This issue of SHOCK compiles another great collection of predominately experimental studies on novel and innovative strategies to improve outcomes after different phenotypes of shock. Following the tradition of the journal, all contributions have been carefully selected and represent state-of-the-art works from different expert groups around the world. A first set of six articles refers to cardiac shock. Ocak et al. (1) have assessed the potential treatment effect of protease-activated receptor-2 (PAR-2) inhibition against neuroinflammation in an experimental asphyxial cardiac arrest model. The results confirm the deleterious effects of PAR-2-mediated neuroinflammation on hippocampal neuronal degeneration along with neurocognitive decline, while PAR-2 inhibition diminished neuroinflammation and reduced hippocampal neuronal degeneration thereby improving function. This neuroprotective effect was at least in part mediated through the ERK1/2 signaling pathway. If this is the primary mechanism of if other mechanisms such as preservation of the blood–brain barrier or antineuronal apoptosis may be involved needs further investigation. The brain hippocampus is also in the focus of the work by Weihs et al. (2). In particular the cornu ammonis 1 (CA1) region of the hippocampus is known to be highly vulnerable to global ischemia and it was hypothesized that histopathological outcome after experimental impact would be dependent on the time point of examination. The authors have used their previously established and clinically relevant model of experimental ventricular fibrillation cardiac arrest and report a consistent reduction in pyramidal cells in the CA1 region in all experimental animals 14 days after impact while in two-thirds of the animals a repopulation of pyramidal cells was observed within 140 days. The yet undefined mechanisms behind this difference may present potential therapeutic targets. Despite several limitations this study points out the importance of long-term examination of specific cell populations after ischemia.
A set of three experimental studies by using a range of models has assessed different approaches to improve outcomes and function after cardiac arrest or intentional cardioplegia (3–5). Chen et al. confirm the protective role of resolvin D1 for vital organs also in the context of global ischemia reperfusion (IR). Resolvin D is considered a bioactive lipid mediator generated enzymatically by an omega-3 fatty acid docosahexaenoic acid. There was a dose-dependent improvement in both cardiac and cerebral outcome through the alleviation of tissue inflammation and oxidative stress. In the next study, Li et al. (4) assessed the effect of experimental mild hypothermia on diaphragma function and microcirculation including timing in a murine CPR model. To more closely mimic the clinical scenario, an intra-resuscitation hypothermia group (IRH) was designed to correspond to in-hospital cardiac arrest and a post-resuscitation hypothermia group (PRH) to correspond to out-of-hospital cardiac arrest, the latter being by far the most common clinical scenario. For IRH rapid cooling to 33°C was carried out immediately at the beginning of CPR and for PRH at 30 min after ROSC; the temperature was maintained for 12 h in both groups. Mild hypothermia preserved diaphragm contractility and fiber dimensions and decreased oxidative stress but did not improve the microcirculatory blood supply during prolonged mechanical ventilation after resuscitation. Early intervention may be more efficient in preventing diaphragm dysfunction as compared with delayed intervention. In the last study, Cong et al. (5) provide first macroscopic and microscopic evidence for myocardial protection of ßARKct gene transfection in experimental cardioplegic arrest following cardiopulmonary bypass. Apparently, ßARKct by inhibiting cardiac G-protein-coupled receptor kinase-2 significantly ameliorated ventricular systolic function and hemodynamics, rescuing ß1-AR-RyR2/SERCA2a signaling and decreasing mitochondrial damage.
Another series of four experimental studies takes on different approaches to improve outcome including survival in different models of sepsis (6–8). Clavier et al. (6) have used the classical intraperitoneal LPS injection model to assess the impact of the Urotensin (UT) antagonist urantide on survival, systemic inflammation, and cardiac function in C57BI/6 mice. Urotensin II is known as a potent vasoactive peptide activating the G protein-coupled receptor UT involved in systemic inflammation and cardiovascular function. In the model, UT treatment significantly improved survival after 1 week along with decreased temporal cytokine profiles and cytosolic NF-kB-p65 in liver and kidney and improved cardiac output. This may be a potential new therapeutic target for septic patients and calls for further investigation. The therapeutic effect of hyaluronic acid (HA) was evaluated by Lee et al. (7) in the same species but using an alternative model of peritonitis-induced sepsis through cecal legation and puncture (CLP). Intraperitoneal high molecular weight HA instillation 4 h after CLP significantly improved blood oxygenation, lung histology, bacterial burden in the peritoneal lavage, and survival.
To date, only very few experimental studies have assessed the impact of sepsis on cardiovascular function or immune-responses in the context of pregnancy. Maternal responses to septic stimuli may be altered during pregnancy resulting in higher mortality but the underlying mechanisms remain scarce. Zölner et al. (8) have targeted this highly relevant issue and have tested whether the metabolic inhibition of the endogenous inhibitor of nitric oxide (NO) synthase would improve outcome in their previously established and robust CLP model in murine pregnancy. Dimethylarginine dimethylaminohydrolase 1-selective inhibitor (L-257) which reduces vascular NO synthesis but without impairing immune cell function combined with broad-spectrum antibiotic Imipenem significantly improved survival up to 50%, prevented cardiovascular collapse and a decline in metabolic markers. Interestingly, the combined approach did neither repress inflammatory cell lung trafficking nor increased cytokine levels in circulation or lung tissue, suggesting that these aspects may be less important for the outcome of sepsis in the context of pregnancy. The lung is also the target of the last work in this series on sepsis. Yang et al. (9), in their fine work, have used a pneumonia sepsis model through intratracheal infection with Pseudomonas aeruginosa to assess the regulatory role of human Surfactant Protein B (hSP-B) genetic variants on lung injury. Surfactant protein B (SP-B) is known to be critical for host defense and controlling alveolar surface tension; single-nucleotide polymorphism alters the N-linked glycosylation thereby potentially affecting its function. Humanized transgenic SP-B-Tand SP-B-C mice expressing either hSP-B C or T allele without mouse SP-B gene showed higher bioluminescence and CFUs, increased inflammation and mortality, more severe lung injury, and reduced numbers of lamellar bodies in type II cells; minimum surface tension increased dramatically in infected mice and cytokines levels in the lung of infected SP-B-C were higher which confirmed that hSP-B variants may differentially regulate susceptibility through modulating the surface activity of surfactant, cell death, and inflammatory signaling in sepsis.
The second section of this issue is dedicated to organo-celullar responses and treatment options after hemorrhagic shock. Loftus et al. (10) hypothesized that intraperitoneal beta-blockade combined with sympathetic outflow inhibition would decrease hematopoietic progenitor mobilization after trauma including hemorrhage and chronic stress. In their experimental model, both compounds attenuated the neuroendocrine response through reduced bone marrow MMP-9 expression, plasma corticosterone levels, and HPC mobilization, together with increased hemoglobin levels. Li et al. (11) could show that treatment with suberoylanilide hydroxamic acid (SAHA) after severe hemorrhagic shock may alleviate lung injury through reversal of decreased histone acetylation and inhibition of the NF-kB pathway. Histone acetylation has been identified as an important form of epigenetic regulation that affects the structure and function of chromatin thereby being closely related to gene expression. It is known that hemorrhagic shock and resuscitation (HS/R) downregulate the extent of histone acetylation. In their previous work, Zhou et al. (12) have discovered that combined peptidylarginine deiminase PAD2/PAD4 inhibitor (YW356) administration may attenuate inflammation and improve survival experimental hemorrhagic shock but without distinction between the two PAD isoforms. In their present report, the group has utilized selective Pad_/_ knockout mice to assess if Pad2_/_ improves survival in the given context. Possible mechanisms by which loss of PAD2 function improved survival were linked to the activation of cell survival pathways, improved tolerance of cardiac ischemia, and improved cardiac function during ischemia. Last but not the least, Li et al. (13), in a proof-of-concept approach and by using an established renal ischemia-reperfusion (IRI) model in the rat, tested the hypothesis that pretreatment of URB602, 30 min before renal IRI alleviates kidney injury and relevant distant organ damage via limiting oxidative stress and inflammation. There is, indeed, accumulating evidence for the endocannabinoid system to provide a promising access for treatment in renal IRI-associated acute kidney injury. The results showed that URB602 potentially acts as a reactive oxygen species scavenger and anti-inflammatory media mainly depending on the activation of the cannabinoid receptor two (CB2).
Hemoglobin (Hb)-based oxygen carriers have been tested in the past as an alternative to classical RBC transfusion but may cause more adverse effects than initially thought. Potential side effects have been linked to their molecular size. Large molecular diameter polymerized Hb (PolyHb) prevents extravasation and kidney damage by size exclusion and promotes clearance of PolyHb via normal Hb scavenging pathways. In their clinically relevant work, Williams et al. (14) tested the hypothesis that extended storage would not impact the safety and efficacy of high MW polymerized bovine Hb (PolybHb). Their results indicate that large molecular diameter PolybHb may be as efficacious as fresh blood in restoring cardiac function after hemorrhagic shock and confirm the lack of degradation of PolybHb's safety or efficacy during long-term storage. In the remaining clinical work, Nie et al. (15) provide a more detailed picture of the clinical characteristics of the severe fever with thrombocytopenia syndrome which is an emerging infectious disease in Asia and the United States caused by a bunyavirus to be carried by ticks. As observed in the current pandemic caused by SARS-CoV-2, early risk stratification based upon clinical signs and symptoms for intensive care and intervention may be lifesaving. The authors report on older age, elevated lactate and creatinine levels to be useful for identifying patients with poor outcome and in need for intensive medical intervention as soon as possible to reduce mortality.
It has been honor and pleasure to highlight and comment once more on the valuable contributions to this issue of SHOCK. This is another great collection of outstanding contributions which each single paper worthwhile paying attention to and reading.
1. Ocak U, Ocak PE, Huang L, Zuo G, Yan J, Hu X, Song Z, Zhang JH. Inhibition of PAR-2 attenuates neuroinflammation and improves short-term neurocognitive functions via ERK1/2 signaling following asphyxia-induced cardiac arrest in rats. Shock
2. Weihs W, Warenits A-M, Ettl F, Magnet IAM, Herkner H, Kramer AM, Teubenbacher U, Lobmeyr E, Schriefl C, Clodi C, et al. CA1 hippocampal pyramidal cells in rats, resuscitated from 8 minutes of ventricular fibrallation cardiac arrest, recover after 20 weeks of survival: a retrospective pilot study. Shock
3. Chen W, Wang H, Wang Z, Zhao C, Xu J, Chen Q. Resolvin D1 improves post-resuscitation cardiac and cerebral outcomes in a porcine model of cardiac arrest. Shock
4. Li S-P, Zhou X-L, Li Q, Zhao Y-Q, Zhao Z-G, Zhao Y. Effect of mild hypothermia on the diaphragmatic microcirculation and function in a murine cardiopulmonary resuscitated model. Shock
5. Cong M, Fan Y, Zhu F, Ji X, Sun L, Yang M, Li N, Li Q, Tan Q. Adenoviral βARKCT cardiac gene therapy ameliorates cardiac function following cardiopulmonary bypass in a swine model. Shock
6. Clavier T, Besnier E, Maucotel J, Arabo A, Desrues L, El Amki M, Perzo N, Richard V, Tamion F, Gandolfo P, et al. Urantide improves cardiac function, modulates systemic cytokine response, and increases survival in a murine model of endotoxic shock. Shock
7. Lee JH, Liu A, Park J-H, Kato H, Hao Q, Zhang X, Zhou L, Lee J-W. Therapeutic effects of hyaluronic acid in peritonitis-induced sepsis in mice. Shock
8. Zölner J, Lambden S, Nasri NM, Johnson MR, Leiper J. Inhibition of dimethylarginine dimethylaminohydrolase 1 improves the outcome of sepsis in pregnant mice. Shock
9. Yang F, Zhang J, Yang Y, Ruan F, Chen X, Guo J, Abdel-Razek O, Zuo YY, Wang G. Regulatory roles of human surfactant protein B variants on genetic susceptibility to pseudomonas aeruginosa
pneumonia-induced sepsis. Shock
10. Loftus TJ, Kannan KB, Mira JC, Brakenridge SC, Efron PA, Mohr AM. Modulation of the HGF/c-Met axis impacts prolonged hematopoietic progenitor mobilization following trauma and chronic stress. Shock
11. Li W, Gao X, Liu W, Liang J, Zhou Y, Chen W, He H. Suberoylanilide hydroxamic acid alleviates acute lung injury induced by severe hemorrhagic shock and resuscitation in rats. Shock
12. Zhou J, Biesterveld BE, Li Y, Wu Z, Tian Y, Williams AM, Tian S, Gao W, Bhatti UF, Duan X, et al. Peptidylarginine deiminase 2 knockout improves survival in hemorrhagic shock. Shock
13. Li X-H, Liu Y-Q, Gong D-YS Hai##K-R, Ke B-W, Zuo Y-W. The critical role of cannabinoid receptor 2 in URB602-induced protective effects against renal ischemia-reperfusion injury in the rat. Shock
14. Williams AT, Lucas A, Muller CR, Munoz C, Bolden-Rush C, Palmer AF, Cabrales P. Resuscitation from hemorrhagic shock with fresh and stored blood and polymerized hemoglobin. Shock
15. Nie Q, Wang D, Ning Z, Li T, Tian X, Bian P, Ding K, Hu C, Peng Z-Y. Analysis of severe fever with thrombocytopenia syndrome in critical ill patients in central China. Shock