bims-heshmo 2021-09-19 papers

bims-heshmo

Biomed News

on Trauma hemorrhagic shock — molecular basis

Issue of 2021‒09‒19
eight papers selected by
Andreia Luís
Ludwig Boltzmann Institute

The emerging therapeutic potential of extracellular vesicles in trauma.
Trauma-induced heme release increases susceptibility to bacterial infection.
Clemastine Fumarate Attenuates Myocardial Ischemia Reperfusion Injury Through Inhibition of Mast Cell Degranulation.
The Toll-Like Receptor 2 Ligand Pam2CSK4 Activates Platelet Nuclear Factor-κB and Bruton's Tyrosine Kinase Signaling to Promote Platelet-Endothelial Cell Interactions.
Indispensable role of mitochondria in maintaining the therapeutic potential of curcumin in acute kidney injury.
Immune Profiling Demonstrates a Common Immune Signature of Delayed Acquired Immunodeficiency in Patients With Various Etiologies of Severe Injury.
The Dietary Supplement γ-Oryzanol Attenuates Hepatic Ischemia Reperfusion Injury via Inhibiting Endoplasmic Reticulum Stress and HMGB1/NLRP3 Inflammasome.
Blocking the Hepatic Branch of the Vagus Aggravates Hepatic Ischemia-Reperfusion Injury via Inhibiting the Expression of IL-22 in the Liver.

J Leukoc Biol. 2021 Sep 17.

The emerging therapeutic potential of extracellular vesicles in trauma.

Nijmeh Alsaadi, Amudan J Srinivasan, Anupamaa Seshadri, Matthew Shiel, Matthew D Neal, Melanie J Scott.

  Traumatic injury is a major cause of morbidity and mortality worldwide, despite significant advances in treatments. Most deaths occur either very early, through massive head trauma/CNS injury or exsanguination (despite advances in transfusion medicine), or later after injury often through multiple organ failure and secondary infection. Extracellular vesicles (EVs) are known to increase in the circulation after trauma and have been used to limited extent as diagnostic and prognostic markers. More intriguingly, EVs are now being investigated as both causes of pathologies post trauma, such as trauma-induced coagulopathy, and as potential treatments. In this review, we highlight what is currently known about the role and effects of EVs in various aspects of trauma, as well as exploring current literature from investigators who have begun to use EVs therapeutically to alter the physiology and pathology of traumatic insults. The potential effectiveness of using EVs therapeutically in trauma is supported by a large number of experimental studies, but there is still some way to go before we understand the complex effects of EVs in what is already a complex disease process.

Keywords:  exosomes; injury; microparticles; microvesicles; treatment

DOI:  https://doi.org/10.1002/JLB.3MIR0621-298R
JCI Insight. 2021 Sep 14. pii: 150813. [Epub ahead of print]

Trauma-induced heme release increases susceptibility to bacterial infection.

Ghee Rye Lee, David Gallo, Rodrigo W Alves de Souza, Shilpa Tiwari-Heckler, Eva Csizmadia, James D Harbison, Sidharth Shankar, Valerie Banner-Goodspeed, Michael B Yaffe, Maria Serena Longhi, Carl J Hauser, Leo E Otterbein.

  Infection is a common complication of major trauma that causes significantly increased morbidity and mortality. The mechanisms however, linking tissue injury to increased susceptibility to infection remain poorly understood. To study this relationship, we present a novel murine model where a major liver crush injury is followed by bacterial inoculation into the lung. We find that such tissue trauma both impaired bacterial clearance and was associated with significant elevations in plasma heme levels. While neutrophil (PMN) recruitment to the lung in response to Staphylococcus aureus was unchanged after trauma, PMN cleared bacteria poorly. Moreover, PMN show >50% less expression of TLR2, which is responsible, in part, for bacterial recognition. Administration of heme effectively substituted for trauma. Last, day 1 trauma patients (n=9) showed similar elevations in free heme to that seen after murine liver injury and circulating PMN showed similar TLR2 reduction compared to volunteers (n=6). These findings correlate to high infection rates.

Keywords:  Bacterial infections; Infectious disease; Inflammation; Neutrophils; Translation

DOI:  https://doi.org/10.1172/jci.insight.150813
Front Pharmacol. 2021 ;12 704852

Clemastine Fumarate Attenuates Myocardial Ischemia Reperfusion Injury Through Inhibition of Mast Cell Degranulation.

Shuqi Meng, Xiaotong Sun, Zhaodong Juan, Mingling Wang, Ruoguo Wang, Lina Sun, Yaozu Li, Anran Xin, Shuping Li, Yao Li.

  Mast cell (MC) activation is associated with myocardial ischemia reperfusion injury (MIRI). Suppression of MC degranulation might be a target of anti-MIRI. This study aimed to determine whether clemastine fumarate (CLE) could attenuate MIRI by inhibiting MC degranulation. A rat ischemia and reperfusion (I/R) model was established by ligating the left anterior descending coronary artery for 30 min followed by reperfusion for 120 min. Compound 48/80 (C48/80) was used to promote MC degranulation. The protective effect of CLE by inhibiting MC degranulation on I/R injury was detected by cardiac function, 2,3,5-triphenyl tetrazolium chloride (TTC) staining, hematoxylin-eosin (HE) staining, arrhythmia, and myocardial enzyme detection. Inflammatory factor mRNA levels, such as TNF-α, interleukin (IL)-1β, and IL-6, were detected. Cultured RBL-2H3 mast cells were pretreated with CLE and subjected to C48/80 treatment to determine whether CLE suppressed MC degranulation. Degranulation of MCs was visualized using tryptase release, Cell Counting Kit-8 (CCK-8), and cell toluidine blue (TB) staining. RBL cells were conditionally cultured with H9C2 cells to explore whether CLE could reverse the apoptosis of cardiomyocytes induced by MC degranulation. Apoptosis of H9C2 cells was detected by CCK-8, the LDH Cytotoxicity Assay Kit (LDH), TUNEL staining, and protein expression of BAX and Bcl-2. We found that CLE pretreatment further inhibited cardiac injury manifested by decreased infarct size, histopathological changes, arrhythmias, MC degranulation, and myocardial enzyme levels, improving cardiac function compared with that in the I/R group. C48/80 combined with I/R exacerbated these changes. However, pretreatment with CLE for C48/80 combined with I/R significantly reversed these injuries. In addition, CLE pretreatment improved the vitality of RBL cells and reduced tryptase release in vitro. Similarly, the supernatant of RBL cells pretreated with CLE decreased the cytotoxicity, TUNEL-positive cell rate, and BAX expression of conditioned H9C2 cells and increased the cell vitality and expression of Bcl-2. These results suggested that pretreatment with CLE confers protection against I/R injury by inhibiting MC degranulation.

Keywords:  clemastine fumarate; degranulation; mast cell; myocardial ischemia reperfusion injury; pretreatment

DOI:  https://doi.org/10.3389/fphar.2021.704852
Front Immunol. 2021 ;12 729951

The Toll-Like Receptor 2 Ligand Pam2CSK4 Activates Platelet Nuclear Factor-κB and Bruton's Tyrosine Kinase Signaling to Promote Platelet-Endothelial Cell Interactions.

Iván Parra-Izquierdo, Hari Hara Sudhan Lakshmanan, Alexander R Melrose, Jiaqing Pang, Tony J Zheng, Kelley R Jordan, Stéphanie E Reitsma, Owen J T McCarty, Joseph E Aslan.

  Circulating platelets establish a variety of immunological programs and orchestrate inflammatory responses at the endothelium. Platelets express the innate immunity family of Toll-like receptors (TLRs). While TLR2/TLR1 ligands are known to activate platelets, the effects of TLR2/TLR6 ligands on platelet function remain unclear. Here, we aim to determine whether the TLR2/TLR6 agonists Pam2CSK4 and FSL-1 activate human platelets. In addition, human umbilical vein endothelial cells (HUVECs) and platelets were co-cultured to analyze the role of platelet TLR2/TLR6 on inflammation and adhesion to endothelial cells. Pam2CSK4, but not FSL-1, induced platelet granule secretion and integrin αIIbβ3 activation in a concentration-dependent manner. Moreover, Pam2CSK4 promoted platelet aggregation and increased platelet adhesion to collagen-coated surfaces. Mechanistic studies with blocking antibodies and pharmacologic inhibitors demonstrated that the TLR2/Nuclear factor-κB axis, Bruton's-tyrosine kinase, and a secondary ADP feedback loop are involved in Pam2CSK4-induced platelet functional responses. Interestingly, Pam2CSK4 showed cooperation with immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling to enhance platelet activation. Finally, the presence of platelets increased inflammatory responses in HUVECs treated with Pam2CSK4, and platelets challenged with Pam2CSK4 showed increased adhesion to HUVECs under static and physiologically relevant flow conditions. Herein, we define a functional role for platelet TLR2-mediated signaling, which may represent a druggable target to dampen excessive platelet activation in thrombo-inflammatory diseases.

Keywords:  BTK; Pam2CSK4; TLR2; adhesion; platelets

DOI:  https://doi.org/10.3389/fimmu.2021.729951
J Cell Mol Med. 2021 Sep 16.

Indispensable role of mitochondria in maintaining the therapeutic potential of curcumin in acute kidney injury.

Ling Li, Shuyun Liu, Yijie Zhou, Meng Zhao, Yizhuo Wang, Chengshi Wang, Peng Lou, Rongshuang Huang, Liang Ma, Yanrong Lu, Ping Fu, Jingping Liu.

  Acute kidney injury (AKI) is a serious disease for which effective therapeutic agents are required. The capacity of curcumin (CUR) to resolve renal inflammation/oxidative stress and mitochondrial damage has been reported, but crosstalk between these effects and the consequence of this crosstalk remain elusive. In this study, a hypoxia/reoxygenation (H/R)-induced renal tubular epithelial cell (TEC) injury model and an ischaemia/reperfusion (I/R)-induced mouse AKI model were treated with CUR with or without mitochondrial inhibitors (rotenone and FCCP) or siRNA targeting mitochondrial transcription factor A (TFAM). Changes in mitochondrial function, inflammation, the antioxidant system and related pathways were analysed. In vitro, CUR suppressed NFκB activation and cytokine production and induced NRF2/HO-1 signalling in TECs under H/R conditions. CUR treatment also reduced mitochondrial ROS (mtROS) and mitochondrial fragmentation and enhanced mitochondrial biogenesis, TCA cycle activity and ATP synthesis in damaged TECs. However, the anti-inflammatory and antioxidant effects of CUR in damaged TECs were markedly abolished upon mitochondrial disruption. In vivo, CUR treatment improved renal function and antioxidant protein (NRF2 and SOD2) expression and reduced oxidative stress (8-OHdG), tubular apoptosis/death, cytokine release/macrophage infiltration and mitochondrial damage in the kidneys of AKI mice. In vitro, the anti-inflammatory and antioxidant effects of CUR in damaged kidneys were impaired when mitochondrial function was disrupted. These results suggest mitochondrial damage is a driving factor of renal inflammation and redox imbalance. The therapeutic capacity of CUR in kidneys with AKI is primarily dependent on mitochondrial mechanisms; thus, CUR is a potential therapy for various diseases characterized by mitochondrial damage.

Keywords:  ROS; acute kidney injury; antioxidant; curcumin; inflammation; mitochondria

DOI:  https://doi.org/10.1111/jcmm.16934
Crit Care Med. 2021 Sep 16.

Immune Profiling Demonstrates a Common Immune Signature of Delayed Acquired Immunodeficiency in Patients With Various Etiologies of Severe Injury.

REALISM study group

OBJECTIVES: The host response plays a central role in the pathophysiology of sepsis and severe injuries. So far, no study has comprehensively described the overtime changes of the injury-induced immune profile in a large cohort of critically ill patients with different etiologies.DESIGN: Prospective observational cohort study.
SETTING: Adult ICU in a University Hospital in Lyon, France.
PATIENTS: Three hundred fifty-three septic, trauma, and surgical patients and 175 healthy volunteers were included in the REAnimation Low Immune Status Marker study.
INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: Extensive immune profiling was performed by assessing cellular phenotypes and functions, protein, and messenger RNA levels at days 1-2, 3-4, and 5-7 after inclusion using a panel of 30 standardized immune markers. Using this immunomonitoring panel, no specificity in the immune profile was observed among septic, trauma, and surgical patients. This common injury-induced immune response was characterized by an initial adaptive (i.e., physiologic) response engaging all constituents of the immune system (pro- and anti-inflammatory cytokine releases, and innate and adaptive immune responses) but not associated with increased risk of secondary infections. In contrary, the persistence in a subgroup of patients of profound immune alterations at the end of the first week after admission was associated with increased risk of secondary infections independently of exposure to invasive devices. The combined monitoring of markers of pro-/anti-inflammatory, innate, and adaptive immune responses allowed a better enrichment of patients with risk of secondary infections in the selected population.
CONCLUSIONS: Using REAnimation Low Immune Status Marker immunomonitoring panel, we detected delayed injury-acquired immunodeficiency in a subgroup of severely injured patients independently of primary disease. Critically ill patients' immune status could be captured through the combined monitoring of a common panel of complementary markers of pro-/anti-inflammatory, innate, and adaptive immune responses. Such immune monitoring needs to be incorporated in larger study cohorts with more extensive immune surveillance to develop specific hypothesis allowing for identification of biological systems affecting altered immune function related to late infection in the setting of acute systemic injury.

DOI: https://doi.org/10.1097/CCM.0000000000005270
Oxid Med Cell Longev. 2021 ;2021 4628050

The Dietary Supplement γ-Oryzanol Attenuates Hepatic Ischemia Reperfusion Injury via Inhibiting Endoplasmic Reticulum Stress and HMGB1/NLRP3 Inflammasome.

Yichao Du, Furui Zhong, Huanli Cheng, Tongxi Li, Yifan Chen, Peng Tan, Meizhou Huang, Tiancheng Liang, Yu Liu, Xianming Xia, Wenguang Fu.

The purpose of this study is to investigate the protective effect of γ-oryzanol (ORY) against hepatic ischemia reperfusion (HIR) injury and the potential protective mechanisms of ORY. ORY is an important biologically active ingredient isolated from rice bran oil, which has anti-inflammatory and antiapoptotic effects. However, it is still unknown whether ORY can protect the liver from the HIR damage. In this study, ORY was administered orally for seven days, after which the animals were subjected to liver ischemia for 60 minutes and reperfused for 6 hours. Related indicators were analyzed. The results showed that ORY pretreatment significantly reduced the levels of AST and ALT, relieved hepatocellular damage and apoptosis, and attenuated the exhaustion of SOD and GSH and accumulation of MDA and MPO. Interestingly, ORY treatment could significantly decreased ER stress. Furthermore, ORY pretreatment remarkably reduced the protein expressions of HMGB1, NLRP3, caspase-1 (p20), and IL-1β to protect the liver from I/R-induced inflammasome activation and apoptosis. In conclusion, we demonstrated the potential effect of ORY in modulating oxidative stress, endoplasmic reticulum stress, and inflammasome activation during HIR.

DOI: https://doi.org/10.1155/2021/4628050
J Immunol Res. 2021 ;2021 6666428

Blocking the Hepatic Branch of the Vagus Aggravates Hepatic Ischemia-Reperfusion Injury via Inhibiting the Expression of IL-22 in the Liver.

Heng Zhou, Juling Xu, Sanxiong Huang, Ying He, Xiaowei He, Lu Guo, Shi Yin, Sheng Lu.

Liver ischemia-reperfusion injury (IRI) is an inevitable process during liver transplantation, hemorrhagic shock, resection, and other liver surgeries. It is an important cause of postoperative liver dysfunction and increased medical costs. The protective effects of the vagus nerve on hepatic IRI have been reported, but the underlying mechanism has not been fully understood. We established a hepatic vagotomy (Hv) mouse model to study the effect of the vagus on liver IRI and to explore the underlying mechanism. Liver IRI was more serious in mice with Hv, which showed higher serum ALT and AST activities and histopathological changes. Further experiments confirmed that Hv significantly downregulated the expression of IL-22 protein and mRNA in the liver, blocking the activation of the STAT3 pathway. The STAT3 pathway in the livers of Hv mice was significantly activated, and liver injury was clearly alleviated after treatment with exogenous IL-22 recombinant protein. In conclusion, Hv can aggravate hepatic IRI, and its mechanism may be related to inhibition of IL-22 expression and downregulation of the STAT3 pathway in the liver.

DOI: https://doi.org/10.1155/2021/6666428