bims-heshmo 2022-01-02 papers

Eur Surg Res. 2021 Dec 24.

Mitochondrial dysfunction in trauma-related coagulopathy - Is there causality? - Study protocol for a prospective observational study.

Péter Jávor, Ferenc Rárosi, Tamara Horváth, László Török, Petra Hartmann.

Hemorrhage control often poses a great challenge for clinicians due to trauma-induced coagulopathy (TIC). The pathogenesis of TIC is not completely revealed; however, growing evidence attributes a central role to altered platelet biology. The activation of thrombocytes and subsequent clot formation are highly energetic processes being tied to mitochondrial activity, and the inhibition of the electron transport chain (ETC) impedes on thrombogenesis, suggesting the potential role of mitochondria in TIC. Our present study protocol provides a guide to quantitatively characterize the derangements of mitochondrial functions in TIC. One hundred eleven severely injured (Injury Severity Score ≥16), bleeding trauma patients with an age of 18 or greater will be included in this prospective observational study. Patients receiving oral antiplatelet agents including cyclooxygenase-1 or adenosine diphosphate receptor inhibitors (aspirin, clopidogrel, prasugrel, and ticagrelor) will be excluded from the final analysis. Hemorrhage will be confirmed and assessed with computer tomography. Conventional laboratory markers of hemostasis such as prothrombin time and international normalized ratio (INR) will be measured and rotational thromboelastometry (ROTEM) will be performed directly upon patient arrival. Platelets will be isolated from venous blood samples and subjected to high-resolution fluororespirometry (Oxygraph-2k, Oroboros Instruments, Innsbruck, Austria) to evaluate the efficacy of mitochondrial respiration. Oxidative phosphorylation (OxPhos), coupling of the ETC, mitochondrial superoxide formation, mitochondrial membrane potential changes and extramitochondrial Ca2+-movement will be recorded. The association between OxPhos capacity of platelet mitochondria and numerical parameters of ROTEM aggregometry will constitute our primary outcome. The relation between OxPhos capacity and results of viscoelastic assays and conventional markers of hemostasis will serve as secondary outcomes. The association of the OxPhos capacity of platelet mitochondria upon patient arrival to the need for massive blood transfusion (MBT) and 24-hour mortality will constitute our tertiary outcomes. Mitochondrial dysfunction and its importance in TIC in are yet to be assessed for the deeper understanding of this common, life-threatening condition. Disclosure of mitochondria-mediated processes in thrombocytes may reveal new therapeutic targets in the management of hemorrhaging trauma patients, thereby leading to a reduction of potentially preventable mortality. The present protocol was registered to ClinicalTrials.gov on 12 August 2021, under the reference number NCT05004844.

DOI: https://doi.org/10.1159/000521670

Pharmaceutics. 2021 Dec 09. pii: 2127. [Epub ahead of print]13(12):

Polymeric Materials for Hemostatic Wound Healing.

Suvash Ghimire, Pritha Sarkar, Kasey Rigby, Aditya Maan, Santanu Mukherjee, Kaitlyn E Crawford, Kausik Mukhopadhyay.

Hemorrhage is one of the greatest threats to life on the battlefield, accounting for 50% of total deaths. Nearly 86% of combat deaths occur within the first 30 min after wounding. While external wound injuries can be treated mostly using visual inspection, abdominal or internal hemorrhages are more challenging to treat with regular hemostatic dressings because of deep wounds and points of injury that cannot be located properly. The need to treat trauma wounds from limbs, abdomen, liver, stomach, colon, spleen, arterial, venous, and/or parenchymal hemorrhage accompanied by severe bleeding requires an immediate solution that the first responders can apply to reduce rapid exsanguinations from external wounds, including in military operations. This necessitates the development of a unique, easy-to-use, FDA-approved hemostatic treatment that can deliver the agent in less than 30 s and stop bleeding within the first 1 to 2 min at the point of injury without application of manual pressure on the wounded area.

Keywords: blood; hemostasis; hydrogels; metals; nanoparticles; polymer; wound

DOI: https://doi.org/10.3390/pharmaceutics13122127

In Vivo. 2022 Jan-Feb;36(1):36(1): 153-160

Description of a Recovery Model in Rabbits for the Study of the Late Phase of Liver Ischemia-Reperfusion Injury.

Athina G Mantelou, Argyro Zacharioudaki, George Pappas-Gogos, Apostolos Papalois, Alexandra Papoudou-Bai, Anna Goussia, Georgios K Glantzounis.

AIM: Description of an anesthetic recovery model with endotracheal intubation in rabbits which provides metabolic stability for the study of the late phase of liver ischemia/reperfusion (I/R) injury.
MATERIALS AND METHODS: Two groups of New Zealand rabbits, n=7 in each, were used: Ischemia/reperfusion (I/R) group (45 min of partial liver ischemia/reperfusion) and no intervention (sham) group. Blood alanine aminotransferase, lactate, pH values, mean arterial pressure and pCO2 were calculated at baseline, and at 2 and 24 h post reperfusion. Tissue samples from left (ischemic) and right (non-ischemic) liver lobes were examined at 2 and 24 h after reperfusion.
RESULTS: The I/R group presented significantly higher levels of alanine aminotransferase (p=0.001) at 2 and 24 h, and of lactate (p=0.016) at 2 h post reperfusion. No differences were documented for pH, mean arterial pressure and pCO2 Histological exanimation revealed significant injury at 24 h post reperfusion for the I/R group.
CONCLUSION: This anesthetic recovery model permitted avoidance of hypoxia and respiratory acidosis, allowing the study of the late phase of I/R injury.

Keywords: Ischemia-reperfusion; anesthesia; intubation; liver; rabbit; recovery

DOI: https://doi.org/10.21873/invivo.12686

FEBS J. 2021 Dec 30.

Nrf2 and Oxidative Stress in liver Ischemia/Reperfusion Injury.

Raquel G Bardallo, Arnau Panisello-Roselló, Sergio Sanchez-Nuno, Norma Alva, Joan Roselló-Catafau, Teresa Carbonell.

In response to stress signal, nuclear factor-erythroid 2 related factor 2 (Nrf2) induces the expression of target genes involved in antioxidant defense and detoxification. Nrf2 activity is strictly regulated through a variety of mechanisms, including regulation of Keap1-Nrf2 stability, transcriptional regulation (NF-ĸB, ATF3, ATF4), and post-transcriptional regulation (miRNA), evidencing that transcriptional responses of Nrf2 are critical for the maintenance of homeostasis. Ischemia-reperfusion (IR) injury is a major cause of graft loss and dysfunction in clinical transplantation and organ resection. During the IR process, the generation of reactive oxygen species (ROS) leads to damage from oxidative stress, oxidation of biomolecules, and mitochondrial dysfunction. Oxidative stress can trigger apoptotic and necrotic cell death. Stress factors also result in the assembly of the inflammasome protein complex and the subsequent activation and secretion of proinflammatory cytokines. After Nrf2 activation, the downstream antioxidant upregulation can act as a primary cellular defense against the cytotoxic effects of oxidative stress and help to promote hepatic recovery during IR. The complex crosstalk between Nrf2 and cellular pathways in liver IR injury and the potential therapeutic target of the Nrf2 inducers will be discussed in the present review.

Keywords: Antioxidant; Inflammation; Ischemia-Reperfusion Injury; Liver; Nrf2; Redox

DOI: https://doi.org/10.1111/febs.16336

Pharmaceuticals (Basel). 2021 Dec 07. pii: 1276. [Epub ahead of print]14(12):

Matrix Metalloproteinase-2 Inhibition in Acute Ischemia-Reperfusion Heart Injury-Cardioprotective Properties of Carvedilol.

Monika Skrzypiec-Spring, Joanna Urbaniak, Agnieszka Sapa-Wojciechowska, Jadwiga Pietkiewicz, Alina Orda, Bożena Karolko, Regina Danielewicz, Iwona Bil-Lula, Mieczysław Woźniak, Richard Schulz, Adam Szeląg.

Matrix metalloproteinase 2 (MMP-2) is activated in hearts upon ischemia-reperfusion (IR) injury and cleaves sarcomeric proteins. It was shown that carvedilol and nebivolol reduced the activity of different MMPs. Hence, we hypothesized that they could reduce MMPs activation in myocytes, and therefore, protect against cardiac contractile dysfunction related with IR injury. Isolated rat hearts were subjected to either control aerobic perfusion or IR injury: 25 min of aerobic perfusion, followed by 20 min global, no-flow ischemia, and reperfusion for 30 min. The effects of carvedilol, nebivolol, or metoprolol were evaluated in hearts subjected to IR injury. Cardiac mechanical function and MMP-2 activity in the heart homogenates and coronary effluent were assessed along with troponin I content in the former. Only carvedilol improved the recovery of mechanical function at the end of reperfusion compared to IR injury hearts. IR injury induced the activation and release of MMP-2 into the coronary effluent during reperfusion. MMP-2 activity in the coronary effluent increased in the IR injury group and this was prevented by carvedilol. Troponin I levels decreased by 73% in IR hearts and this was abolished by carvedilol. Conclusions: These data suggest that the cardioprotective effect of carvedilol in myocardial IR injury may be mediated by inhibiting MMP-2 activation.

Keywords: carvedilol; ischemia-reperfusion injury; isolated heart perfusion; matrix metalloproteinase-2; β-blockers

DOI: https://doi.org/10.3390/ph14121276

Front Med (Lausanne). 2021 ;8 794561

New Applications of HBOC-201: A 25-Year Review of the Literature.

Min Cao, Yong Zhao, Hongli He, Ruiming Yue, Lingai Pan, Huan Hu, Yingjie Ren, Qin Qin, Xueliang Yi, Tao Yin, Lina Ma, Dingding Zhang, Xiaobo Huang.

If not cured promptly, tissue ischemia and hypoxia can cause serious consequences or even threaten the life of the patient. Hemoglobin-based oxygen carrier-201 (HBOC-201), bovine hemoglobin polymerized by glutaraldehyde and stored in a modified Ringer's lactic acid solution, has been investigated as a blood substitute for clinical use. HBOC-201 was approved in South Africa in 2001 to treat patients with low hemoglobin (Hb) levels when red blood cells (RBCs) are contraindicated, rejected, or unavailable. By promoting oxygen diffusion and convective oxygen delivery, HBOC-201 may act as a direct oxygen donor and increase oxygen transfer between RBCs and between RBCs and tissues. Therefore, HBOC-201 is gradually finding applications in treating various ischemic and hypoxic diseases including traumatic hemorrhagic shock, hemolysis, myocardial infarction, cardiopulmonary bypass, perioperative period, organ transplantation, etc. However, side effects such as vasoconstriction and elevated methemoglobin caused by HBOC-201 are major concerns in clinical applications because Hbs are not encapsulated by cell membranes. This study summarizes preclinical and clinical studies of HBOC-201 applied in various clinical scenarios, outlines the relevant mechanisms, highlights potential side effects and solutions, and discusses the application prospects. Randomized trials with large samples need to be further studied to better validate the efficacy, safety, and tolerability of HBOC-201 to the extent where patient-specific treatment strategies would be developed for various clinical scenarios to improve clinical outcomes.

Keywords: HBOC-201; clinical settings; oxygen bridge; oxygen-carrying capacities; red blood cell

DOI: https://doi.org/10.3389/fmed.2021.794561