This issue of SHOCK is outstanding with many diverse reports investigating the molecular mechanisms of trauma, sepsis, and shock down to the transcriptome level. At the same time, still other reports explore large data patient outcomes probing fundamental gaps in knowledge at the epicenter of chronic inflammation, immune dysregulation, sepsis pathophysiology, traumatic injury, and inflammation recovery. It is our pleasure and privilege to review, analyze, deconstruct, and assimilate these scientific communications against the world stage of human knowledge.
Sepsis induces a variety of immune cell compromise through the processes of apoptosis, necrosis, and NETosis that releases a significant amount of intracellular DNA into the blood. Laukova et al. sought to characterize the early dynamics of plasma extracellular (ecDNA) in a mouse model of Escherichia coli-induced sepsis, in conjunction with plasma deoxy ribonuclease (DNase) activity (1). The plasma ecDNA levels steadily rose for 5 h at which point they were 20-fold higher. In addition, the plasma DNase activity rose slowly, but exhibited high individual variability. This group should be congratulated as the first to describe the dynamics of plasma ecDNA and DNase activity during early sepsis.
Continuing to elucidate the impact of transcriptomic processes in sepsis, Skibsted et al. used leukocyte RNA sequencing to characterize biological functions driving sepsis (2). They have analyzed sequential data from patients with sepsis compared with 90 days after discharge. RNA sequencing revealed 916 unique transcripts differentially expressed during sepsis with 73% upregulated and 27% downregulated genes. Forty-three cellular pathways were activated during sepsis with the top pathways (Toll-like receptor, NFkβ, IL-10, TREM1, IL-6) closely associated with inflammation. Validation occurred in 18 septic and 25 nonseptic control patients with 76% of identified genes. The researchers conclude that highly dynamic transcriptional activity occurs in leukocytes during sepsis activating key cellular pathways.
One of the most important aspects of sepsis progression is the proinflammatory response associated with early mortality. Glucocorticoids (GC) have been administered during sepsis to help resolve damaging inflammation. Tsc22d3 is a gene encoding the GC-induced leucine zipper protein, one of the most important anti-inflammatory mediators. Ballegeer et al. found that patients and mice with sepsis demonstrate downregulated Tsc22d3 levels compared with healthy controls (3). In addition, the authors found that increased Tsc22d3 in peritoneal cells improved phagocytosis of bacteria linking GC therapy to enhanced cellular function and improved patient survival in sepsis.
The preceding study dovetails nicely into the next report by Zhu et al., who analyzed the effectiveness of corticosteroid therapy in adult patients with septic shock (4). The outcomes of this meta-analysis showed that corticosteroid therapy did not significantly reduce the 28-day mortality. However, corticosteroids therapy was associated with a significantly shorter ICU length of stay (LOS), 90-day mortality, ICU mortality, in-hospital mortality, hospital LOS, and reversal of shock. They conclude that corticosteroid therapy reduces ICU LOS in the most critically ill patients limiting their exposure to ongoing complications.
Predicting patient outcomes during sepsis is an ongoing struggle. Hu et al. reduced the question of prognosis in sepsis to one between sex and clinical outcome in a diverse population (5). Given the mixed diversity of the world population, the authors undertook a retrospective analysis of the impact of patient sex on sepsis outcome. Male patients with sepsis had a higher 1-year mortality rate (55.6% vs. 51.4%) compared with females. Males were also more likely to require dialysis, ventilation support, and more vasoactive therapy during the ICU period. The findings confirm that male patients suffer more long-term mortality and consume more heathcare resources than female patients.
Our understanding of the complex puzzle of molecular mechanisms regulating inflammation during sepsis continues to evolve. In this issue, Cordoba-Moreno et al. provide evidence of the complementary interactions of IL-10 and GC in the compensatory anti-inflammatory response syndrome (CARS) (6). In an LPS model of endotoxic shock, IL-10 KO mice had high levels of proinflammatory mediators, significant organ damage, and mortality, despite elevated levels of GC. Although the use of a synthetic GC was protective in WT animals, it improved survival when LPS was administered at very low doses (5 μg IP) in KO animals. With low doses, an induction of endotoxemia tolerance occurred in IL-10 KO animals; however, maintenance of this state was easily disrupted by the GC antagonist RU486. This indicates that GC participation in CARS may be attributed to modulation of IL-10.
The impact of CARS is not trivial and indeed predisposes for previously immunocompetent host to be colonized by Candida or to succumb to invasive form (IC), as hypothesized by Arens et al. (7). The authors proposed that detecting distinct immunological impairments associated with these conditions could provide better insight on mechanisms of fungal infection. Using a flow cytometry approach complemented by ex vivo cytokine secretion experiments, these authors found no clear differences among total leukocyte numbers or T-cell subsets comparing noncolonization, colonization, or IC. However, B- and NK-cell populations were markedly reduced, and stimulated ex vivo secretion of IL-8 (immune cell functionality) was noticeably blunted in patients with Candida colonization and even more in IC. Although limited by the number of patients, future validation by a larger study could serve as foundation for a more robust risk stratification and differentiation between colonization and IC.
Given the dysregulated host response related to alterations in the immune response induced by cancer and its treatment, Kim et al. propose the use of platelet–lymphocyte ratios (PLR) and its responsiveness to granulocyte colony-stimulating factor (G-CSF) as a dynamic prognosticator (8). In a prospective series of patients with chemotherapy-induced febrile neutropenia (FN) and septic shock, G-CSF was administered after initiation of antibiotics at a dose of 5 mg/kg/d and continued to an intended goal of absolute neutrophil count (ANC) of 500/μL. PLRs were calculated, both at admission and at 24 h after first G-CSF dose. A positive increase in PLR was found to be a significant predictor of 1-month survival in multivariate logistic regression model especially when combined with APACHE-II less than 28. The authors conclude that an increase in PLR could imply an earlier recovery of the bone marrow and support G-CSF administration.
Therapeutic hypothermia (TH) is the only adjunct to cardiopulmonary resuscitation known to improve survival with meaningful neurologic outcomes after cardiac arrest (CA). The molecular mechanisms in which TH confers neuroprotection include the release of proapoptotic cytochrome C of which the mitochondrial permeability pore (PTP) complex may be central. Interestingly, NIM, a cyclosporine A derivative, can interfere with PTP. In this issue, Jahandiez et al. find that TH mimicked the mitochondrial effects of NIM and neuroprotection; yet no added protection was found when both were used in combination, suggesting a common pathway (9). Furthermore, they analyzed the activation of reperfusion injury salvage kinase (RISK) pathway of the two upstream components (Akt and ERK). Only Akt was phosphorylated by HT, NIM, and their combination. Akt, therefore, remains a promising target in the prevention of neurologic injury in CA.
Remote camera-based photo plethysmography (cbPPG) emerges as a promising noninvasive optical technology for better assessments of flow and volume changes in the cutaneous microcirculation. Rasche et al. use this device on 70 critically ill patients recovering from cardiac surgery (10). Over 12,000 measurements were obtained and simultaneously compared with classic hemodynamic parameters. Although the authors observed the responsiveness of cbPPG to changes in peripheral circulation to mean arterial pressure (MAP) and pulse pressure (PP), they found that tracings had smaller variability within a patient but larger variation between the patients. In addition, cbPPG signal is influenced by light absorption of hemoglobin and thus may be attenuated in patients with anemia and hypothermia.
In an excellent study, Wepler et al. used a slow release mitochondrial targeted donor of hydrogen sulphide (AP39) in a rodent model of thoracic trauma with hemorrhagic shock (11). Since its discovery in 1996, hydrogen sulfide has been shown to participate in various processes by reduction of oxidative stress. The authors report that AP 39 in high doses resulted in reduced expression of iNO and ikB. However, AP39 did not affect levels of injury or inflammation in the lung or kidney. There were no changes in the mitochondrial respiration in diaphragm, heart, liver, or kidney. Moreover, whereas high-dose AP39 caused vasodilatory shock and mortality, low-dose AP 39 did not have these systemic hypotensive effects. The authors conclude that a narrow therapeutic window may exist for its use in future studies.
In an elegant study using autopsy samples of human lungs from patients with necrotizing enterocolitis (NEC) and adoptive transfer of specific T cells in immune incompetent mice, Jia et al. show that NEC-induced lung injury is mediated through TLR4-induced regulation of balance between T regs and Th17 cells (12). First, the authors show an induction of Th17 cells in the lungs of mice and humans with NEC was associated with induction of the lung disease. Adoptive transfer of CD4 positive T cells isolated from lungs of mice with NEC into the immune incompetent mice-induced inflammation and conversely the depletion of T regs exacerbated NEC-induced lung injury. In addition, the instillation of TLR4 small molecule inhibitor compound 34 (C34) or deletion of TLR4 from the Surfactant Protein C-1 (Sftpc1) positive cells in the lungs restored the T reg/Th17 balance and reduced the degree of NEC-induced lung injury.
Zhang et al. explored the mechanisms associated with the protective effect of ischemic postconditioning (13). This involves the application of intermittent interruptions of blood flow resulting in hypoxia. The same authors in a previous study showed that the long noncoding RNA, H19, protects H9c2 cells against hypoxia-induced injury. The authors concluded that H/Post only had protective effects on the normal myocytes but not senescent ones. The mechanisms involved in the senescent myocytes involved reduction in H19. Moreover, the authors report that the H19 mediated the protective effect observed with H/Post is via the inhibition of miR-29b-3p.
Pierce et al. report on the whole-exome sequence (WES) of adult and pediatric cohorts of a rare disorder systemic capillary leak syndrome (SCLS) (14). SCLS is characterized by episodes of leakage of plasma into extravascular tissues causing hypotension and multiorgan failure. The genetic contribution to this disease is currently not known. The authors studied the children and adults with SCLC along with their first-degree relatives and performed a WES using high throughput sequencing technology. The clinical characteristics of children and adults with SCLS were similar. They did not identify a uniform germline genetic etiology for SCLS. The authors also suggest a possibility of a nongenetic cause.
Hu et al. examine the role of augmented liver regenerator (ALR), a growth factor with antiapoptotic and antioxidative properties (15) in acetaminophen (APAP)-induced acute liver injury. Their observations include that ALR is a marker of stress in this injury; its use is associated with reduction in liver injury, inflammation, and oxidative stress. In addition, the use of ALR was associated with induction of autophagy, a process that is inhibited in APAP-mediated liver injury. The authors studied the specific markers of autophagic flux including microtubule-associated protein light chain 3 (LC3) and p62. With ALR, a conversion of LC3 I to LC3 II (closure of the autophagic vacuole) and degradation of p62 (fusion of autophagosomes and lysosomes) occurred. ALR may offer a therapeutic target in the treatment of APAP-induced liver injury.
In an elegant study by Nicholson et al., the authors evaluated the gut-neuronal axis by studying the gut microbiome in a rodent TBI cortical impact model (16). Genomic DNA was then quantified, and behavior assessments of the animals were performed. Significant changes in the GI microbiome were evident as early as 2 h after TBI. The authors observed that the peak MRI lesion volume, functional deficits, microbial composition alterations, and the greatest reduction in α-diversity occurred at an interval of 2 to 3 days after TBI. The larger brain lesion was associated with greater decreases in levels of Firmicutes (beneficial bacteria) and an increase in Proteobacteria (pathogenic organisms). The authors conclude that the evolution of the lesion directly correlated with changes in the GI microbiome.
Finally, a study by Evans et al. examined the association of fever and antipyretics in patients who were mechanically ventilated (17). Using a retrospective analysis of 1,264 patients, the authors concluded that a high fever of more than 39.5°C was associated with increased mortality, whereas moderate fever in patients with sepsis was found to be protective. The authors conclude that a cause and effect of fever and mortality could not be ascertained and suggested future studies on this subject.
It is worth pointing out that many of the reports in this issue have originated outside the United States, indicating that the Journal reach, desirability, and readership are expanding.
1. Lauková L, Bertolo EMJ, Zelinková M, Borbélyová V, Čonka J, Kovalčíková AG, Domonkos E, Viková B, Celec P. Early dynamics of plasma DNA in a mouse model of sepsis. Shock
2. Skibsted S, Bhasin MK, Henning DJ, Jaminet SC, Lewandowski J, Kirkegaard H, Aird WC, Shapiro NI. Leukocyte transcriptional response in sepsis. Shock
3. Ballegeer M, Vandewalle J, Eggermont M, Van Isterdael G, Dejager L, De Bus L, Decruyenaere J, Vandenbroucke RE, Libert C. Overexpression of Gilz protects mice against lethal septic peritonitis. Shock
4. Wen Y, Zhu Y, Jiang Q, Guo N, Cai Y, Shen X. The effectiveness and safety of corticosteroids therapy in adult critical ill patients with septic shock: a meta-analysis of randomized controlled trials. Shock
5. Xu J, Tong L, Yao J, Guo Z, Lui KY, Hu XG, Cao L, Zhu Y, Huang F, Guan X, Cai C. Association of sex with clinical outcome in critically ill sepsis patients: a retrospective analysis of the large clinical database MIMIC-III. Shock
6. Córdoba-Moreno MO, Todero MF, Fontanals A, Pineda G, Daniela M, Yokobori N, Ramos MV, Barrientos G, Toblli JE, Isturiz MA, et al. Consequences of the lack of IL-10 in different endotoxin effects and its relationship with glucocorticoids. Shock
7. Arens C, Kramm T, Decker S, Spannenberger J, Brenner T, Richter DC, Weigand MA, Uhle F, Lichtenstern C. Association of immune cell subtypes and phenotype with subsequent invasive candidiasis in patients with abdominal sepsis. Shock
8. Kim Y-J, Kang J, Ryoo SM, Ahn S, Huh JW, Kim WY. Platelet–lymphocyte ratio after granulocyte colony stimulating factor administration: an early prognostic marker in septic shock patients with chemotherapy-induced febrile neutropenia. Shock
9. Jahandiez V, Cour M, Abrial M, Loufouat J, Ovize M, Argaud L. Therapeutic hypothermia after cardiac arrest: involvement of the risk pathway in mitochondrial PTP-mediated neuroprotection. Shock
10. Rasche S, Trumpp A, Schmidt M, Plötze K, Gätjen F, Malberg H, Matschke K, Rudolf M, Baum F, Zaunseder S. Remote photoplethysmographic assessment of the peripheral circulation in critical care patients recovering from cardiac surgery. Shock
11. Wepler M, Merz T, Wachter U, Vogt J, Calzia E, Scheuerle A, Möller P, Gröger M, Kress S, Fink M, et al. The mitochondria-targeted H2
S-donor AP39 in a murine model of combined hemorrhagic shock and blunt chest trauma. Shock
12. Jia H, Sodhi CP, Yamaguchi Y, Lu P, Ladd MR, Werts A, Fulton WB, Wang S, Prindle T Jr, Hackam DJ. Toll like receptor 4 mediated lymphocyte imbalance induces NEC-induced lung injury. Shock
13. Zhang X, Cheng L, Xu L, Zhang Y, Yang Y, Fu Q, Mi W, Li H. The lncRNA, H19
mediates the protective effect of hypoxia postconditioning against hypoxia-reoxygenation injury to senescent cardiomyocytes by targeting microRNA-29b-3p
14. Pierce R, Ji W, Chan EC, Xie Z, Long LM, Khokha M, Lakhani S, Druey KM. Whole-exome sequencing of adult and pediatric cohorts of the rare vascular disorder systemic capillary leak syndrome. Shock
15. Hu T, Sun H, Deng W-Y, Huang W-Q, Liu Q. Augmenter of liver regeneration protects against acetaminophen-induced acute liver injury in mice by promoting autophagy. Shock
16. Nicholson SE, Watts LT, Burmeister DM, Merrill D, Scroggins S, Zou Y, Lai Z, Grandhi R, Lewis AM, Newton LM, et al. Moderate traumatic brain injury alters the gastrointestinal microbiome in a time-dependent manner. Shock
17. Evans EM, Doctor RJ, Gage BF, Hotchkiss RS, Fuller BM, Drewry AM. The association of fever and antipyretic medication with outcomes in mechanically ventilated patients: a cohort study. Shock