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  • 1
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    Data_Sheet_1.PDF
    Frontiers Media SA ; 2022
    In:  Frontiers in Medicine Vol. 9 ( 2022-4-29)
    Details
    In: Frontiers in Medicine, Frontiers Media SA, Vol. 9 ( 2022-4-29)
    Abstract: Sodium thiosulfate (STS) is a recognized drug with antioxidant and H 2 S releasing properties. We recently showed that STS attenuated organ dysfunction and injury during resuscitation from trauma-and-hemorrhage in CSE-ko mice, confirming its previously described organ-protective and anti-inflammatory properties. The role of H 2 S in diabetes mellitus type 1 (DMT1) is controversial: genetic DMT1 impairs H 2 S biosynthesis, which has been referred to contribute to endothelial dysfunction and cardiomyopathy. In contrast, development and severity of hyperglycemia in streptozotocin(STZ)-induced DMT1 was attenuated in CSE-ko mice. Therefore, we tested the hypothesis whether STS would also exert organ-protective effects in CSE-ko mice with STZ-induced DMT1, similar to our findings in animals without underlying co-morbidity. Methods Under short-term anesthesia with sevoflurane and analgesia with buprenorphine CSE-ko mice underwent DMT1-induction by single STZ injection (100 μg⋅g –1 ). Seven days later, animals underwent blast wave-induced blunt chest trauma and surgical instrumentation followed by 1 h of hemorrhagic shock (MAP 35 ± 5 mmHg). Resuscitation comprised re-transfusion of shed blood, lung-protective mechanical ventilation, fluid resuscitation and continuous i.v. norepinephrine together with either i.v. STS (0.45 mg⋅g –1 ) or vehicle ( n = 9 in each group). Lung mechanics, hemodynamics, gas exchange, acid–base status, stable isotope-based metabolism, and visceral organ function were assessed. Blood and organs were collected for analysis of cytokines, chemokines, and immunoblotting. Results Diabetes mellitus type 1 was associated with more severe circulatory shock when compared to our previous study using the same experimental design in CSE-ko mice without co-morbidity. STS did not exert any beneficial therapeutic effect. Most of the parameters measured of the inflammatory response nor the tissue expression of marker proteins of the stress response were affected either. Conclusion In contrast to our previous findings in CSE-ko mice without underlying co-morbidity, STS did not exert any beneficial therapeutic effect in mice with STZ-induced DMT1, possibly due to DMT1-related more severe circulatory shock. This result highlights the translational importance of both integrating standard ICU procedures and investigating underlying co-morbidity in animal models of shock research.
    Type of Medium: Online Resource
    ISSN: 2296-858X
    URL: Article
    URL: Article
    DOI: 10.3389/fmed.2022.878823
    DOI: 10.3389/fmed.2022.878823.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2775999-4
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  • 2
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    The Mitochondria-Targeted H2S-Donor AP39 in a Murine Model of Combined Hemorrhagic Shock and Blunt Chest Trauma
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Shock Vol. 52, No. 2 ( 2019-08), p. 230-239
    Details
    In: Shock, Ovid Technologies (Wolters Kluwer Health), Vol. 52, No. 2 ( 2019-08), p. 230-239
    Abstract: Hemorrhagic shock (HS) accounts for 30% to 40% of trauma-induced mortality, which is due to multi-organ-failure subsequent to systemic hyper-inflammation, triggered by hypoxemia and tissue ischemia. The slow-releasing, mitochondria-targeted H 2 S donor AP39 exerted beneficial effects in several models of ischemia-reperfusion injury and acute inflammation. Therefore, we tested the effects of AP39-treatment in a murine model of combined blunt chest trauma (TxT) and HS with subsequent resuscitation. Methods: After blast wave-induced TxT or sham procedure, anesthetized and instrumented mice underwent 1 h of hemorrhage followed by 4 h of resuscitation comprising an i.v. bolus injection of 100 or 10 nmol kg −1 AP39 or vehicle, retransfusion of shed blood, fluid resuscitation, and norepinephrine. Lung mechanics and gas exchange were assessed together with hemodynamics, metabolism, and acid-base status. Blood and tissue samples were analyzed for cytokine and chemokine levels, western blot, immunohistochemistry, mitochondrial oxygen consumption (JO 2 ), and histological changes. Results: High dose AP39 attenuated systemic inflammation and reduced the expression of inducible nitric oxide synthase (iNOS) and IκBα expression in lung tissue. In the combined trauma group (TxT + HS), animals treated with high dose AP39 presented with the lowest mean arterial pressure and thus highest norepinephrine requirements and higher mortality. Low dose AP39 had no effects on hemodynamics, leading to unchanged norepinephrine requirements and mortality rates. Conclusion: AP39 is a systemic anti-inflammatory agent. In our model of trauma with HS, there may be a narrow dosing and timing window due to its potent vasodilatory properties, which might result in or contribute to aggravation of circulatory shock-related hypotension.
    Type of Medium: Online Resource
    ISSN: 1073-2322 , 1540-0514
    URL: Article
    DOI: 10.1097/SHK.0000000000001210
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 2011863-6
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  • 3
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    Effects of Sodium Thiosulfate During Resuscitation From Trauma-and-Hemorrhage in Cystathionine Gamma Lyase (CSE) Knockout Mice
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Shock Vol. 57, No. 1 ( 2022-01), p. 131-139
    Details
    In: Shock, Ovid Technologies (Wolters Kluwer Health), Vol. 57, No. 1 ( 2022-01), p. 131-139
    Abstract: Sodium thiosulfate (Na 2 S 2 O 3 ) is a clinically established drug with antioxidant and sulphide-releasing properties. Na 2 S 2 O 3 mediated neuro- and cardioprotective effects in ischemia/reperfusion models and anti-inflammatory effects in LPS-induced acute lung injury. Moreover, Na 2 S 2 O 3 improved lung function during resuscitation from hemorrhagic shock in swine with pre-existing atherosclerosis, characterized by decreased expression of cystathionine γ-lyase (CSE), a major source of hydrogen sulfide (H 2 S) synthesis in the vasculature. Based on these findings, we investigated the effects of Na 2 S 2 O 3 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. Na 2 S 2 O 3 (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: Na 2 S 2 O 3 treatment improved arterial paO 2 ( P = 0.03) coinciding with higher lung tissue glucocorticoid receptor expression. Norepinephrine requirements were lower in the Na 2 S 2 O 3 group ( P 〈 0.05), which was associated with lower endogenous glucose production and higher urine output. Na 2 S 2 O 3 significantly increased renal tissue IκBα and heme oxygenase-1 expression, whereas it lowered kidney IL-6 and MCP-1 levels. Conclusion: Na 2 S 2 O 3 exerted beneficial effects during resuscitation of murine trauma-and-hemorrhage in CSE −/− mice, confirming and extending the previously described organ-protective and anti-inflammatory properties of Na 2 S 2 O 3 . The findings make Na 2 S 2 O 3 a potentially promising therapeutic option in the context of impaired CSE activity and/or reduced endogenous H 2 S availability.
    Type of Medium: Online Resource
    ISSN: 1073-2322 , 1540-0514
    URL: Article
    DOI: 10.1097/SHK.0000000000001828
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 2011863-6
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