bims-heshmo 2021-04-11 papers

Mol Med. 2021 04 08. 27(1): 35

Increased complement activation 3 to 6 h after trauma is a predictor of prolonged mechanical ventilation and multiple organ dysfunction syndrome: a prospective observational study.

Ingrid Nygren Rognes, Søren Erik Pischke, William Ottestad, Jo Røislien, Jens Petter Berg, Christina Johnson, Torsten Eken, Tom Eirik Mollnes.

BACKGROUND: Complement activation is a central mechanism in systemic inflammation and remote organ dysfunction following major trauma. Data on temporal changes of complement activation early after injury is largely missing. We aimed to describe in detail the kinetics of complement activation in individual trauma patients from admission to 10 days after injury, and the association with trauma characteristics and outcome.
METHODS: In a prospective cohort of 136 trauma patients, plasma samples obtained with high time resolution (admission, 2, 4, 6, 8 h, and thereafter daily) were assessed for terminal complement complex (TCC). We studied individual TCC concentration curves and calculated a summary measure to obtain the accumulated TCC response 3 to 6 h after injury (TCC-AUC3-6). Correlation analyses and multivariable linear regression analyses were used to explore associations between individual patients' admission TCC, TCC-AUC3-6, daily TCC during the intensive care unit stay, trauma characteristics, and predefined outcome measures.
RESULTS: TCC concentration curves showed great variability in temporal shapes between individuals. However, the highest values were generally seen within the first 6 h after injury, before they subsided and remained elevated throughout the intensive care unit stay. Both admission TCC and TCC-AUC3-6 correlated positively with New Injury Severity Score (Spearman's rho, p-value 0.31, 0.0003 and 0.21, 0.02) and negatively with admission Base Excess (- 0.21, 0.02 and - 0.30, 0.001). Multivariable analyses confirmed that deranged physiology was an important predictor of complement activation. For patients without major head injury, admission TCC and TCC-AUC3-6 were negatively associated with ventilator-free days. TCC-AUC3-6 outperformed admission TCC as a predictor of Sequential Organ Failure Assessment score at day 0 and 4.
CONCLUSIONS: Complement activation 3 to 6 h after injury was a better predictor of prolonged mechanical ventilation and multiple organ dysfunction syndrome than admission TCC. Our data suggest that the greatest surge of complement activation is found within the first 6 h after injury, and we argue that this time period should be in focus in the design of future experimental studies and clinical trials using complement inhibitors.

Keywords: Complement activation; Complement membrane attack complex; Humans; Mortality; Multiple organ failure; Systemic inflammatory response syndrome; Wounds and injuries

DOI: https://doi.org/10.1186/s10020-021-00286-3

FEBS J. 2021 Apr 07.

AMPK, Metabolism and Vascular Function.

Claudia Rodríguez, Mercedes Muñoz, Cristina Contreras, Dolores Prieto.

Adenosine monophosphate-activated protein kinase (AMPK) is a cellular energy sensor activated during energy stress that plays a key role in maintaining energy homeostasis. This ubiquitous signaling pathway has been implicated in multiple functions including mitochondrial biogenesis, redox regulation, cell growth and proliferation, cell autophagy and inflammation. The protective role of AMPK in cardiovascular function and the involvement of dysfunctional AMPK in the pathogenesis of cardiovascular disease have been highlighted in recent years. In this review, we summarize and discuss the role of AMPK in the regulation of blood flow in response to metabolic demand and the basis of the AMPK physiological anticontractile, antioxidant, anti-inflammatory and antiatherogenic actions in the vascular system. Investigations by others and us have demonstrated the key role of vascular AMPK in the regulation of endothelial function, redox homeostasis and inflammation, in addition to its protective role in the hypoxia and ischemia/reperfusion (I/R) injury. The pathophysiological implications of AMPK involvement in vascular function with regard to the vascular complications of metabolic disease and the therapeutic potential of AMPK activators are also discussed.

Keywords: AMPK; endothelium; inflammation; ischemia/reperfusion; metabolism; mitochondria; reactive oxygen species; vascular smooth muscle

DOI: https://doi.org/10.1111/febs.15863

Am Surg. 2021 Apr 08. 3134820954824

Morbidity and Mortality in the Obese Trauma Intensive Care Unit Patient.

Hope L Conrad, Robert A Hutchinson, Jessica Pittman, Joseph A Ewing, John D Cull.

INTRODUCTION: Obesity is an epidemic in the United States, known to be associated with comorbidities. However, some data show that obesity may be a protective factor in some instances. The purpose of this study is to determine if there are differences in morbidity and mortality when comparing the obese and non-obese critically ill trauma patient populations.
MATERIALS AND METHODS: This was a retrospective study conducted at Prisma Health Upstate in Greenville, South Carolina, an Adult Level 1 Trauma Center. Patients over the age of 18 years admitted due to trauma from February 6, 2016 to February 28, 2019 were included in this study. Burn patients were excluded. An online trauma database was used to obtain age, sex, body mass index, Glasgow coma score (GCS), injury severity score (ISS), revised trauma score (RTS), days on mechanical ventilation, hospital length of stay (LOS), and intensive care unit (ICU) LOS.
RESULTS: There were 2365 critically ill trauma patients who met inclusion criteria for this study. 1570 patients were men (66.38%) and mean age was 53.2 ± 20.9. Of the patients, 2166 patients had blunt trauma (91.59%). Median GCS was 15 (interquartilerange [IQR]: 12, 15), median RTS was 12 (IQR: 11, 12), and median ISS was 17 (IQR: 9, 22). Obese critically ill trauma patients had significantly lower odds of mortality than nonobese (OR .686, CI 0.473-.977). Penetrating traumas (OR: 4.206, CI: 2.478, 6.990), increased ISS (OR: 1.095, CI: .473, 1.112), and increased age (OR: 1.036, CI: 1.038, 1.045) were associated with significantly increased odds of mortality.
DISCUSSION: The obesity paradox is observed in the obese critically ill trauma patient population.

Keywords: intensive care unit; trauma; trauma acute care

DOI: https://doi.org/10.1177/0003134820954824

Sci Rep. 2021 Apr 05. 11(1): 7508

Estradiol-induced inhibition of endoplasmic reticulum stress normalizes splenic CD4 + T lymphocytes following hemorrhagic shock.

Peng Wang, Li-Na Jiang, Chen Wang, Ying Li, Meng Yin, Hui-Bo Du, Hong Zhang, Ze-Hua Fan, Yan-Xu Liu, Meng Zhao, An-Ling Kang, Ding-Ya Feng, Shu-Guang Li, Chun-Yu Niu, Zi-Gang Zhao.

The aim is to investigate that 17β-estradiol (E2)/estrogen receptors (ERs) activation normalizes splenic CD4 + T lymphocytes proliferation and cytokine production through inhibition of endoplasmic reticulum stress (ERS) following hemorrhage. The results showed that hemorrhagic shock (hemorrhage through femoral artery, 38-42 mmHg for 90 min followed by resuscitation of 30 min and subsequent observation period of 180 min) decreased the CD4+ T lymphocytes proliferation and cytokine production after isolation and incubation with Concanavalin A (5 μg/mL) for 48 h, induced the splenic injury with evidences of missed contours of the white pulp, irregular cellular structure, and typical inflammatory cell infiltration, upregulated the expressions of ERS biomarkers 78 kDa glucose-regulated protein (GRP78) and activating transcription factor 6 (ATF6). Either E2, ER-α agonist propyl pyrazole triol (PPT) or ERS inhibitor 4-Phenylbutyric acid administration normalized these parameters, while ER-β agonist diarylpropionitrile administration had no effect. In contrast, administrations of either ERs antagonist ICI 182,780 or G15 abolished the salutary effects of E2. Likewise, ERS inducer tunicamycin induced an adverse effect similarly to that of hemorrhagic shock in sham rats, and aggravated shock-induced effects, also abolished the beneficial effects of E2 and PPT, respectively. Together, the data suggest that E2 produces salutary effects on CD4+ T lymphocytes function, and these effects are mediated by ER-α and GPR30, but not ER-β, and associated with the attenuation of hemorrhagic shock-induced ERS.

DOI: https://doi.org/10.1038/s41598-021-87159-1

Burns Trauma. 2021 Jan;9 tkab001

Traumatic injury is associated with reduced deoxyribonuclease activity and dysregulation of the actin scavenging system.

Jon Hazeldine, Robert J Dinsdale, David N Naumann, Animesh Acharjee, Jonathan R B Bishop, Janet M Lord, Paul Harrison.

Background: Traumatic injury is associated with increased concentrations of cell-free DNA (cfDNA) in the circulation, which contribute to post-injury complications. The endonuclease deoxyribonuclease 1 (DNase-1) is responsible for removing 90% of circulating cfDNA. Recently, DNase activity was reported to be significantly reduced following major non-traumatic brain injury (TBI), but the processes responsible were not investigated. Moreover, it is not known how quickly following injury DNase activity is reduced and whether this also occurs after TBI.
Methods: At 3 post-injury time points (≤1, 4-12 and 48-72 hours), blood samples were obtained from 155 adult trauma patients that had sustained an isolated TBI (n = 21), TBI with accompanying extracranial injury (TBI+) (n = 53) or an extracranial injury only (ECI) (n = 81). In addition to measuring cfDNA levels and the activity and expression of DNase, circulating concentrations of monomeric globular action (G-actin), an inhibitor of DNase-1, and the actin scavenging proteins gelsolin (GSN) and vitamin D binding protein (VDBP) were determined and values compared to a cohort of healthy controls.
Results: Significantly elevated concentrations of plasma cfDNA were seen in TBI, TBI+ and ECI patients at all study time points when compared to healthy controls. cfDNA levels were significantly higher at ≤1 hour post-injury in ECI patients who subsequently developed multiple organ dysfunction syndrome when compared to those who did not. Plasma DNase-1 protein was significantly elevated in all patient groups at all sampling time points. In contrast, DNase enzyme activity was significantly reduced, with this impaired function evident in TBI+ patients within minutes of injury. Circulating concentrations of G-actin were elevated in all patient cohorts in the immediate aftermath of injury and this was accompanied by a significant reduction in the levels of GSN and VDBP.
Conclusions: The post-traumatic increase in circulating cfDNA that occurs following extracranial trauma and TBI is accompanied by reduced DNase activity. We propose that, secondary to reduced GSN and VDBP levels, elevated circulating concentrations of G-actin underlie the post-injury reduction in DNase activity. Reducing circulating cfDNA levels via therapeutic restoration of DNase-1 activity may improve clinical outcomes post-injury.

Keywords: Cell-free DNA; Deoxyribonuclease; Extracellular actin scavenging system; Pre-hospital; Trauma

DOI: https://doi.org/10.1093/burnst/tkab001

J Appl Physiol (1985). 2021 Apr 08.

Effects of Ketamine Analgesia on Cardiorespiratory Responses and Survival to Trauma and Hemorrhage in Rats.

Harold G Klemcke, Mariam L Calderon, Stephen L Crimmins, Kathy L Ryan, Lusha Xiang, Carmen Hinojosa-Laborde.

Ketamine is the recommended analgesic on the battlefield for Soldiers with hemorrhage, despite a lack of supportive evidence from laboratory or clinical studies. Hence, this study determined the effects of ketamine analgesia on cardiorespiratory responses and survival to moderate (37% blood volume; n=8/group) or severe hemorrhage (50% blood volume; n=10/group) after trauma in rats. We used a conscious hemorrhage model with extremity trauma (fibular fracture + soft tissue injury) while measuring mean arterial pressure (MAP), heart rate (HR), and body temperature (Tb) by telemetry, and respiration rate (RR), minute volume (MV), and tidal volume (TV) via whole body plethysmography . Male rats received saline (S) or 5.0 mg/kg ketamine (K) (100 µl/100 gram body weight) intra-arterially after trauma and hemorrhage. All rats survived 37% hemorrhage. For 50% hemorrhage, neither survival times (180 min (SD 78) vs 209 min (SD 66) nor percent survival (60% vs 80%) differed between S and K-treated rats. After 37% hemorrhage, K (compared with S) increased MAP, and decreased Tb and MV. After 50% hemorrhage, K (compared with S) increased MAP but decreased HR and MV. K effects on cardiorespiratory function were time-dependent, significant but modest, and transient at the analgesic dose given. K effects on Tb were also significant but modest, and more prolonged. Using this rat model, our data support the use of K as an analgesic in injured, hypovolemic patients.

Keywords: analgesic; cardiovascular; hemorrhage; ketamine; respiration

DOI: https://doi.org/10.1152/japplphysiol.00476.2020