Hydrogen Sulfide Mitigates Reperfusion Injury in a Porcine Model of Vascularized Composite Autotransplantation.
ABSTRACT Devastating extremity injuries are prevalent but often survivable on the modern battlefield. These complex injuries require advanced methods of reconstruction, involving prolonged ischemic periods and reperfusion injury. Using our group's validated porcine model of gracilis myocutaneous flap transplantation, this study demonstrates that an interim perfusion of hydrogen sulfide (H2S) mitigates the effects of reperfusion injury in the setting of delayed restoration of blood flow.
A gracilis myocutaneous flap (200-400 g; surface area, 250 cm) was procured from the hind limb of a Yorkshire swine (70-90 kg, n = 16). The right external carotid artery and the internal jugular vein are the recipient axis. Group 1 (control, n = 6) underwent delayed anastomosis with a 3-hour ischemic period. Group 2 (n = 10) underwent a similar delayed anastomosis with an interim perfusion of H2S during the ischemic period. The animals survived for 14 days. Systemic biomarker assays for skeletal muscle tissue injury (creatine kinase, lactate dehydrogenase, and aspartate transaminase) and proinflammatory markers (tumor necrosis factor α and interleukin 6) provide assessment of reperfusion injury at the cellular level.
The control animals (3 hours of ischemia with an interim perfusion of heparinized saline) demonstrated increased levels of injury biomarkers and proinflammatory cytokines compared with the animals receiving H2S infusion and identical ischemic interval. The control flaps had a mean creatine kinase level of 280 × 10 U/L (±80 × 10), compared with the H2S group, which had a mean of 99 × 10 U/L (±14 × 10; P = 0.0007 at postoperative day 2). Lactate dehydrogenase levels (mean) were 26 × 10 U/L (±8 × 10) versus 9 × 10 U/L (±3 × 10; P = 0.0004) and aspartate transaminase levels (mean) were 1651 U/L (±324) versus (873 U/L [±279]; P = 0.0013) for the control and treatment groups, respectively. Similarly, an intergroup difference in IL-6 was found, although not statistically significant. Tumor necrosis factor α levels (mean) were 93 pg/mL (±14) versus 39 pg/mL (±4; P = 0.0013) for the control and treatment groups, respectively.
This study demonstrated the mitigating properties of H2S on reperfusion injury. Interim perfusion with H2S resulted in diminution of ischemia-dependent biomarkers after 3 hours of ischemia. Follow-up studies will translate these findings as an evolving method for reconstructing previously unreconstructable injuries.
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ABSTRACT: Cellular and tissue injury induced by ischemia is often exacerbated by restoring perfusion to the affected organ system. The injury, termed ischemia-reperfusion injury, is mediated in large part by the inflammatory response generated in the setting of reperfusion. Recent research has demonstrated that the administration of hydrogen sulfide as a therapeutic agent in the setting of ischemia-reperfusion can markedly attenuate the inflammatory response with subsequent mitigation of tissue injury and improved function. This beneficial anti-inflammatory effect has been observed in multiple organ systems, subject to ischemia-reperfusion injury, the details of which are the subject of this chapter. © 2015 Elsevier Inc. All rights reserved.
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ABSTRACT: Hydrogen sulfide (H2S) is a novel endogenous gaseous signal transducer (gasotransmittor). Its emerging role in multiple facets of inter- and intra-cellular signaling as a metabolic, inflammatory, neuro and vascular modulator has been increasingly realized. Although H2S is known for its effects as an anti-hypertensive, anti-inflammatory and anti-oxidant molecule, the relevance of these effects in skeletal muscle biology during health and during metabolic syndromes is unclear. H2S has been implicated in vascular relaxation and vessel tone enhancement, which might lead to mitigation of vascular complications caused by the metabolic syndromes. Metabolic complications may also lead to mitochondrial remodeling by interfering with fusion and fission, therefore, leading to mitochondrial mitophagy and skeletal muscle myopathy. Mitochondrial protection by H2S enhancing treatments may mitigate deterioration of muscle function during metabolic syndromes. In addition, H2S might upregulate uncoupling proteins and might also cause browning of white fat, resulting in suppression of imbalanced cytokine signaling caused by abnormal fat accumulation. Likewise, as a source for H(+) ions, it has the potential to augment anaerobic ATP synthesis. However, there is a need for studies to test these putative H2S benefits in different patho-physiological scenarios before its full-fledged usage as a therapeutic molecule. The present review highlights current knowledge with regard to exogenous and endogenous H2S roles in skeletal muscle biology, metabolism, exercise physiology and related metabolic disorders, such as diabetes and obesity, and also provides future directions. Copyright © 2014. Published by Elsevier Inc.Nitric Oxide 11/2014; 46. DOI:10.1016/j.niox.2014.11.012 · 3.18 Impact Factor