bims-heshmo 2022-01-09 papers

bims-heshmo

Biomed News

on Trauma hemorrhagic shock — molecular basis

Issue of 2022‒01‒09
fifteen papers selected by
Andreia Luís
Ludwig Boltzmann Institute

The effect of shock duration on trauma-induced coagulopathy in a murine model.
Plasma and Platelet Transfusion Strategies in Critically Ill Children Following Severe Trauma, Traumatic Brain Injury, and/or Intracranial Hemorrhage: From the Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding.
Circular RNA ciRs-126 promotes hypoxia/reoxygenation cardiac injury possibly through miR-21.
CU06-1004 enhances vascular integrity and improves cardiac remodeling by suppressing edema and inflammation in myocardial ischemia-reperfusion injury.
Administration of Particulate Oxygen Generators Improves Skeletal Muscle Contractile Function Following Ischemia-Reperfusion Injury in the Rat Hind Limb.
Weibel Palade Bodies: Unique Secretory Organelles of Endothelial Cells that Control Blood Vessel Homeostasis.
Platelet SHARPIN regulates platelet adhesion and inflammatory responses through associations with αIIbβ3 and LUBAC.
A Glucagon-like Peptide 1 Analogue Protects Mitochondria and Attenuates Hypoxia-reoxygenation Injury in Cultured Cardiomyocytes.
The effect of HES130/0.4 sodium chloride solution on kidney function following early fluid resuscitation in shock patients.
Circ-Sirt1 inhibits vascular smooth muscle cells proliferation via the c-Myc/cyclin B1 axis.
SIRT2 tyrosine nitration by peroxynitrite in response to renal ischaemia/reperfusion injury.
TRPA1 channel activation with cinnamaldehyde induces cutaneous vasodilation through NOS, but not COX and KCa channel, mechanisms in humans.
c-Fos is a mechanosensor that regulates inflammatory responses and lung barrier dysfunction during ventilator-induced acute lung injury.
Protective role of antithrombin III in suppressing acute responses in a rat model of renal ischemia-reperfusion injury.
Trimethylamine-N-oxide-stimulated hepatocyte-derived exosomes promote inflammation and endothelial dysfunction through nuclear factor-kappa B signaling.

Intensive Care Med Exp. 2022 Jan 07. 10(1): 1

The effect of shock duration on trauma-induced coagulopathy in a murine model.

Pieter H Sloos, M Adrie W Maas, Markus W Hollmann, Nicole P Juffermans, Derek J B Kleinveld.

  BACKGROUND: Trauma-induced coagulopathy (TIC) is a life-threatening condition associated with high morbidity and mortality. TIC can present with different coagulation defects. In this study, the aim was to determine the effect of shock duration on TIC characteristics. We hypothesized that longer duration of shock leads to a more hypocoagulable rotational thromboelastometry (ROTEM) profile compared to a shorter duration of shock.METHODS: Male B57BL/6J(c) mice (n = 5-10 per group) were sedated and mechanically ventilated. Trauma was induced by bilateral lower limb fractures and crush injuries to the liver and small intestine. Shock was induced by blood withdrawals until a mean arterial pressure of 25-30 mmHg was achieved. Groups reflected trauma and shock for 30 min (TS30) and trauma and shock for 90 min (TS90). Control groups included ventilation only (V90) and trauma only (T90).
RESULTS: Mice in the TS90 group had significantly increased base deficit compared to the V90 group. Mortality was 10% in the TS30 group and 30% in the TS90 group. ROTEM profile was more hypocoagulable, as shown by significantly lower maximum clot firmness (MCF) in the TS30 group (43.5 [37.5-46.8] mm) compared to the TS90 group (52.0 [47.0-53.0] mm, p = 0.04). ROTEM clotting time and parameters of clot build-up did not significantly differ between groups.
CONCLUSIONS: TIC characteristics change with shock duration. Contrary to the hypothesis, a shorter duration of shock was associated with decreased maximum clotting amplitudes compared to a longer duration of shock. The effect of shock duration on TIC should be further assessed in trauma patients.

Keywords:  Coagulopathy; Shock; Trauma

DOI:  https://doi.org/10.1186/s40635-021-00428-1
Pediatr Crit Care Med. 2022 Jan 01. 23(Supplement 1 1S): e14-e24

Plasma and Platelet Transfusion Strategies in Critically Ill Children Following Severe Trauma, Traumatic Brain Injury, and/or Intracranial Hemorrhage: From the Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding.

Transfusion and Anemia EXpertise Initiative–Control/Avoidance of Bleeding (TAXI-CAB), the Pediatric Critical Care Blood Research Network (BloodNet), and the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network

OBJECTIVES: To present consensus statements and supporting literature for plasma and platelet transfusions in critically ill children with severe trauma, traumatic brain injury, and/or intracranial hemorrhage from the Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding.DESIGN: Systematic review and consensus conference of international, multidisciplinary experts in platelet and plasma transfusion management of critically ill children.
SETTING: Not applicable.
PATIENTS: Critically ill neonates and children with severe trauma, traumatic brain injury, and/or intracranial hemorrhage.
INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: A panel of eight experts developed expert-based statements for plasma and platelet transfusions in critically ill neonates and children with severe trauma, traumatic brain injury, and/or intracranial hemorrhage. These statements were reviewed and ratified by the 29 Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding experts. A systematic review was conducted using MEDLINE, EMBASE, and Cochrane Library databases, from inception to December 2020. Consensus was obtained using the Research and Development/University of California, Los Angeles Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. We developed one good practice statement and six expert consensus statements.
CONCLUSIONS: The lack of evidence precludes proposing recommendations on monitoring of the coagulation system and on plasma and platelets transfusion in critically ill pediatric patients with severe trauma, severe traumatic brain injury, or nontraumatic intracranial hemorrhage.

DOI: https://doi.org/10.1097/PCC.0000000000002855
Thromb J. 2022 Jan 04. 20(1): 2

Circular RNA ciRs-126 promotes hypoxia/reoxygenation cardiac injury possibly through miR-21.

Changming Tan, Jianming Li, Zhaoshun Yuan, Yongxin Mu.

  BACKGROUND: This study aimed to analyze the role of circular RNA ciRs-126 in hypoxia/reoxygenation cardiac injury (H/R).METHODS: Expression of ciRs-126 and miR-21 in plasma samples from patients with H/R and healthy controls was determined by RT-qPCR. Correlations were analyzed by linear regression. Overexpression of ciRs-126 and miR-21 was achieved in cardiomyocytes to explore their crosstalk. The roles of ciRs-126 and miR-21 in H/R-induced apoptosis of cardiomyocytes were analyzed using cell apoptosis assay.
RESULTS: CiRs-126 was upregulated and miR-21 was downregulated in H/R patients. They were inversely correlated across plasma samples from H/R patients. In H/R cardiomyocytes, ciRs-126 was upregulated and miR-21 was downregulated. In cardiomyocytes, ciRs-126 overexpression decreased miR-21 level and reduced the inhibitory effects of miR-21 overexpression on H/R-induced cell apoptosis.
CONCLUSIONS: Circular RNA ciRs-126 may suppress miR-21 expression to promote H/R cardiac injury.

Keywords:  Apoptosis; Hypoxia/reoxygenation cardiac injury; ciRs-126; miR-21

DOI:  https://doi.org/10.1186/s12959-021-00355-x
Exp Mol Med. 2022 Jan 07.

CU06-1004 enhances vascular integrity and improves cardiac remodeling by suppressing edema and inflammation in myocardial ischemia-reperfusion injury.

Haiying Zhang, Hyeok Kim, Bong Woo Park, Minyoung Noh, Yeomyeong Kim, Jeongeun Park, Jae-Hyun Park, Jin-Ju Kim, Woo-Sup Sim, Kiwon Ban, Hun-Jun Park, Young-Guen Kwon.

Ischemia-reperfusion (I/R) injury accelerates the cardiomyocytes (CMs) death by oxidative stress, and thereby deteriorates cardiac function. There has been a paradigm shift in the therapeutic perspective more towards the prevention or amelioration of damage caused by reperfusion. Cardiac microvascular endothelial cells (CMECs) are more vulnerable to reperfusion injury and play the crucial roles more than CMs in the pathological process of early I/R injury. In this study, we investigate that CU06-1004, as a vascular leakage blocker, can improve cardiac function by inhibiting CMEC's hyperpermeability and subsequently reducing the neutrophil's plugging and infiltration in infarcted hearts. CU06-1004 was delivered intravenously 5 min before reperfusion and the rats were randomly divided into three groups: (1) vehicle, (2) low-CU06-1004 (1 mg/kg, twice at 24 h intervals), and (3) high-CU06-1004 (5 mg/kg, once before reperfusion). CU06-1004 treatment reduced necrotic size and cardiac edema by enhancing vascular integrity, as demonstrated by the presence of intact junction proteins on CMECs and surrounding pericytes in early I/R injury. It also decreased the expression of vascular cell adhesion molecule 1 (VCAM-1) on CMECs, resulting in reduced infiltration of neutrophils and macrophages. Echocardiography showed that the CU06-1004 treatment significantly improved cardiac function compared with the vehicle group. Interestingly, single high-dose treatment with CU06-1004 provided a greater functional improvement than repetitive low-dose treatment until 8 weeks post I/R. These findings demonstrate that CU06-1004 enhances vascular integrity and improves cardiac function by preventing lethal myocardial I/R injury. It can provide a promising therapeutic option, as potential adjunctive therapy to current reperfusion strategies.

DOI: https://doi.org/10.1038/s12276-021-00720-w
J Appl Physiol (1985). 2022 Jan 06.

Administration of Particulate Oxygen Generators Improves Skeletal Muscle Contractile Function Following Ischemia-Reperfusion Injury in the Rat Hind Limb.

Sarah E Dyer, J David Remer, Kelsey E Hannifin, Aishwarya Hombal, Joseph C Wenke, Thomas J Walters, George J Christ.

  Extended tourniquet application, often associated with battlefield extremity trauma, can lead to severe ischemia-reperfusion (I/R) injury in skeletal muscle. Particulate oxygen generators (POGs) can be directly injected into tissue to supply oxygen to attenuate the effects of I/R injury in muscle. The goal of this study was to investigate the efficacy of a sodium percarbonate (SPO)-based POG formulation in reducing ischemic damage in a rat hind limb during tourniquet application. Male Lewis rats were anesthetized and underwent tourniquet application for 3 hours, at a pressure of 300 mmHg. Shortly after tourniquet inflation animals received intramuscular injections of either 0.2 mg/mL SPO with catalase (n=6) or 2.0 mg/mL SPO with catalase (n=6) directly into the tibialis anterior (TA) muscle. An additional Tourniquet-Only group (n=12) received no intervention. Functional recovery was monitored using in vivo contractile testing of the hind limb at 1-, 2-, and 4-weeks post-injury. By the 4 week time point, the Low Dose POGs group continued to show improved functional recovery (85% of baseline) compared to the Tourniquet-Only (48%) and High Dose POG (56%) groups. In short, the Low Dose POGs formulation appeared, at least in part, to mitigate the impact of ischemic tissue injury, thus improving contractile function following tourniquet application. Functional improvement correlated with maintenance of larger muscle fiber cross sectional area, and the presence of fewer fibers containing centrally located nuclei. As such, POGs represent a potentially attractive therapeutic solution for addressing I/R injuries associated with extremity trauma.

Keywords:  Ischemia-Reperfusion Injury; Oxygen Generators; Skeletal Muscle Function; Tourniquet

DOI:  https://doi.org/10.1152/japplphysiol.00259.2021
Front Cell Dev Biol. 2021 ;9 813995

Weibel Palade Bodies: Unique Secretory Organelles of Endothelial Cells that Control Blood Vessel Homeostasis.

Johannes Naß, Julian Terglane, Volker Gerke.

  Vascular endothelial cells produce and release compounds regulating vascular tone, blood vessel growth and differentiation, plasma composition, coagulation and fibrinolysis, and also engage in interactions with blood cells thereby controlling hemostasis and acute inflammatory reactions. These interactions have to be tightly regulated to guarantee smooth blood flow in normal physiology, but also allow specific and often local responses to blood vessel injury and infectious or inflammatory insults. To cope with these challenges, endothelial cells have the remarkable capability of rapidly changing their surface properties from non-adhesive (supporting unrestricted blood flow) to adhesive (capturing circulating blood cells). This is brought about by the evoked secretion of major adhesion receptors for platelets (von-Willebrand factor, VWF) and leukocytes (P-selectin) which are stored in a ready-to-be-used form in specialized secretory granules, the Weibel-Palade bodies (WPB). WPB are unique, lysosome related organelles that form at the trans-Golgi network and further mature by receiving material from the endolysosomal system. Failure to produce correctly matured VWF and release it through regulated WPB exocytosis results in pathologies, most importantly von-Willebrand disease, the most common inherited blood clotting disorder. The biogenesis of WPB, their intracellular motility and their fusion with the plasma membrane are regulated by a complex interplay of proteins and lipids, involving Rab proteins and their effectors, cytoskeletal components as well as membrane tethering and fusion machineries. This review will discuss aspects of WPB biogenesis, trafficking and exocytosis focussing on recent findings describing factors contributing to WPB maturation, WPB-actin interactions and WPB-plasma membrane tethering and fusion.

Keywords:  calcium; exocytosis; hemostasis; lysosome-related organelle; secretory organelles

DOI:  https://doi.org/10.3389/fcell.2021.813995
Blood Adv. 2022 Jan 06. pii: bloodadvances.2021005611. [Epub ahead of print]

Platelet SHARPIN regulates platelet adhesion and inflammatory responses through associations with αIIbβ3 and LUBAC.

Ana Kasirer-Friede, Emilia Peuhu, Johanna Ivaska, Sanford J Shattil.

Platelets form hemostatic plugs to prevent blood loss and they modulate immunity and inflammation in several ways. A key event during hemostasis is activation of integrin αIIbβ3 through direct interactions of the β3 cytoplasmic tail with talin and kindlin-3. Recently, we showed that human platelets express the adapter molecule, SHARPIN, that can associate directly with the αIIb cytoplasmic tail and can separately promote NF-κB pathway activation as a member of the Met-1 linear ubiquitination activation complex (LUBAC). Here we investigated the role of SHARPIN in platelets after crossing Sharpin flox/flox (fl/fl) mice with PF4-Cre or GPIbα-Cre mice to selectively delete SHARPIN in platelets. SHARPIN-null platelets adhered to immobilized fibrinogen through αIIbβ3, and they spread more extensively than littermate control platelets in a manner dependent on feedback stimulation by platelet adenosine diphosphate (ADP) (P < 0.01). SHARPIN-null platelets showed increased colocalization of αIIbβ3 with talin as assessed by super-resolution microscopy and increased binding of soluble fibrinogen in response to sub-maximal concentrations of ADP (P < 0.05). However, mice with SHARPIN-null platelets showed compromised thrombus growth on collagen and slightly prolonged tail bleeding times. Platelets lacking SHARPIN also showed reduced NF-κB activation and linear ubiquitination of protein substrates upon challenge with classical platelet agonists. Furthermore, the loss of platelet SHARPIN resulted in significant reduction in inflammation in murine models of colitis and peritonitis (P < 0.01). Thus, SHARPIN plays differential and context-dependent roles in platelets to regulate important inflammatory and integrin adhesive functions of these anucleate cells.

DOI: https://doi.org/10.1182/bloodadvances.2021005611
J Cardiovasc Pharmacol. 2021 Dec 31.

A Glucagon-like Peptide 1 Analogue Protects Mitochondria and Attenuates Hypoxia-reoxygenation Injury in Cultured Cardiomyocytes.

Miyuki Kobara, Hiroe Toba, Tetsuo Nakata.

ABSTRACT: Glucagon-like peptide 1 (GLP-1) analogues improve glycemic control in diabetes and protect the heart against ischemia-reperfusion injury. However, the mechanisms underlying this protection remain unclear. Mitochondria are essential for myocyte homeostasis. Therefore, we herein examined the effects of a GLP-1 analogue on mitochondria after the hypoxia-reoxygenation of rat neonatal cultured cardiomyocytes. Cardiomyocytes were subjected to hypoxia for 5 hours followed by reoxygenation for 30 minutes in the presence or absence of exendin 4 (50 nmol/L), a GLP-1 analogue. Hypoxia-reoxygenation increased lactate dehydrogenase and caspase-3 activities, indicators of lethal myocyte injury and apoptosis, respectively, and exendin 4 attenuated these increases. The content of ATP in myocytes decreased after hypoxia-reoxygenation, but was preserved by exendin 4. The membrane potential and shape of mitochondria were assessed using a fluorescent probe. Exendin 4 attenuated the hypoxia-reoxygenation-induced disruption of the mitochondrial membrane potential and shortening. Mitochondrial quality control-related factors, such as optic atrophy protein 1 (OPA1), mitofusin 2 (Mfn2), dynamin-related protein 1 (Drp1), and parkin, were examined by Western blotting. Exendin 4 significantly increased the expression of the fusion proteins, OPA1 and Mfn2, and decreased that of the mitophagy-related protein, parkin, without altering Drp1 expression levels. Exendin 4 also preserved Akt phosphorylation levels after hypoxia-reoxygenation, while wortmannin, an inhibitor of the PI3K-Akt pathway, blunted exendin 4-induced myocyte protection and its effects on mitochondrial quality control factors. In conclusion, exendin 4 protected mitochondria by preserving the phosphorylation of Akt and fusion proteins, leading to the attenuation of hypoxia-reoxygenation-induced injury in cultured myocytes.

DOI: https://doi.org/10.1097/FJC.0000000000001218
Transl Androl Urol. 2021 Nov;10(11): 4288-4297

The effect of HES130/0.4 sodium chloride solution on kidney function following early fluid resuscitation in shock patients.

Haiyan Jiang, Yuting Ren, Guangdong Qi, Yue Wang, Cheng Xu, Guomin Mao, Guiwen Liang, Dajun Yan, Yan Yan, Yansong Dong, Zhongwei Huang, Lei Qi.

  Background: Doctors often use a small dose of hydroxyethyl starch (HES) 130/0.4 sodium chloride solution in the emergency room; however, its effect on kidney function remains controversial. This study aimed to evaluate the effect of a small dose of HES130/0.4 sodium chloride solution on kidney function in shock patients during early fluid resuscitation.Methods: This cohort study retrospectively analyzed the data of 129 shock patients requiring fluid resuscitation who had been admitted to the Emergency Department of the Affiliated Hospital of Nantong University from January 2019 to December 2020. Patients were divided into the observation group (n=40) and control group (n=89) according to the type of fluid resuscitation. In relation to the fluid resuscitation treatment, the observation group was treated with crystalloid solution, while the control group was treated with crystalloid and HES130/0.4 sodium chloride solution. To further explore the effect of a small dose of HES130/0.4 sodium chloride solution, the patients were further divided into the following 4 groups based on the specific fluid administered: (I) the HES(+), lactated Ringer's (LR)(+) group (n=85); (II) the HES(+), LR(-) group (n=4); (III) the HES(-), LR(+) group (n=31); and (IV) the HES(-), LR(-) group (n=9). The outcomes were in-hospital mortality and changes in creatinine (CR) level after fluid resuscitation.
Results: There were no significant differences in the in-hospital mortality rates between the observation and control groups (P=0.343). The CR levels of patients in the control and HES(+), LR(+) groups were reduced after fluid resuscitation (P=0.034; P=0.028). There was no significant change in patients' CR levels in the HES(+), LR(-) group after fluid resuscitation (P=0.999).
Conclusions: Administering a small dose of HES 130/0.4 sodium chloride in patients with shock does not appear to affect kidney function and in-hospital mortality; however, these findings should be considered exploratory, and further studies should be conducted to confirm these results.

Keywords:  Shock; fluid resuscitation; hydroxyethyl starch 130/0.4 sodium solution; kidney function

DOI:  https://doi.org/10.21037/tau-21-972
Cell Biol Int. 2022 Jan 06.

Circ-Sirt1 inhibits vascular smooth muscle cells proliferation via the c-Myc/cyclin B1 axis.

Minhua Huang, Yujie Dong, Guangbin Sun, Yuan Yu.

  Vascular smooth muscle cells（VSMCs）are an important cellular component of vascular wall. Restenosis is mainly due to VSMC excessive proliferation. However, little is known about the role of circRNAs in VSMC proliferation and phenotypic switching. Herein, using FISH assay and RT-qPCR, we found that circ-Sirt1 was markedly downregulated in neointimal formation after injury and in VSMCs treated with PDGF-BB. BrdU and MTT assays confirmed the inhibitory role of circ-Sirt1 on cell proliferation. Mechanistically, circ-Sirt1 was mainly expressed in the cytoplasm of VSMCs. Through RIP and RNA pull-down assays, we found that circ-Sirt1 bound c-Myc, protein associated with proliferation of VSMCs. ChIP assay also provided evidence that the overexpression of circ-Sirt1 almost ceased PDGF-BB-induced binding of c-Myc to the promoter of cyclin B1 in VSMCs. These results indicated that circ-Sirt1 had an inhibitory effect on c-Myc activity, providing a mechanism for suppressing PDGF-BB-induced VSMC proliferation by direct interactions with c-Myc and its sequestration in the cytoplasm. Overall, our study demonstrated that a previously unrecognized circ-Sirt1/c-Myc/cyclin B1 axis in VSMCs mediates neointimal formation following injury. This article is protected by copyright. All rights reserved.

Keywords:  Biochemistry; Heart/lung/blood vessels; Intercellular communication; VSMCs; c-Myc; circ-Sirt1; cyclin B1; restenosis

DOI:  https://doi.org/10.1002/cbin.11758
Free Radic Res. 2022 Jan 04. 1-45

SIRT2 tyrosine nitration by peroxynitrite in response to renal ischaemia/reperfusion injury.

Yan Wang, Chun Jie Wu, Yu Du, Yu Qing Liu, Jing Ran Cai, Xue Qing Wu, Shu Qun Hu.

  Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are the production of renal ischaemia/reperfusion (I/R). The current study is to elucidate a mechanism of SIRT2 tyrosine nitration to accelerate the cell apoptosis induced by peroxynitrite (ONOO‾), the most reactive and deleterious RNS type in renal ischaemia/reperfusion (I/R) injury. Our results demonstrate that there is a significant enhancement of the 3-nitrotyrosine levels in renal tissues of Acute Kidney Injury (AKI) patients and rats that underwent renal I/R, and a positive correlation between the 3-nitrotyrosine level and renal function impairment, indicative of an accumulation of peroxynitrite. Notably, peroxynitrite-evoked nitration of SIRT2 destroyed its enzymatic activity and the capability to deacetylate FOXO3a, and enhanced expression of Bim and caspase3, facilitating renal cell apoptosis in renal ischaemia/reperfusion and SIN-1(peroxynitrite donor) treatment in vitro, and these effects were reversed by FeTMPyP, a peroxynitrite decomposition scavenger. Importantly, we identified that the tyrosine 86 is responsible for SIRT2 nitration and inactivation using site-mutation assay and Mass Spectrography analysis. Altogether, these findings point to a novel protective mechanism that an inhibition of SIRT2 tyrosine nitration can be a promising strategy to prevent ischaemic renal diseases involving AKI.

Keywords:  Cell apoptosis; Ischaemia/reperfusion; Peroxynitrite; Sirtuins; Tyrosine nitration

DOI:  https://doi.org/10.1080/10715762.2021.2024529
J Cardiovasc Pharmacol. 2021 Dec 02.

TRPA1 channel activation with cinnamaldehyde induces cutaneous vasodilation through NOS, but not COX and KCa channel, mechanisms in humans.

Yufuko Kataoka, Glen P Kenny, Takeshi Nishiyasu, Tatsuro Amano, Toby Mündel, Huixin Zheng, Tze-Huan Lei, Koichi Watanabe, Naoto Fujii.

ABSTRACT: Transient receptor potential ankyrin 1 (TRPA1) channel activation induces cutaneous vasodilation in humans in vivo. However, the mechanisms underlying this response remains equivocal. We hypothesized that nitric oxide (NO) synthase (NOS) and Ca2+ activated K+ (KCa) channels contribute to the TRPA1 channel-induced cutaneous vasodilation with no involvement of cyclooxygenase (COX). Cutaneous vascular conductance (CVC) in 9 healthy young adults was assessed at four dorsal forearm skin sites treated by intradermal microdialysis with either: 1) vehicle control (98% propylene glycol + 1.985% dimethyl sulfoxide + 0.015% lactated Ringer solution), 2) 10 mM L-NAME, a non-selective NOS inhibitor, 3) 10 mM ketorolac, a non-selective COX inhibitor, or 4) 50 mM tetraethylammonium, a non-selective KCa channel blocker. Cinnamaldehyde, a TRPA1 channel activator, was administered to each skin site in a dose-dependent manner (2.9, 8.8, 26 and 80 %, each lasting ≥30min). Administration of ≥8.8% cinnamaldehyde increased CVC from baseline at the vehicle control site by as much as 27.4% [95 % confidence interval of 5.3] (P<0.001). NOS inhibitor attenuated the cinnamaldehyde induced-increases in CVC at the 8.8, 26.0, and 80.0% concentrations relative to the vehicle control site (all P≤0.05). In contrast, both the COX inhibitor and KCa channel blockers did not attenuate the cinnamaldehyde induced-increases in CVC relative to the vehicle control site for all concentrations (all P≥0.130). We conclude that in human skin in vivo, NOS plays a role in modulating the regulation of cutaneous vasodilation in response to TRPA1 channel activation with no detectable contributions of COX and KCa channels.

DOI: https://doi.org/10.1097/FJC.0000000000001188
BMC Pulm Med. 2022 Jan 06. 22(1): 9

c-Fos is a mechanosensor that regulates inflammatory responses and lung barrier dysfunction during ventilator-induced acute lung injury.

Leilei Zhou, Chunju Xue, Zongyu Chen, Wenqing Jiang, Shuang He, Xianming Zhang.

  BACKGROUND: As one of the basic treatments performed in the intensive care unit, mechanical ventilation can cause ventilator-induced acute lung injury (VILI). The typical features of VILI are an uncontrolled inflammatory response and impaired lung barrier function; however, its pathogenesis is not fully understood, and c-Fos protein is activated under mechanical stress. c-Fos/activating protein-1 (AP-1) plays a role by binding to AP-1 within the promoter region, which promotes inflammation and apoptosis. T-5224 is a specific inhibitor of c-Fos/AP-1, that controls the gene expression of many proinflammatory cytokines. This study investigated whether T-5224 attenuates VILI in rats by inhibiting inflammation and apoptosis.METHODS: The SD rats were divided into six groups: a control group, low tidal volume group, high tidal volume group, DMSO group, T-5224 group (low concentration), and T-5224 group (high concentration). After 3 h, the pathological damage, c-Fos protein expression, inflammatory reaction and apoptosis degree of lung tissue in each group were detected.
RESULTS: c-Fos protein expression was increased within the lung tissue of VILI rats, and the pathological damage degree, inflammatory reaction and apoptosis in the lung tissue of VILI rats were significantly increased; T-5224 inhibited c-Fos protein expression in lung tissues, and T-5224 inhibit the inflammatory reaction and apoptosis of lung tissue by regulating the Fas/Fasl pathway.
CONCLUSIONS: c-Fos is a regulatory factor during ventilator-induced acute lung injury, and the inhibition of its expression has a protective effect. Which is associated with the antiinflammatory and antiapoptotic effects of T-5224.

Keywords:  Acute respiratory distress syndrome; Fas/Fasl; T-5224; Ventilator-induced acute lung injury; c-Fos

DOI:  https://doi.org/10.1186/s12890-021-01801-2
Mol Cell Biochem. 2022 Jan 05.

Protective role of antithrombin III in suppressing acute responses in a rat model of renal ischemia-reperfusion injury.

Alena Firdus, Nesina Avdagić, Muhamed Fočak, Maja Mitrašinović-Brulić, Damir Suljević.

  Renal ischemia-reperfusion (IR) produces-induced injury and is characterized by restriction of blood supply to the kidney followed by restoration and re-oxygenation of the tissue. IR injury in the kidney contributes to pathological processes known as acute renal injury (ARI). Ischemia-perfusion injury (IRI) of the left renal artery has been demonstrated in Wistar rats. A total of 32 animals were divided into four groups: control group (SHAM), IR animals with induced ischemia-reperfusion, AT-IR animals treated by antithrombin III (AT) before IR, and AT-IR-AT animals with AT administered before and after IR. IR-induced hyperproteinemia, hyperalbuminemia, hyperglobulinemia, and a significantly low A/G ratio. Exogenous administration of AT prior to IR development effectively regulates protein fraction levels by establishing normoproteinemia. The preventive effect of AT regulates serum protein levels and reduces acute inflammation by reducing globulin and establishing physiological levels of A/G ratios. The therapeutic effect of AT given after IR is not effective compared to AT administered before IR. Protein fractions can serve as an important predictive marker for the prognosis and duration of acute inflammation. Serum globulin levels and the A/G ratio may serve as effective prognostic markers in acute inflammation caused by ischemia-reperfusion injury of the kidney. A strong correlation between globulin and the A/G ratio suggests novel markers associated with acute inflammation that can lead to chronic kidney disease.

Keywords:  Albumin/globulin ratio; Hyperglobulinemia; Ischemia–reperfusion injury; Total protein

DOI:  https://doi.org/10.1007/s11010-021-04322-y
Ann Transl Med. 2021 Nov;9(22): 1670

Trimethylamine-N-oxide-stimulated hepatocyte-derived exosomes promote inflammation and endothelial dysfunction through nuclear factor-kappa B signaling.

Xiang Liu, Yijia Shao, Jiazichao Tu, Jiapan Sun, Lifu Li, Jun Tao, Jimei Chen.

  Background: Trimethylamine-N-oxide (TMAO) has been proven to be a new proatherogenic compound for promoting inflammation and endothelial dysfunction. Hepatocyte-derived exosomes (Exos), including those derived from hepatocytes, play a pivotal role in the regulation of inflammation and endothelial function. As TMAO is produced in the liver, hepatocytes may be the potential target of TMAO. However, it is not yet clear whether TMAO can directly stimulate hepatocytes to produce Exos to mediate the detrimental effects of TMAO on vascular endothelial cells (VECs).Methods: Hepatocytes treated with TMAO and Exos (TMAO-Exos) were isolated from the supernatant, and added to human aortic endothelial cells (HAECs). The expressions of interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α) were detected by quantitative polymerase chain reaction (qPCR). Cell apoptosis was evaluated using Hoechst 33342 staining and flow cytometry assay, and cell migration was assessed by scratch and transwell assay. C57BL/6 mice were treated with Exos for 24 h and the thoracic aortas were isolated, then the in vitro aortic ring bioassay was conducted to determine the changes of vasodilation. The expressions of cluster of differentiation 81, tumor susceptibility gene 101, nuclear factor-kappa B (NF-κB) p65, and Phospho-NF-κB p65 were detected by western blotting. The micro ribonucleic acid (miRNA) profiles of the Exos were then identified using RNA-sequencing and validated by qPCR. The miRNA-messenger RNA networks were constructed, and the biological functions of the target genes were annotated using bioinformatics methods.
Results: TMAO was found to stimulate hepatocytes to release Exos that could be taken up by HAECs, thus inducing inflammation and cell apoptosis, impairing cell migration, and inhibiting endothelium-dependent vasodilation. Additionally, the miRNAs such as miR-302d-3p carried by the TMAO-Exos were quite different to those in the TMAO-free group. A further analysis showed that the potential target genes for these miRNAs, such as mitogen-activated protein kinase 8, caspase 9 and BCL2-like 11, appeared to be involved with inflammation and endothelial function. Finally, we found that NF-κB signaling could be activated by TMAO-Exos.
Conclusions: These novel findings provide evidence that TMAO can indirectly talk to VECs by promoting hepatocytes to produce Exos that carry important genetic information.

Keywords:  Trimethylamine-N-oxide (TMAO); endothelial function; hepatocyte-derived exosomes; inflammation; microRNA

DOI:  https://doi.org/10.21037/atm-21-5043