bims-heshmo Biomed News
on Trauma hemorrhagic shock — molecular basis
Issue of 2021‒12‒05
six papers selected by
Andreia Luís
Ludwig Boltzmann Institute
  1. Senkyunolide I alleviates renal Ischemia-Reperfusion injury by inhibiting oxidative stress, endoplasmic reticulum stress and apoptosis.
  2. Role of TLR5 in the Translocation and Dissemination of Commensal Bacteria in the Intestine after Traumatic Hemorrhagic Shock.
  3. Delivery of coenzyme Q10 with mitochondria-targeted nanocarrier attenuates renal ischemia-reperfusion injury in mice.
  4. USP11 regulates autophagy-dependent ferroptosis after spinal cord ischemia-reperfusion injury by deubiquitinating Beclin 1.
  5. An engineered activated factor V for the prevention and treatment of acute traumatic coagulopathy and bleeding in mice.
  6. Pharmacological inhibition of translocon is sufficient to alleviate endoplasmic reticulum stress and improve Ca2+ handling and contractile recovery of stunned myocardium.
  1. Int Immunopharmacol. 2021 Nov 30. pii: S1567-5769(21)01029-8. [Epub ahead of print] 108393
    Senkyunolide I alleviates renal Ischemia-Reperfusion injury by inhibiting oxidative stress, endoplasmic reticulum stress and apoptosis.
    Ya-Lin Zhu, Jie Huang, Xue-Ying Chen, Jian Xie, Qing Yang, Jia-Feng Wang, Xiao-Ming Deng.
      BACKGROUND: Ligusticum striatum DC. is traditionally used to treat ischemic diseases because of its potent effect against blood stasis and thrombosis, including various cardiovascular, cerebral and renal diseases. Senkyunolide I (SEI), which is the major active phthalide ingredient of Ligusticum striatum DC., is mainly distributed in kidney and has been shown to attenuate ischemia reperfusion injury in liver. However, the underlying effect of SEI against renal ischemia-reperfusion injury (IRI) remain unclear.METHODS: Renal ischemia reperfusion mice model was established by clamping bilateral renal pedicles. In vitro oxidative stress model was induced by H2O2. Level of blood urea nitrogen (BUN) and serum creatinine (SCr) was tested for in vivo model evaluation, while cell viability was tested using CCK8 to evaluate in vitro model. SEI solution containing 1% DMSO was injected intraperitoneally in the I/R group, while normal saline containing 1% DMSO injected in the Sham group. Reduced glutathione (GSH) solution containing 1% DMSO was used as a positive control.
    RESULTS: SEI protected renal function and structural integrity. It reversed the I/R-induced elevation of BUN, SCr levels and renal pathological injury. The secretion of proinflammatory cytokines including TNF-α and IL-6 was inhibited, and the renal apoptosis was attenuated by SEI. In addition, SEI played a protective role by reducing the production of reactive oxidative species (ROS), as shown by the elevated expression of antioxidant proteins including Nrf2, HO-1, NQO1, and reduced expression of endoplasmic reticulum stress (ERS) related proteins including GRP78 and CHOP. It also attenuated HK2 cell injury in an in vitro model induced by H2O2.
    CONCLUSIONS: SEI alleviates renal injury induced by ischemia reperfusion with anti-inflammatory, anti-endoplasmic reticulum stress, anti-oxidative and anti-apoptotic effect.
    Keywords:  Apoptosis; Endoplasmic reticulum stress; Oxidative stress; Renal ischemia-reperfusion; Senkyunolide I
    DOI:  https://doi.org/10.1016/j.intimp.2021.108393
  2. J Immunol Res. 2021 ;2021 6417658
    Role of TLR5 in the Translocation and Dissemination of Commensal Bacteria in the Intestine after Traumatic Hemorrhagic Shock.
    Yun Zhang, Jian Zhang, Tao Xu, Cheng Zhang, Wen-Qiao Yu, Tao Wei, Bo Zhang, Qi Chen, Jun-Yu Qiu, Hai-Jun Li, Ting-Bo Liang.
      Enterogenous infection is a major cause of death during traumatic hemorrhagic shock (THS). It has been reported that Toll-like receptor 5 (TLR5) plays an integral role in regulating mucosal immunity and intestinal homeostasis of the microbiota. However, the roles played by TLR5 on intestinal barrier maintenance and commensal bacterial translocation post-THS are poorly understood. In this research, we established THS models in wild-type (WT) and Tlr5-/- (genetically deficient in TLR5 expression) mice. We found that THS promoted bacterial translocation, while TLR5 deficiency played a protective role in preventing commensal bacteria dissemination after THS. Furthermore, intestinal microbiota analysis uncovered that TLR5 deficiency enhanced the mucosal biological barrier by decreasing RegIIIγ-mediated bactericidal activity against G+ anaerobic bacteria. We then sorted small intestinal TLR5+ lamina propria dendritic cells (LPDCs) and analyzed TH1 differentiation in the intestinal lamina propria and a coculture system consisting of LPDCs and naïve T cells. Although TLR5 deficiency attenuated the regulation of TH1 polarization by LPDCs, it conferred stability to the cells during THS. Moreover, retinoic acid (RA) released from TLR5+ LPDCs could play a key role in modulating TH1 polarization. We also found that gavage administration of RA alleviated bacterial translocation in THS-treated WT mice. In summary, we documented that TLR5 signaling plays a pivotal role in regulating RegIIIγ-induced killing of G+ anaerobic bacteria, and LPDCs mediated TH1 differentiation via RA. These processes prevent intestinal bacterial translocation and enterogenous infection after THS, suggesting that therapeutically targeting LPDCs or gut microbiota can interfere with bacterial translocation after THS.
    DOI:  https://doi.org/10.1155/2021/6417658
  3. Mater Sci Eng C Mater Biol Appl. 2021 Dec;pii: S0928-4931(21)00676-7. [Epub ahead of print]131 112536
    Delivery of coenzyme Q10 with mitochondria-targeted nanocarrier attenuates renal ischemia-reperfusion injury in mice.
    Zhaohui Liu, Yan Li, Chunlei Li, Lili Yu, Yulin Chang, Min Qu.
      Ischemia-reperfusion (I/R) injury causes high morbidity, mortality, and healthcare costs. I/R induces acute kidney injury through exacerbating the mitochondrial damage and increasing inflammatory and oxidative responses. Here, we developed the mitochondria-targeted nanocarrier to delivery of Coenzyme Q10 (CoQ10) for renal I/R treatment in animal model. The mitochondria-targeted TPP CoQ10 nanoparticles (T-NPCoQ10) were synthesized through ABC miktoarm polymers method and characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The I/R mouse model and oxygen-glucose deprivation/reperfusion (D/R) model were created to examine the role of T-NPCoQ10 on renal I/R. Mitochondrial DNA damage, apoptosis, and inflammatory cytokines were measured in I/R injury mice. Plasma creatinine, urea nitrogen, tubular injury score was tested to assess the renal function. T-NPCoQ10 nanoparticles could be delivered to renal mitochondria preciously and efficiently. T-NPCoQ10 administration attenuated oxidative injury in both cell and animal models significantly, alleviated mtDNA damage, suppressed inflammatory and apoptotic responses, and improved renal function. The mitochondria specific CoQ10 delivery provided a precious and efficient method for protecting inflammatory and oxidative responses of I/R-induced renal damage.
    Keywords:  Apoptosis; CoQ10; I/R injury; Inflammation; Mitochondria-targeted nanoparticle; Oxidative stress
    DOI:  https://doi.org/10.1016/j.msec.2021.112536
  4. Cell Death Differ. 2021 Nov 27.
    USP11 regulates autophagy-dependent ferroptosis after spinal cord ischemia-reperfusion injury by deubiquitinating Beclin 1.
    Yuluo Rong, Jin Fan, Chengyue Ji, Zhuanghui Wang, Xuhui Ge, Jiaxing Wang, Wu Ye, Guoyong Yin, Weihua Cai, Wei Liu.
      Spinal cord ischemia-reperfusion injury (SCIRI) is a serious trauma that can lead to loss of sensory and motor function. Ferroptosis is a new form of regulatory cell death characterized by iron-dependent accumulation of lipid peroxides. Ferroptosis has been studied in various diseases; however, the exact function and molecular mechanism of ferroptosis in SCIRI remain unknown. In this study, we demonstrated that ferroptosis is involved in the pathological mechanism of SCIRI. Inhibition of ferroptosis could promote the recovery of motor function in mice after SCIRI. In addition, we found that ubiquitin-specific protease 11 (USP11) was significantly upregulated in neuronal cells after hypoxia-reoxygenation and in the spinal cord in mice with I/R injury. Knockdown of USP11 in vitro and KO of USP11 in vivo (USP11-/Y) significantly decreased neuronal cell ferroptosis. In mice, this promotes functional recovery after SCIRI. In contrast, in vitro, USP11 overexpression leads to classic ferroptosis events. Overexpression of USP11 in mice resulted in increased ferroptosis and poor functional recovery after SCIRI. Interestingly, upregulating the expression of USP11 also appeared to increase the production of autophagosomes and to cause substantial autophagic flux, a potential mechanism through which USP11 may enhance ferroptosis. The decreased autophagy markedly weakened the ferroptosis mediated by USP11 and autophagy induction had a synergistic effect with USP11. Importantly, USP11 promotes autophagy activation by stabilizing Beclin 1, thereby leading to ferroptosis. In conclusion, this study shows that ferroptosis is closely associated with SCIRI, and that USP11 plays a key role in regulating ferroptosis and additionally identifies USP11-mediated autophagy-dependent ferroptosis as a promising target for the treatment of SCIRI.
    DOI:  https://doi.org/10.1038/s41418-021-00907-8
  5. Blood Adv. 2021 Dec 03. pii: bloodadvances.2021005257. [Epub ahead of print]
    An engineered activated factor V for the prevention and treatment of acute traumatic coagulopathy and bleeding in mice.
    Bilgimol Chumappumkal Joseph, Byron Y Miyazawa, Charles Esmon, Mitchell J Cohen, Annette von Drygalski, Laurent O Mosnier.
      Acute traumatic coagulopathy (ATC) occurs in ≈30% of trauma patients and is associated with increased mortality. Excessive generation of activated protein C (APC) and hyperfibrinolysis are believed to be driving forces for ATC. Two mouse models were used to investigate whether an engineered activated FV variant (superFVa) that is resistant to inactivation by APC and contains a stabilizing A2-A3 domain disulfide bond, is able to reduce traumatic bleeding and normalize hemostasis parameters in ATC. First, ATC was induced by the combination of trauma and shock. ATC was characterized by APTT prolongation and reductions of FV, FVIII, and fibrinogen, but not FII and FX. Administration of superFVa normalized the APTT, returned FV and FVIII clotting activity levels to their normal range, and reduced APC and thrombin-antithrombin (TAT) levels, indicating improved hemostasis. Next, a liver laceration model was used where ATC develops as the consequence of severe bleeding. SuperFVa prophylaxis prior to liver laceration reduced bleeding, prevented APTT prolongation, depletion of FV and FVIII, and excessive generation of APC. Thus, prophylactic administration of superFVa prevented the development of ATC. SuperFVa intervention started after the development of ATC stabilized bleeding, reversed the prolonged APTT, returned FV and FVIII levels to their normal range, and reduced TAT levels that were increased by ATC. In summary, superFVa prevented ATC and traumatic bleeding when administered prophylactically, and superFVa stabilized bleeding and reversed abnormal hemostasis parameters when administered while ATC was in progress. Thus, superFVa may be an attractive strategy to intercept ATC and mitigate traumatic bleeding.
    DOI:  https://doi.org/10.1182/bloodadvances.2021005257
  6. Eur J Pharmacol. 2021 Nov 30. pii: S0014-2999(21)00821-9. [Epub ahead of print] 174665
    Pharmacological inhibition of translocon is sufficient to alleviate endoplasmic reticulum stress and improve Ca2+ handling and contractile recovery of stunned myocardium.
    Juan Ignacio Elio Mariángelo, Carlos Alfredo Valverde, Leticia Vittone, Matilde Said, Cecilia Mundiña-Weilenmann.
      INTRODUCTION: The function of endoplasmic reticulum (ER), a Ca2+ storage compartment and site of protein folding, is altered by disruption of intracellular homeostasis. Misfolded proteins accumulated in the ER lead to ER stress (ERS), unfolded protein response (UPR) activation and ER Ca2+ loss. Myocardial stunning is a temporary contractile dysfunction, which occurs after brief ischemic periods with minimal or no cell death, being oxidative stress and Ca2+ overload potential underlying mechanisms. Myocardial stunning induces ERS response with negatively impact on the post-ischemic mechanical performance through an unknown mechanism.AIMS: In this study, we explored whether ER Ca2+ efflux through the translocon, a major Ca2+ leak channel, contributes to Ca2+ mishandling and the consequent contractile abnormalities of the stunned myocardium.
    METHODS: Mechanical performance, cytosolic Ca2+, UPR markers and oxidative state were evaluated in perfused rat/mouse hearts subjected to a brief ischemia followed by reperfusion (I/R) in absence or presence of the translocon inhibitor, emetine (1 μM), comparing its effects with those of the chaperones TUDCA (30 μM) and 4-PBA (3 mM).
    RESULTS: Emetine treatment precluded the I/R-induced increase in UPR signaling markers and improved the contractile recovery together with a remarkable attenuation in myocardial stiffness when compared to I/R hearts with no drug. This alleviation of I/R-induced mechanical abnormalities was more effective than that obtained with the chemical chaperones, TUDCA and 4-PBA. Moreover, emetine treatment produced a striking improvement in diastolic Ca2+ handling with a partial recovery of the I/R-induced oxidative stress.
    CONCLUSION: Blocking ER Ca2+ store depletion via translocon suppressed ER stress and improved mechanical performance and diastolic Ca2+ handling of stunned myocardium. Modulation of translocon permeability emerges as a therapeutic approach to face dysfunctional consequences of the I/R injury.
    Keywords:  Endoplasmic RETICULUM STRESS; MYOCARDIAL ISCHEMIA/Reperfusion; TRANSLOCON
    DOI:  https://doi.org/10.1016/j.ejphar.2021.174665
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