Metabolic Effects of Sodium Thiosulfate During Resuscitation from Trauma and Hemorrhage in Cigarette-Smoke-Exposed Cystathionine-γ-Lyase Knockout Mice
Background: Acute and chronic pre-traumatic cigarette smoke exposure increases morbidity and mortality after trauma and hemorrhage. In mice with a genetic deletion of the H<sub>2</sub>S-producing enzyme cystathione-γ-lyase (CSE<sup>−/−</sup>), providing exogenous H<sub>...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-11-01
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| Series: | Biomedicines |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2227-9059/12/11/2581 |
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| Summary: | Background: Acute and chronic pre-traumatic cigarette smoke exposure increases morbidity and mortality after trauma and hemorrhage. In mice with a genetic deletion of the H<sub>2</sub>S-producing enzyme cystathione-γ-lyase (CSE<sup>−/−</sup>), providing exogenous H<sub>2</sub>S using sodium thiosulfate (Na<sub>2</sub>S<sub>2</sub>O<sub>3</sub>) improved organ function after chest trauma and hemorrhagic shock. Therefore, we evaluated the effect of Na<sub>2</sub>S<sub>2</sub>O<sub>3</sub> during resuscitation from blunt chest trauma and hemorrhagic shock on CSE<sup>−/−</sup> mice with pre-traumatic cigarette smoke (CS) exposure. Since H<sub>2</sub>S is well established as being able to modify energy metabolism, a specific focus was placed on whole-body metabolic pathways and mitochondrial respiratory activity. Methods: Following CS exposure, the CSE<sup>−/−</sup> mice underwent anesthesia, surgical instrumentation, blunt chest trauma, hemorrhagic shock for over 1 h (target mean arterial pressure (MAP) ≈ 35 ± 5 mmHg), and resuscitation for up to 8 h comprising lung-protective mechanical ventilation, the re-transfusion of shed blood, fluid resuscitation, and continuous i.v. noradrenaline (NoA) to maintain an MAP ≥ 55 mmHg. At the start of the resuscitation, the mice randomly received either i.v. Na<sub>2</sub>S<sub>2</sub>O<sub>3</sub> (0.45 mg/g<sub>bodyweight</sub>; n = 14) or the vehicle (NaCl 0.9%; n = 11). In addition to the hemodynamics, lung mechanics, gas exchange, acid–base status, and organ function, we quantified the parameters of carbohydrate, lipid, and protein metabolism using a primed continuous infusion of stable, non-radioactive, isotope-labeled substrates (gas chromatography/mass spectrometry) and the post-mortem tissue mitochondrial respiratory activity (“high-resolution respirometry”). Results: While the hemodynamics and NoA infusion rates did not differ, Na<sub>2</sub>S<sub>2</sub>O<sub>3</sub> was associated with a trend towards lower static lung compliance (<i>p</i> = 0.071) and arterial PO<sub>2</sub> (<i>p</i> = 0.089) at the end of the experiment. The direct, aerobic glucose oxidation rate was higher (<i>p</i> = 0.041) in the Na<sub>2</sub>S<sub>2</sub>O<sub>3</sub>-treated mice, which resulted in lower glycemia levels (<i>p</i> = 0.050) and a higher whole-body CO<sub>2</sub> production rate (<i>p</i> = 0.065). The mitochondrial respiration in the heart, kidney, and liver tissue did not differ. While the kidney function was comparable, the Na<sub>2</sub>S<sub>2</sub>O<sub>3</sub>-treated mice showed a trend towards a shorter survival time (<i>p</i> = 0.068). Conclusions: During resuscitation from blunt chest trauma and hemorrhagic shock in CSE<sup>−/−</sup> mice with pre-traumatic CS exposure, Na<sub>2</sub>S<sub>2</sub>O<sub>3</sub> was associated with increased direct, aerobic glucose oxidation, suggesting a switch in energy metabolism towards preferential carbohydrate utilization. Nevertheless, treatment with Na<sub>2</sub>S<sub>2</sub>O<sub>3</sub> coincided with a trend towards worsened lung mechanics and gas exchange, and, ultimately, shorter survival. |
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| ISSN: | 2227-9059 |