What's New in Shock, July 2021?

As we enter the summer months, the July issue of Shock offers a refreshing combination of clinical, translational, and basic science papers that provide novel insights into pathophysiology of trauma, shock, resuscitation, and sepsis. In particular, this issue is a testament to the outstanding progress made by our esteemed basic science colleagues in understanding sepsis pathobiology. This month's issue features four invited review articles, an equal number of clinical and basic science studies (six), and two letters to the editor.

We start the issue with an excellent review from Huang et al. (1) which offers an in-depth review of the importance of the calpain protease in sepsis-induced multi-organ failure (MOF). The authors portray calpain as a linchpin molecule with downstream effects on a variety of inflammatory mediators and immune cells. The authors address the consequences of the culmination of these processes on individual organ systems. In doing so they build an impressive case for the value of calpain in the etiology of MOF in the septic patient. Further, they propose calpain as a target for novel therapeutic interventions in sepsis.

A spotlight is cast on the hematopoietic lineage of stem cells by Kelly et al. (2). The authors underscore the need to investigate the role of hematopoietic precursors in trauma, hemorrhage, and sepsis, in addition to the traditional focus on endothelial stem cells. They paint a picture depicting hematopoietic precursors sensing and reacting to a maelstrom of molecular signaling. The net of these interactions culminates in a molecular signature that drives hematologic cell differentiation. The authors draw attention to the myriad of avenues by which these cells influence the pathophysiology of injury and they propose that clinical outcome is intimately tied to the downstream consequences of hematopoiesis and the disposition of the hematopoietic progenitor cell. The group from Gainesville continues to shine a light on the molecular foundation of injury and illness in this engaging review.

The current principles of hemorrhage resuscitation stand in stark contrast to those touted 20 years ago. Black et al. (3) chronicle the evolution of the modern era of damage control resuscitation (DCR). They begin by describing a fork in the road for transfusion protocols in the late 2000s and recount the evidence that led trauma guidelines down the path of a balanced transfusion ratio over intravenous fluid and red blood cell-heavy resuscitation strategies. However, they emphasize that the shift to DCR was a gradual one. Subsequently, the delineation and comparison of the pre- and post-DCR eras is difficult in some respects. The authors postulate that adjunct interventions in resuscitation like tranexamic acid may further muddy the water when attempting to appraise the benefit of a balanced transfusion ratio. Despite these obstacles, Black et al. (3) have developed a strong case for the benefits of DCR in reference to clinical outcomes, complications, and physiologic derangement. Regardless, the pursuit of the optimal management of hemorrhagic shock continues. These authors hint that whole blood versus balanced component therapy-based resuscitation may represent the next fork in the road.

This issue of Shock shows us that there are many ways to optimize the resuscitation of the critically ill patient. Kwak et al. (4) illustrate the value of the early identification of patients requiring vasopressor support, including improved clinical outcomes. The authors have leveraged the power of deep learning algorithms to identify those patients who will go on to require vasopressors. They report a respectable accuracy for this novel prediction model, which is derived from routinely available clinical variables. Kwak et al. present considerable evidence that deep learning strategies can optimize performance in the management of the critically ill.

We continue our theme of resuscitation as Tiba et al. invite readers to consider a new perspective on tissue perfusion (5). These authors emphasize the importance of surrogate markers for tissue oxygenation in the management of the critically ill patient. They characterize the deficiencies in strategies reliant on invasive central venous catheter (CVC) placement. Fortunately, this group from Michigan offers a novel method to provide a continuous, safe, and reliable approximation of tissue perfusion by the way of resonance Raman spectroscopy. This innovation in the management of the critically ill presents exciting potential.

A second manuscript challenges common practices regarding CVC placement. Edakubo et al. (6) question the appropriate timing of this procedure in the septic patient. They consider the complications associated with attempting central line access in the acutely ill and they ask if the risks outweigh the benefits. To this end, the authors queried a nationwide Japanese database to compare outcomes between early and late CVC placement in patients with severe sepsis. They present evidence to support current trends moving away from early CVC placement in unstable septic patients. This group provides an excellent example of how big data can be translated into context for common clinical decisions at the bedside.

Neutrophils are a crucial component of the innate immune system yet also play a decisive role in the development of organ dysfunction during critical illness. We are only recently gaining clarity on their phenotypic alterations and mechanistic role in post-trauma complications. This month's issue features three articles related to neutrophil biology and function following trauma and sepsis. To start us off, Janicova and Relja (7) provide an excellent review of the current knowledge in this field, highlighting key advances in our understanding of neutrophil production and release of reactive oxygen species, phagocytosis, apoptosis, and neutrophil extracellular trap formation in the setting of trauma and sepsis. Importantly, the authors redefine the prevailing paradox that neutrophils are simple pro-inflammatory phagocytes by examining recent findings surrounding specific neutrophil subsets with immunosuppressive properties.

Defects in neutrophil function contribute to increased susceptibility to infection following burn injury, yet the mechanisms are unclear. Beckman et al. (8) utilize a scald injury model to examine mechanisms underlying suppressed neutrophil chemotaxis in mice. Interestingly, they demonstrate that neutrophils exhibit decreased CXCL1-driven chemotaxis that persists for at least 21 days after burn injury. Loss of chemotactic function was associated with increased neutrophil ceramide, which decreased CXCR2 expression and subsequent phosphorylation of Akt. Treating neutrophils isolated from burn-injured mice with an inhibitor of PTEN, a negative regulator of Akt phosphorylation, increased phospho-Akt levels and reversed neutrophil chemotaxis defects. Together, these data indicate that inhibiting ceramide production or preventing downstream signaling through inhibition of PTEN could restore neutrophil function and prevent infection in patients with burns.

Along this similar theme, Zhang et al. (9) examined the role of mitochondrial formyl peptides (mtFPs) released by injured tissue in impaired neutrophil migration to the alveolar space. Using conditioned media generated by exposing peripheral blood mononuclear cells (PBMCs) to bacteria, the authors characterize essential PBMC-derived chemoattractants that are potent drivers of neutrophil chemotaxis. In addition, they show that mtFPs released by damaged tissue bind to neutrophil FPR1 to trigger initial migration. However, they further show that this interaction paradoxically causes simultaneous internalization of neutrophil chemokine receptors that limit their ability to reach the lung, thereby providing mechanistic insights into defects in neutrophil chemotaxis and risk of secondary lung infection. Interestingly, Zhang et al. demonstrate in rodent models that administration of exogenous, naive neutrophils to injured and infected lungs could provide a novel future therapeutic to improve bacterial clearance and mitigate the burden of nosocomial pneumonia in trauma patients.

The transcription factor hypoxia-inducible factor I alpha (HIF-1α) is a known regulator of the cellular response to hypoxic injury that has been linked to metabolic and immune dysfunction in septic patients. In this issue, Ferreira et al. (10) provide an in-depth analysis of hypoxia signaling pathway gene expression patterns in serial sepsis patient leukocyte samples and healthy donors. Interestingly, when specifically examining hypoxia-related genes, they find that most are downregulated in patients upon admission compared with healthy donors, a finding that could be indicative of prevalent immune suppression. Compared with sepsis survivors, those who did not survive demonstrated hypoxia-related gene upregulation, including HIF1A, PDK1, and LDHA. Conversely, HIF-1α inhibitors were under expressed in all patients. The authors further report alterations in specific genes related to hemolysis, coagulation, and nitric oxide production among non-survivors. Altogether, these data nicely highlight alterations in hypoxia pathway genes that are differently modulated between survivors and non-survivors of sepsis and indicate that therapeutics aimed at targeting this pathway should be approached with careful consideration.

Myocardial dysfunction (MD) plays a key role in the pathogenesis of multiple organ failure following septic shock, necessitating novel cardio-protective therapeutics. Mesenchymal stem/stromal cell (MSC) administration is emerging as a novel therapy to mitigate dysregulation of the host immune response to infection; however, the precise mechanisms behind their immunosuppressive properties remain poorly defined. To better understand this, Ektesabi et al. (11) performed transcriptomic and microRNA profiling on whole hearts of mice that had undergone cecal ligation and puncture to induce polymicrobial sepsis, randomized to either MSC or placebo treatment. The authors demonstrate reduced expression of inflammatory and apoptotic genes, and increased structural and functional gene expression in hearts from mice treated with MSCs. Importantly, miR-187, a negative regulator of pro-inflammatory gene transcription, was prominently upregulated in response to MSC therapy. In addition, miR-187 destabilizes the mRNAs of immune regulators, Itpkc, Lrrc59, and Tbl1xr1, which were decreased in mice receiving MSCs. Together, the authors conclude that differential expression of miR-187 is a central mechanism through which MSCs regulate the host immune response to infection, thereby attenuating MD and improving outcomes following sepsis.

Microglial activation plays a central role in the development of sepsis-associated encephalopathy; however, the precise mechanisms driving this activation and subsequent pro-inflammatory sequelae are not well understood. In this month's issue, Giga et al. (12) bring us a step closer to understanding this important pathogenic mechanisms by revealing a key role for mitochondrial translocator protein 18 kDa (TSPO) in microglial activation and subsequent neuroinflammation. The authors demonstrate that hippocampal TSPO expression is upregulated in a mouse model of sepsis, which preceded an increase in pro-inflammatory cytokine release. In a series of elegant studies, Giga et al. show that inhibition of TSPO with ONO-2952 or genetic TSPO knockout results in reduced activation of TSPO-expressing microglia and significantly improved behavioral and locomotor metrics. These findings implicate a clear role for TSPO in SEA and indicate that monitoring TSPO activity clinically and developing novel inhibitors to TSPO could mitigate neurological deficits and improve recover from sepsis.

The plight of the elderly septic patient is confronted by Chen et al. (13) in their most recent manuscript. They hypothesize that the limitations of applying findings from studies based on young healthy animals to an aging population may be in part responsible for the poor outcomes observed in this demographic. The authors attempt to rectify these shortcomings by focusing their research on aged human subjects and mice. Chen et al. report a prominent role for the immune regulator triggering receptor expressed on myeloid cells-2 (TREM-2) in the pathophysiology of sepsis in older patients. Further, supplementation with TREM-2-overexpressed macrophages appears to provide a protective effect for septic, elderly mice through the modulation of inflammatory pathways. By concentrating on an aging population, the authors offer a better understanding of the etiology of sepsis in the elderly and provide the groundwork for tailored interventions in the future.

A series of Letters to the Editor in this month's issue includes an important conversation concerning the limitations of rodent models of sepsis. An eloquent opinion by Dr. Antonio De Maio in the November 2020 issue discusses the current limitations to interpretation of data from rodent sepsis models that have resulted in a lack of robust, new therapeutics for sepsis (14). Indeed, the need for animal models that recapitulate human disease is pressing and poor translatability of most current models has resulted in reduced federal funds for basic science sepsis research. In a reply, Drs. Moldawer, Darden, and Efron agree that blame for disrepute of rodent sepsis models lies with the investigators, not the rodents (15). Unwillingness to perform the painstaking tasks of improving translatability of these models is the result of complacency. These esteemed authors and other leaders in the field have taken specific actions to overcome shortcomings of these models by establishing guidelines that improve upon preclinical animal models of sepsis. These include use of aged mice, appropriate fluid and antibiotic support, sub-lethal modeling, and objective outcome measures of organ function. Adherence to such a framework will hopefully advance translatability of rodent sepsis models and improve extrapolation to human disease and delivery of novel life-saving interventions.

As we venture back to the clinical and translational realm, we find novel biomarkers and assessment strategies for sepsis patients are a common theme. Mohammed et al. (16) lean on advancements in artificial intelligence to assail inefficiency in the diagnosis of sepsis within the critical care unit. The authors employ machine learning software to harness the power of a robust longitudinal data set from Memphis, Tennessee intensive care units. This algorithm is capable of identifying sepsis patients prior to traditional clinical sign and symptom development. The authors recognize the need to validate this model. However, hopes are high that these modern methods can be used to improve patient outcomes in the future.

The utility of physiologic biomarkers in critical care is debated in this letter to the editor by Arslantas et al. (17). The authors comment on a previous publication in Shock by Kong et al. (18) heralding lactate:albumin ratio as an index of 30-day mortality risk in critically ill patients. Arslantas et al. (17) postulate that the difference between lactate and albumin is a superior representative of disease severity. This group from Turkey test their hypothesis using a large critical care data set and report a superior area under the curve for their proposed model. They find an improved sensitivity compared with the original lactate:albumin ratio algorithm, albeit with some loss of specificity. The dialogue regarding the optimal prognostic intensive care biomarkers continues, and we look forward to a rebuttal by Kong et al.

In this issue, Puskarich et al. (19) ask us to contemplate a new role for branched chain amino acids in the assessment of the septic shock patient. They discuss the various factors that have slowed the progress of improved patient care in septic shock and offer a new approach based on cardiac metabolism. The authors describe the potential influence of sepsis and vasopressors on metabolic dysfunction in cardiac myocytes. In their analysis of serum metabolites, the authors have identified branched chain amino acids associated with septic shock resolution. Puskarich et al. (19) comment that these results may symbolize more than a prognostic biomarker. In fact, they may provide a glimpse into the underlying mechanisms driving septic shock outcomes.

Zhang et al. (20) submit an alternative approach to the management of sepsis through mitochondria transplantation. The authors summarize the body of growing evidence supporting a crucial role for mitochondria in the pathophysiology of sepsis. They point out that previous mitochondria-based intervention strategies, for example, antioxidant therapies, have thus far furnished disheartening results. This group from China lay out the reasoning behind mitochondria transplantation as a plausible therapeutic intervention in sepsis. Zhang et al. (20) demonstrate a survival benefit for septic mice utilizing this novel therapeutic modality. These results are buttressed by findings of enhanced bacterial elimination and quantifiable alterations in relevant areas of gene expression. They present convincing evidence to support the study of this largely unexplored facet of sepsis.

We congratulate all of the investigators published in the July issue of Shock on their outstanding science and wish everyone happy reading.

1. Huang Y, Wang G, Peng T. Calpain activation and organ failure in sepsis: molecular insights and therapeutic perspectives. Shock 56:5–15, 2021. 2. Kelly LS, Darden DB, Fenner BP, Efron PA, Mohr AM. The hematopoietic stem/progenitor cell response to hemorrhage, injury, and sepsis: a review of pathophysiology. Shock 56:30–41, 2021. 3. Black JA, Pierce VP, Juneja K, Holcomb JB. Complications of hemorrhagic shock and massive transfusion—a comparison before and after the damage control resuscitation ersa. Shock 56:42–51, 2021. 4. Kwak GH, Ling L, Hui P. Predicting the need for vasopressors in the intensive care unit using an attention based deep learning model. Shock 56:73–79, 2021. 5. Tiba MH, Awad AB, Pennington A, Fung CM, Napolitano LM, Park PK, Machado-Aranda DA, Gunnerson KJ, Romfh P, Ward KR. Resonance Raman spectroscopy derived tissue hemoglobin oxygen saturation in critically ill and injured patients. Shock 56:92–97, 2021. 6. Edakubo S, Inoue N, Fushimi K. Effect of early central venous catheterization on mortality among patients with severe sepsis: a nationwide inpatient database study. Shock 56:52–57, 2021. 7. Janicova A, Relja B. Neutrophil phenotypes and functions in trauma and trauma-related sepsis. Shock 56:16–29, 2021. 8. Beckmann N, Schumacher F, Kleuser B, Gulbins E, Nomellini V, Caldwell CC. Burn injury impairs neutrophil chemotaxis through increased ceramide. Shock 56:125–132, 2021. 9. Zhang Q, Kwon WY, Vlková B, Riça I, Kaczmarek E, Park J, Kim HI, Konecna B, Jung F, Douglas G, et al. Direct airway instillation of neutrophils overcomes chemotactic deficits induced by injury. Shock 56:119–124, 2021. 10. Ferreira BL, Leite GGF, Brunialti MKC, Assuncao M, Pontes Azevedo LC, Freitas F, Salomao R. HIF-1α and hypoxia responsive genes are differentially expressed in leukocytes from survivors and non-survivors patients during clinical sepsis. Shock 56:80–91, 2021. 11. Ektesabi AM, Mori K, Tsoporis JN, Vaswani C, Gupta S, Walsh CM, Varkouhi AK, Mei SHJ, Stewart DJ, Liles WC, et al. Mesenchymal stem/stromal cells increase cardiac miR-187-3p expression in polymicrobial animal model of sepsis. Shock 56:133–141, 2021. 12. Giga H, Ji B, Kikutani K, Fukuda S, Kitajima T, Katsumata S, Matsumata M, Suhara T, Yamawaki S, Shime N, et al. Pharmacological and genetic inhibition of translocator protein 18 kDa ameliorated neuroinflammation in murine endotoxemia model. Shock 56:142–149, 2021. 13. Chen Q, Yang Y, Wu X, Yang S, Zhang Y, Shu Q, Fang X. Triggering receptor expressed on myeloid cells-2 protects aged mice against sepsis by mitigating the IL-23/IL-17A response. Shock 56:98–107, 2021. 14. De Maio A. Do not blame the rodent for the failure of developing sepsis therapies. Shock 54 (5): 631–632, 2020. 15. Moldawer LL, Darden DB, Efron PA. Reply to “Do not blame the rodent for the failure of developing sepsis therapies”. Shock, 56:152–153, 2021. 16. Mohammed A, Van Wyk F, Chinthala LK, Khojandi A, Davis RL, Coopersmith CM, Kamaleswaran R. Temporal differential expression of physiomarkers predicts sepsis in critically ill adults. Shock 56:58–64, 2021. 17. Arslantas MK, Arslantas R, Dincer PC, Altun GT, Kararmaz A. Prognostic value of the lactate–albumin difference in predicting 30-day mortality in critically ill patients. Shock 56:150–151, 2021. 18. Kong T, Chung SP, Lee HS, Kim S, Lee J, Hwang SO, Shin SD, Song KJ, Cha KC, You JS. Korean Cardiac Arrest Research Consortium (KoCARC) Investigators. The prognostic usefulness of the lactate/albumin ratio for predicting clinical outcomes in out-of-hospital cardiac arrest: a Prospective, Multicenter Observational Study (koCARC) study. Shock 53 (4):442–451, 2020. 19. Puskarich MA, McHugh C, Flott TL, Karnovsky A, Jones AE, Stringer KA. On behalf of the RACE Trial Investigators. Serum levels of branched chain amino acids predict duration of cardiovascular organ failure in septic shock. Shock 56:65–72, 2021. 20. Zhang Z, Yan C, Miao J, Pu K, Ma H, Wang Q. Muscle-derived mitochondrial transplantation reduces inflammation, enhances bacterial clearance, and improves survival in sepsis. Shock 56:108–118, 2021.

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