blast wave-induced blunt chest trauma and surgical instrumentation, CSE knockout (CSE-/-) mice underwent 1 h of hemorrhagic shock (MAP 35 +/- 5 mm Hg). At the beginning of resuscitation comprising retransfusion, norepinephrine support and lung-protective mechanical ventilation, animals received either i.v. Na2S2O3 (0.45 mg g(-1), n =12) or vehicle (saline, n =13). Hemodynamics, acid-base status, metabolism using stable isotopes, and visceral organ function were assessed. Blood and organs were collected for analysis of cytokines, mitochondrial respiratory capacity, and immunoblotting. Results: Na2S2O3 treatment improved arterial paO(2) (P=0.03) coinciding with higher lung tissue glucocorticoid receptor expression. Norepineph rine requirements were lower in the Na2S2O3 group (P< 0.05), which was associated with lower endogenous glucose production and higher urine output. Na2S2O3 significantly increased renal tissue I kappa B alpha and heme oxygenase-1 expression, whereas it lowered kidney IL-6 and MCP-1 levels. Conclusion: Na2S2O3 exerted beneficial effects during resuscitation of murine trauma-and-hemorrhage in CSE 4- mice, confirming and extending the previously described organ-protective and anti-inflammatory properties of Na2S2O3. The findings make Na2S2O3 a potentially promising therapeutic option in the context of impaired CSE activity and/or reduced endogenous H2S availability.

Automated summary

This study investigated the effects of sodium thiosulfate (Na2S2O3) administration during resuscitation from trauma-and-hemorrhage in mice under conditions of whole body cystathionine gamma-lyase (CSE) deficit. The results showed that Na2S2O3 exerted beneficial effects in terms of organ protection and anti-inflammatory properties, improving lung function, reducing norepinephrine requirements, increasing urine output, and regulating inflammatory response and oxidative stress in the kidney tissue. These findings suggest that Na2S2O3 could be a potential therapeutic option in the context of impaired CSE activity and/or reduced endogenous H2S availability.