bims-heshmo 2021-11-07 papers

bims-heshmo

Biomed News

on Trauma hemorrhagic shock — molecular basis

Issue of 2021–11–07
six papers selected by
Andreia Luís, Ludwig Boltzmann Institute

A New Trauma Frontier: Exploratory Pilot Study of Platelet Transcriptomics in Trauma Patients.
Beclin1 controls caspase-4 inflammsome activation and pyroptosis in mouse myocardial reperfusion-induced microvascular injury.
Assessment of Protection Offered by The Nrf2 Pathway Against Hyperoxia-Induced Acute Lung Injury In Nrf2 Knockout Rats.
Effect of tranexamic acid on thrombotic events and seizures in bleeding patients: a systematic review and meta-analysis.
Endothelial cell autophagy keeps neutrophil trafficking under control.
Design and construction of three-dimensional physiologically-based vascular branching networks for respiratory assist devices.

J Trauma Acute Care Surg. 2021 Nov 02.

A New Trauma Frontier: Exploratory Pilot Study of Platelet Transcriptomics in Trauma Patients.

Alexander T Fields, Man-Cheung Lee, Fahima Mayer, Yale A Santos, Cedric M V Bainton, Zachary A Matthay, Rachael A Callcut, Nasima Mayer, Joseph Cuschieri, Kord M Kober, Roland J Bainton, Lucy Z Kornblith.

BACKGROUND: The earliest measurable changes to post-injury platelet biology may be in the platelet transcriptome, as platelets are known to carry messenger ribonucleic acids (RNAs), and there is evidence in other inflammatory and infectious disease states of differential and alternative platelet RNA splicing in response to changing physiology. Thus, the aim of this exploratory pilot study was to examine the platelet transcriptome and platelet RNA splicing signatures in trauma patients compared to healthy donors.
METHODS: Pre-resuscitation platelets purified from trauma patients (n = 9) and healthy donors (n = 5) were assayed using deep RNA sequencing. Differential gene expression analysis, weighted gene co-expression network analysis, and differential alternative splicing analyses were performed. In parallel samples, platelet function was measured with platelet aggregometry, and clot formation was measured with thromboelastography.
RESULTS: Differential gene expression analysis identified 49 platelet RNAs to have differing abundance between trauma patients and healthy donors. Weighted gene co-expression network analysis identified co-expressed platelet RNAs that correlated with platelet aggregation. Differential alternative splicing analyses revealed 1188 splicing events across 462 platelet RNAs that were highly statistically significant (false discovery rate < 0.001) in trauma patients compared to healthy donors. Unsupervised principal component analysis of these platelet RNA splicing signatures segregated trauma patients in two main clusters separate from healthy controls.
CONCLUSIONS: Our findings provide evidence of finetuning of the platelet transcriptome through differential alternative splicing of platelet RNA in trauma patients, and that this finetuning may have relevance to downstream platelet signaling. Additional investigations of the trauma platelet transcriptome should be pursued to improve our understanding of the platelet functional responses to trauma on a molecular level.Study typeBasic Science.
LEVEL OF EVIDENCE: N/A.

DOI: https://doi.org/10.1097/TA.0000000000003450
Cell Commun Signal. 2021 Nov 03. 19(1): 107

Beclin1 controls caspase-4 inflammsome activation and pyroptosis in mouse myocardial reperfusion-induced microvascular injury.

Wenjing Sun, Hongquan Lu, Shujuan Dong, Rui Li, Yingjie Chu, Nan Wang, Yu Zhao, Yabin Zhang, Limeiting Wang, Lin Sun, Di Lu.

   BACKGROUND: Myocardial reperfusion injury is often accompanied by cell death and inflammatory reactions. Recently, pyroptosis is gradually recognized as pivotal role in cardiovascular disease. However, little is known about the regulatory role of beclin1 in the control of caspase-4 activation and pyroptosis. The present study confirmed whether beclin1 regulates caspase-4 mediated pyroptosis and thereby protects Human Cardiac microvascular endothelial cells (HCMECs) against injury.
METHODS: TTC and Evan's blue dye, western blot, immunofluorescence and immunohistochemistry staining were performed in wild mice and transgenic mice with overexpression of beclin 1(BECN1-Tg). CMECs were transfected with a beclin1 lentivirus. The cell cytotoxicity was analyzed by LDH-Cytotoxicity Assay Kit. The protein levels of autophagy protein (Beclin1, p62 and LC3II/LC3I) and caspase-4/GSDMD pathway were determined by western blot. Autophagic vacuoles in cells were monitored with RFP-GFP-LC3 using fluorescence microscope.
RESULTS: I/R caused caspase-4 activity and gasdermin D expression increase in vivo and in vitro. Overexpression of beclin1 in heart tissue and CMECs suppressed the caspase-4 activity and decreased the levels of gasdermin D; meanwhile beclin1 overexpression also reduced IL-1β levels, promoted autophagy (p62 expression was inhibited while LC3II expression was increased) in the heart and CMECs. Interestingly, beclin1 overexpression increased animal survival and attenuated myocardial infarct size (45 ± 6.13 vs 22 ± 4.37), no-reflow area (39 ± 5.22 vs 16 ± 2.54) post-myocardial ischemia reperfusion.
CONCLUSIONS: Induction of beclin-1 signaling can be a potential therapeutic target in myocardial reperfusion-induced microvascular injury. Video Abstract.

Keywords:  Beclin1; Caspase-4 inflammasome; Ischemia/reperfusion; Pyroptosis

DOI:  https://doi.org/10.1186/s12964-021-00786-z
Shock. 2021 Nov 03.

Assessment of Protection Offered by The Nrf2 Pathway Against Hyperoxia-Induced Acute Lung Injury In Nrf2 Knockout Rats.

Said H Audi, Elizabeth R Jacobs, Pardis Taheri, Swetha Ganesh, Anne V Clough.

ABSTRACT: Nuclear factor erythroid 2-related factor (Nrf2) is a redox-sensitive transcription factor that responds to oxidative stress by activating expressions of key antioxidant and cytoprotective enzymes via the Nrf2-antioxidant response element (ARE) signaling pathway. Our objective was to characterize hyperoxia-induced acute lung injury (HALI) in Nrf2 knock-out (KO) rats to elucidate the role of this pathway in HALI. Adult Nrf2 wildtype (WT), and KO rats were exposed to room air (normoxia) or >95% O2 (hyperoxia) for 48 h, after which selected injury and functional endpoints were measured in vivo and ex vivo. Results demonstrate that the Nrf2-ARE signaling pathway provides some protection against HALI, as reflected by greater hyperoxia-induced histological injury and higher pulmonary endothelial filtration coefficient in KO versus WT rats. We observed larger hyperoxia-induced increases in lung expression of glutathione (GSH) synthetase, 3-nitrotyrosine (index of oxidative stress), and interleukin-1β, and in vivo lung uptake of the GSH-sensitive SPECT biomarker 99mTc-HMPAO in WT compared to KO rats. Hyperoxia also induced increases in lung expression of myeloperoxidase in both WT and KO rats, but with no difference between WT and KO. Hyperoxia had no effect on expression of Bcl-2 (anti-apoptotic protein) or peroxiredoxin-1. These results suggest that the protection offered by the Nrf2-ARE pathway against HALI is in part via its regulation of the GSH redox pathway. To the best of our knowledge, this is the first study to assess the role of the Nrf2-ARE signaling pathway in protection against HALI using a rat Nrf2 knockout model.

DOI: https://doi.org/10.1097/SHK.0000000000001882
Crit Care. 2021 Nov 01. 25(1): 380

Effect of tranexamic acid on thrombotic events and seizures in bleeding patients: a systematic review and meta-analysis.

Shuhei Murao, Hidekazu Nakata, Ian Roberts, Kazuma Yamakawa.

   BACKGROUND: Tranexamic acid (TXA) reduces surgical bleeding and reduces death from bleeding after trauma and childbirth. However, its effects on thrombotic events and seizures are less clear. We conducted a systematic review and meta-analysis to examine the safety of TXA in bleeding patients.
METHODS: For this systematic review and meta-analysis, we searched MEDLINE, EMBASE and the Cochrane Central Register of Controlled trials from inception until June 1, 2020. We included randomized trials comparing intravenous tranexamic acid and placebo or no intervention in bleeding patients. The primary outcomes were thrombotic events, venous thromboembolism, acute coronary syndrome, stroke and seizures. A meta-analysis was performed using a random effects model and meta-regression analysis was performed to evaluate how effects vary by dose. We assessed the certainty of evidence using the grading of recommendations, assessment, development and evaluations (GRADE) approach.
RESULTS: A total of 234 studies with 102,681 patients were included in the meta-analysis. In bleeding patients, there was no evidence that TXA increased the risk of thrombotic events (RR = 1.00 [95% CI 0.93-1.08]), seizures (1.18 [0.91-1.53]), venous thromboembolism (1.04 [0.92-1.17]), acute coronary syndrome (0.88 [0.78-1.00]) or stroke (1.12 [0.98-1.27]). In a dose-by-dose sensitivity analysis, seizures were increased in patients receiving more than 2 g/day of TXA (3.05 [1.01-9.20]). Meta-regression showed an increased risk of seizures with increased dose of TXA (p = 0.011).
CONCLUSION: Tranexamic acid did not appear to increase the risk of thrombotic events in bleeding patients. However, because there may be dose-dependent increase in the risk of seizures, very high doses should be avoided.

Keywords:  Bleeding; Meta-analysis; Seizure; Surgery; Thrombotic events; Tranexamic acid

DOI:  https://doi.org/10.1186/s13054-021-03799-9
Autophagy. 2021 Oct 31. 1-3

Endothelial cell autophagy keeps neutrophil trafficking under control.

Natalia Reglero-Real, Lorena Pérez-Gutiérrez, Sussan Nourshargh.

  A defining feature of an inflammatory reaction is infiltration of neutrophils into tissues, a response that requires breaching of endothelial cells (ECs) that line the lumenal aspect of blood vessels. Dysregulated neutrophil trafficking is a hallmark of pathology, but details of the molecular mechanisms that terminate neutrophil breaching of venular walls remain unclear. In this work, we have identified EC autophagy as a negative regulator of neutrophil diapedesis in acute physiological inflammation. Specifically, in vivo, inflamed venular ECs upregulate autophagy, a response that is selectively localized to EC contacts and temporally aligned with the peak of neutrophil trafficking. Genetic ablation of EC autophagy leads to excessive neutrophil tissue infiltration in multiple inflammatory models and supports enhanced neutrophil transendothelial migration (TEM), while pharmacological induction of autophagy inhibits neutrophil migration. Mechanistically, autophagy machinery regulates the architecture of EC contacts and controls the reorganization and degradation of adhesion molecules, constituting a physiological brake on leukocyte trafficking.

Keywords:  ATG16L1; ATG5; endothelium; inflammation; junctions; neutrophils

DOI:  https://doi.org/10.1080/15548627.2021.1987675
Lab Chip. 2021 Nov 03.

Design and construction of three-dimensional physiologically-based vascular branching networks for respiratory assist devices.

Jose A Santos, Alla A Gimbel, Athanasios Peppas, James G Truslow, Daniel A Lang, Sivaprasad Sukavaneshvar, Derek Solt, Thomas J Mulhern, Alex Markoski, Ernest S Kim, James C-M Hsiao, Diana J Lewis, Daniel I Harjes, Christopher DiBiasio, Joseph L Charest, Jeffrey T Borenstein.

Microfluidic lab-on-a-chip devices are changing the way that in vitro diagnostics and drug development are conducted, based on the increased precision, miniaturization and efficiency of these systems relative to prior methods. However, the full potential of microfluidics as a platform for therapeutic medical devices such as extracorporeal organ support has not been realized, in part due to limitations in the ability to scale current designs and fabrication techniques toward clinically relevant rates of blood flow. Here we report on a method for designing and fabricating microfluidic devices supporting blood flow rates per layer greater than 10 mL min-1 for respiratory support applications, leveraging advances in precision machining to generate fully three-dimensional physiologically-based branching microchannel networks. The ability of precision machining to create molds with rounded features and smoothly varying channel widths and depths distinguishes the geometry of the microchannel networks described here from all previous reports of microfluidic respiratory assist devices, regarding the ability to mimic vascular blood flow patterns. These devices have been assembled and tested in the laboratory using whole bovine or porcine blood, and in a porcine model to demonstrate efficient gas transfer, blood flow and pressure stability over periods of several hours. This new approach to fabricating and scaling microfluidic devices has the potential to address wide applications in critical care for end-stage organ failure and acute illnesses stemming from respiratory viral infections, traumatic injuries and sepsis.

DOI: https://doi.org/10.1039/d1lc00287b