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Selective Inhibition of IL-6 Trans-Signaling Has No Beneficial Effect on the Posttraumatic Cytokine Release after Multiple Trauma in Mice. Life (Basel) 2021; 11:life11111252. [PMID: 34833127 PMCID: PMC8617644 DOI: 10.3390/life11111252] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/02/2021] [Accepted: 11/13/2021] [Indexed: 12/26/2022] Open
Abstract
While improvements in pre-hospital and in-hospital care allow more multiple trauma patients to advance to intensive care, the incidence of posttraumatic multiple organ dysfunction syndrome (MODS) is on the rise. Herein, the influence of a selective IL-6 trans-signaling inhibition on posttraumatic cytokine levels was investigated as an approach to prevent MODS caused by a dysbalanced posttraumatic immune reaction. Therefore, the artificial IL-6 trans-signaling inhibitor sgp130Fc was deployed in a murine multiple trauma model (femoral fracture plus bilateral chest trauma). The traumatized mice were treated with sgp130Fc (FP) and compared to untreated mice (WT) and IL-6 receptor knockout mice (RKO), which received the same traumas. The overall trauma mortality was 4.4%. Microscopic pulmonary changes were apparent after multiple trauma and after isolated bilateral chest trauma. Elevated IL-6, MCP-3 and RANTES plasma levels were measured after trauma, indicating a successful induction of a systemic inflammatory reaction. Significantly reduced IL-6 and RANTES plasma levels were visible in RKO compared to WT. Only a little effect was visible in FP compared to WT. Comparable cytokine levels in WT and FP indicate neither a protective nor an adverse effect of sgp130Fc on the cytokine release after femoral fracture and bilateral chest trauma.
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Miyauchi H, Fujioka K, Okubo S, Nishida K, Ashina M, Ikuta T, Okata Y, Maeda K, Iijima K, Bitoh Y. Insulin therapy for hyperglycemia in neonatal sepsis using a preterm mouse model. Pediatr Int 2020; 62:581-586. [PMID: 31885143 DOI: 10.1111/ped.14126] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 11/21/2019] [Accepted: 12/25/2019] [Indexed: 11/29/2022]
Abstract
BACKGROUND Stress-induced hyperglycemia is a frequent complication of neonatal sepsis. Hyperglycemia induces oxidative stress and immunosuppression. We investigated the glucose kinetics and effect of insulin administration during stress-induced hyperglycemia in a neonatal sepsis mouse model. METHODS A stock cecal slurry (CS) solution was prepared from adult cecums and 3.0 mg of CS/g (LD40 ) was administered intraperitoneally to 4-day-old FVB mouse pups. Blood glucose levels were measured at 1.5, 3, 6, and 9 h post-sepsis induction and compared with basal levels. Two different doses of ultrafast-acting insulin were administered subcutaneously, and blood glucose levels and survival rates were monitored. RESULTS Blood glucose levels were significantly higher than those of baseline levels with a peak at 3 h, which progressively decreased from 6 to 9 h post-sepsis induction. Insulin treatment reduced post-sepsis-induced hyperglycemia at 1.5 and 3 h. The mortality rate of CS-only pups (39%) was similar to that of CS + 1 U/kg insulin pups (60%). However, the mortality rate of CS + 5 U/kg insulin pups (82%) was significantly higher than that of CS-only pups. CONCLUSIONS Marked hyperglycemia was induced immediately after post-sepsis induction, and the high-dose insulin treatment increased mortality post-induction. Stress-induced hyperglycemia could therefore be a physiological and protective response for preterm sepsis, and aggressive treatment of this hyperglycemia might be contraindicated.
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Affiliation(s)
- Harunori Miyauchi
- Department of Pediatric Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kazumichi Fujioka
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Saki Okubo
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kosuke Nishida
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Mariko Ashina
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Toshihiko Ikuta
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yuichi Okata
- Department of Pediatric Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kosaku Maeda
- Department of Pediatric Surgery, Kobe Children's Hospital, Kobe, Japan
| | - Kazumoto Iijima
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yuko Bitoh
- Department of Pediatric Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
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Traumatic injury pattern is of equal relevance as injury severity for experimental (poly)trauma modeling. Sci Rep 2019; 9:5706. [PMID: 30952899 PMCID: PMC6450898 DOI: 10.1038/s41598-019-42085-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 03/21/2019] [Indexed: 01/02/2023] Open
Abstract
This study aims to elaborate the relevance of trauma severity and traumatic injury pattern in different multiple and/or polytrauma models by comparing five singular trauma to two different polytrauma (PT) models with high and one multiple trauma (MT) model with low injury-severity score (ISS). The aim is to provide a baseline for reducing animal harm according to 3Rs by providing less injury as possible in polytrauma modeling. Mice were randomly assigned to 10 groups: controls (Ctrl; n = 15), Sham (n = 15); monotrauma groups: hemorrhagic shock (HS; n = 15), thoracic trauma (TxT; n = 18), osteotomy with external fixation (Fx; n = 16), bilateral soft tissue trauma (bSTT; n = 16) or laparotomy (Lap; n = 16); two PT groups: PT I (TxT + HS + Fx; ISS = 18; n = 18), PT II (TxT + HS + Fx + Lap; ISS = 22; n = 18), and a MT group (TxT + HS + bSTT + Lap, ISS = 13; n = 18). Activity and mortality were assessed. Blood gas analyses and organ damage markers were determined after 6 h. Significant mortality occurred in TxT, PT and MT (11.7%). Activity decreased significantly in TxT, HS, both polytrauma and MT vs. Ctrl/Sham. PT-groups and MT had significantly decreased activity vs. bsTT, Lap or Fx. MT had significantly lower pCO2vs. Ctrl/Sham, Lap or bsTT. Transaminases increased significantly in PT-groups and MT vs. Ctrl, Sham or monotrauma. Traumatic injury pattern is of comparable relevance as injury severity for experimental multiple or (poly)trauma modeling.
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Severe Hemorrhagic Shock Leads to a Delayed Fracture Healing and Decreased Bone Callus Strength in a Mouse Model. Clin Orthop Relat Res 2017; 475:2783-2794. [PMID: 28795328 PMCID: PMC5638746 DOI: 10.1007/s11999-017-5473-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Accepted: 08/02/2017] [Indexed: 01/31/2023]
Abstract
BACKGROUND Multiple trauma is frequently associated with hemorrhagic shock and fractures of the extremities. Clinically, the rate of impaired fracture healing (delayed healing and nonunion) seems to be increased in patients with multiple injuries compared with patients with isolated fractures. As the underlying pathogenesis remains poorly understood, we aimed to analyze the biomechanical properties during fracture healing in a murine model. QUESTIONS The aim of this study was to determine whether fracture healing after severe hemorrhagic shock results in (1) delayed bridging as determined by macroscopic and radiographic assessment, (2) altered conditions of callus components as determined by µCT, and (3) decreased maximum bending moment measured by a three-point-bending test compared with ordinary fracture healing. METHODS Male C57BL/6NCrl mice were randomly assigned to five groups and four different times (five to 10 mice per group and time). Only the right femur from each mouse was used for analysis: the trauma hemorrhage (TH) group received a pressure-controlled hemorrhagic shock via catheter; the osteotomy (Fx) group underwent osteotomy and implantation of an external fixator on the right femur; the combined trauma (THFx) group received hemorrhagic shock and an external fixator with osteotomy; the sham group underwent implantation of a catheter and external fixator but had no blood loss or osteotomy, and the control group underwent no interventions. After 2, 3, 4, or 6 weeks, five to 10 animals of each group were sacrificed. Bones were analyzed macroscopically and via radiographs, µCT, and three-point-bending test. Statistical significance was set at a probability less than 0.05. Comparisons were performed using the Mann-Whitney U or the Kruskal-Wallis test. RESULTS In the Fx group, the osteotomy gap was stable and bridged after 2 weeks in contrast to some bones in the THFx group where stable bridging did not occur. No difference was observed between the groups. µCT analysis showed reduced density of bone including callus (THFx: 1.17 g/cm3; interquartile range [IQR], 0.04 g/cm3; Fx: 1.22 g/cm3; IQR, 0.04 g/cm3; p = 0.002; difference of medians [DM], -0.048; 95% CI, -0.073 to -0.029) and increased share of callus per volume of bone mass (%) after 2 weeks in the THFx group compared with the Fx group (THFx: 44.16%; IQR, 8.66%; Fx: 36.73%; IQR, 4.39%; p = 0.015; DM, 7.634; 95% CI, 2.018-10.577). The three-point-bending test established a decreased maximum bending moment in the THFx group compared with the Fx group 2 weeks after surgery (THFx: 7.10 Nmm; IQR, 11.25 Nmm; Fx: 11.25 Nmm; IQR, 5.70 Nmm; p = 0.026; DM, -5.043; 95% CI, -10.867 to -0.74). No differences were observed between the THFx and Fx groups after more than 2 weeks. CONCLUSION In this in vivo mouse fracture model, we conclude that hemorrhagic shock retards fracture healing during the early phase of the facture healing process. CLINICAL RELEVANCE A severe hemorrhagic shock in patients could result in initial delayed fracture healing and needs special attention. We plan to conduct a prospective, observational clinical research study to analyze if delayed fracture healing occurs in patients after severe blood loss.
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Franklin JL, Bennett WL, Messina JL. Insulin attenuates TNFα-induced hemopexin mRNA: An anti-inflammatory action of insulin in rat H4IIE hepatoma cells. Biochem Biophys Rep 2017; 9:211-216. [PMID: 28956007 PMCID: PMC5614554 DOI: 10.1016/j.bbrep.2016.12.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Revised: 11/15/2016] [Accepted: 12/21/2016] [Indexed: 12/20/2022] Open
Abstract
Proinflammatory cytokines, including TNF-α and IL-6, can contribute to insulin resistance. Conversely, insulin has some actions that can be considered anti-inflammatory. Hemopexin is a Class 2 acute phase reactant and control of its transcription is predominantly regulated by IL-6, with TNF-α and IL-1β also inducing hemopexin gene expression. Thus, we asked whether insulin could inhibit the ability of TNF-α to stimulate hemopexin mRNA expression. In cultured rat hepatoma (H4IIE) cells, TNF-α significantly increased hemopexin mRNA accumulation. The TNF-α-induced increase of hemopexin mRNA was dramatically attenuated by insulin, even though TNF-α reduced peak insulin activation of ERK. Thus, even though TNF-α can contribute to insulin resistance, the residual insulin response was still able to counteract TNF-α actions.
The TNF-α-induced increase of hemopexin mRNA was dramatically attenuated by insulin. This occurred even though TNF-α significantly decreased insulin activation of ERK. This suggests an additional mechanism for the anti-inflammatory action of insulin. Cytokine-induced insulin resistance does not abolish insulin’s anti-inflammatory effect.
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Affiliation(s)
- J Lee Franklin
- University of Alabama at Birmingham, Department of Pathology, Division of Molecular and Cellular Pathology, Birmingham, AL 35294, United States
| | - William L Bennett
- Yale University, Interventional Cardiology, New Haven, CT 06510, United States
| | - Joseph L Messina
- University of Alabama at Birmingham, Department of Pathology, Division of Molecular and Cellular Pathology, Birmingham, AL 35294, United States.,Veterans Administration Medical Center, Birmingham, AL 35294, United States
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Liang F, Cao J, Qin WT, Wang X, Qiu XF, Sun BW. Regulatory effect and mechanisms of carbon monoxide-releasing molecule II on hepatic energy metabolism in septic mice. World J Gastroenterol 2014; 20:3301-3311. [PMID: 24696611 PMCID: PMC3964400 DOI: 10.3748/wjg.v20.i12.3301] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Revised: 12/20/2013] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the possible mechanisms of exogenous carbon monoxide-releasing molecule II (CORM-2) intervention on hepatic energy metabolism in experimental sepsis.
METHODS: Forty-eight C57BL/6 mice were randomly divided into four groups (n = 12): sham group; cecal ligation and puncture (CLP) group; CLP + CORM-2 group and CLP + iCORM-2 (inactive CORM-2) group. Survival rates were determined after 72 h. Twenty-four similarly treated mice (n = 6 in each group) were assayed for post-operative continuous blood glucose in the first 36 h. Thirty-six similarly treated mice (n = 9 in each group) underwent micro-positron emission tomography (PET) scanning after tail vein injection of 18F-fluorodeoxyglucose (FDG) 24 h after operation. Plasma and liver specimens were collected for assay of liver pathology, alanine transaminase (ALT) and aspartate transaminase (AST) activities. Hepatic glucokinase activity, lactic acid levels and mitochondrial swelling were also determined.
RESULTS: Improved survival was observed in CORM-2 treated mice. Both the CLP and CLP + CORM-2 groups had sustained low blood glucose levels within the first post-operative 36 h. 18F-FDG micro-PET images showed abnormally high levels of hepatic glucose metabolism (standardized uptake value) in the CLP group (2.76 ± 0.39 vs 0.84 ± 0.14, P < 0.01), which declined to normal levels after CORM-2 intervention (1.29 ± 0.32 vs 2.76 ± 0.39, P < 0.05). glucokinase activity was markedly increased in the CLP group (6.38 ± 0.56 U/g vs 4.60 ± 0.21 U/g, P < 0.01), but was normal after CORM-2 intervention (4.74 ± 0.14 U/g vs 6.38 ± 0.56 U/g, P < 0.05). CORM-2 suppressed plasma lactic acid levels (4.02 ± 0.02 mmol/L vs 7.72 ± 2.37 mmol/L, P < 0.05) and protected hepatic mitochondria in CLP mice. CORM-2 intervention also reduced elevated plasma AST (199.67 ± 11.08 U/L vs 379.67 ± 16.34 U/L, P < 0.05) and ALT (63.67 ± 12.23 U/L vs 112.67 ± 9.74 U/L, P < 0.05) activities in CLP mice.
CONCLUSION: The release of CO molecules by CORM-2 protects mitochondria and maintains a stable level of hepatic glucose metabolism. Thus, CORM-2 improves liver function and survival in septic mice.
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Zou B, Chen Q, Tang S, Gao T, Zhang J, Xi F, Yu W. Timing of insulin therapy affects the inflammatory response in endotoxemic rats. Inflammation 2012; 35:723-9. [PMID: 21809046 DOI: 10.1007/s10753-011-9367-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The aim of the present study was to determine whether timing of insulin administration influences the hepatic and serum proinflammatory and anti-inflammatory cytokines during endotoxemia stimulated by lipopolysaccharide (LPS). Eighty-one male Sprague-Dawley rats were divided into different time groups and insulin was given 30 min pre-LPS administration or hour 0, 1, 3, 6, 12, 24 after the induction of endotoxemia, respectively. Hepatic and serum proinflammatory cytokines IL-1β, IL-6, and TNF-α, and anti-inflammatory cytokine IL-10 were detected 24 and 48 h after the induction of endotoxemia. Compared with sham control rats, serum concentrations of proinflammatory cytokines IL-1β, IL-6, and TNF-α and anti-inflammatory cytokine IL-10 significantly increased on 24 and 48 h after induction of endotoxemia. Similarly, LPS administration also significantly increased the hepatic IL-1β, TNF-α, IL-6, and IL-10 protein concentration 48 h after LPS injection. Compared with levels in positive LPS controls animals receiving saline, on 24 and 48 h after LPS injection, insulin administrated ahead of 6 h after LPS injection significantly decreased the serum IL-1β, IL-6, and TNF-a concentration (P < 0.05), and significantly increased anti-inflammatory cytokine IL-10 concentration (P < 0.05); hepatic IL-1β and IL-6 expression were (P < 0.05) significantly decreased compared with levels in positive LPS controls. But, the significant decrease of hepatic TNF-a expression and significant increase of hepatic IL-10 were only seen in the animals in which insulin was administrated at 30 min pre-LPS or coadministrated with LPS. Insulin administrated 6 h after LPS injection lost the ability to significantly reduce serum or hepatic IL-1β, TNF-α, and IL-6 concentrations. Insulin has a protective role in systemic inflammatory response syndrome related to sepsis, such as downregulation of proinflammatory cytokines and upregulation of anti-inflammatory cytokine production. However, timing of insulin administrated may change its effect of inflammatory response in endotoxemic rats. Insulin administrated 6 h after LPS injection weaken the ability to protect inflammatory response related to sepsis.
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Affiliation(s)
- Bo Zou
- Medical School of Nanjing University, Nanjing 210093, Jiangsu Province, China
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Selective blockade of interleukin-6 trans-signaling improves survival in a murine polymicrobial sepsis model*. Crit Care Med 2011; 39:1407-13. [DOI: 10.1097/ccm.0b013e318211ff56] [Citation(s) in RCA: 118] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Experimental trauma models: an update. J Biomed Biotechnol 2011; 2011:797383. [PMID: 21331361 PMCID: PMC3035380 DOI: 10.1155/2011/797383] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2010] [Accepted: 12/17/2010] [Indexed: 01/31/2023] Open
Abstract
Treatment of polytrauma patients remains a medical as well as socioeconomic challenge. Although diagnostics and therapy improved during the last decades, multiple injuries are still the major cause of fatalities in patients below 45 years of age. Organ dysfunction and organ failure are major complications in patients with major injuries and contribute to mortality during the clinical course. Profound understanding of the systemic pathophysiological response is crucial for innovative therapeutic approaches. Therefore, experimental studies in various animal models are necessary. This review is aimed at providing detailed information of common trauma models in small as well as in large animals.
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Gosemann JH, van Griensven M, Barkhausen T, Kobbe P, Thobe BM, Haasper C, Pape HC, Krettek C, Hildebrand F, Frink M. TLR4 influences the humoral and cellular immune response during polymicrobial sepsis. Injury 2010; 41:1060-7. [PMID: 20591432 DOI: 10.1016/j.injury.2010.05.021] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2009] [Revised: 04/24/2010] [Accepted: 05/24/2010] [Indexed: 02/02/2023]
Abstract
As part of the innate immune system, Toll-like receptors (TLRs) react rapidly on a pathogen challenge without prior exposure. Although it is well known that TLR4 is associated with the receptor for lipopolysaccharide (LPS), its role during sepsis has not yet been clearly defined. To study this,polymicrobial sepsis was induced in male C3H/HeN (TLR4 wild type) and C3H/HeJ (TLR4 mutant) mice by caecal ligation and puncture (CLP).A total of 48 h following the surgical procedure, the mice were sacrificed and plasma was collected.Kupffer cells were isolated and ex vivo cytokine production and plasma levels were determined. Lung neutrophil influx was investigated by myeloperoxidase (MPO) content and immunohistochemistry. T-cell subtypes in blood and spleen were determined by flow cytometry.Mice with intact TLR4 (wild type) had increased Kupffer cell IL-6 production and increased plasma levels as compared with C3H/HeJ mice following sepsis. Furthermore, wild type mice showed increased neutrophil influx in lungs and lower percentages of CD8+ splenocytes. This was accompanied with less activity, increased weight loss and decreased core temperature.We conclude that TLR4 influences the humoral and cellular response during the course of sepsis and lack of TLR4 reduces markers of the systemic inflammatory response as well as distant organ damage.Therefore, TLR4 could act as a future therapeutic target modulating the immune response during sepsis.
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Affiliation(s)
- Jan H Gosemann
- Trauma Department, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
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Abstract
It is still a major problem to achieve successful therapy in polymicrobial sepsis. Stimulation of the innate immune system via Toll-like receptors (TLRs) 2 and 6 had beneficial effects on chronic inflammatory disorders and a severe peritonitis model when administered 4 days before induction. In the present study, the hypothesis whether the TLR-2 and TLR-6 pathway can also be used as a therapeutic agent parallel to sepsis induction and several hours after the induction was tested. Therefore, the TLR-2 and TLR-6 agonist macrophage-activating lipopeptide 2 (MALP-2) was applied simultaneous to cecal ligation and puncture-sepsis induction and 6 h thereafter. Vehicle-treated animals served as controls. Survival, activity, cytokine levels at different time points, and pulmonary neutrophil infiltration were determined. Improved survival was found after both MALP-2 treatments in comparison with untreated controls. The treatment resulted in reduced monocyte chemotactic protein 1 levels in the plasma; furthermore, pulmonary infiltration by neutrophils was decreased. These results demonstrate a beneficial effect of MALP-2 as a therapeutic agent in polymicrobial sepsis in the cecal ligation and puncture mouse model.
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Lee SM, Jang YS, Lee CT, Kim YW, Han SK, Shim YS, Yoo CG. Role of Insulin in the Activation of NF-κB/IκB Pathway in Macrophage Cells. Tuberc Respir Dis (Seoul) 2010. [DOI: 10.4046/trd.2010.68.3.168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- Sang-Min Lee
- Department of Internal Medicine and Lung Institute of Medical Research Center, Seoul National University College of Medicine, Seoul, Korea
| | - Yeon Sil Jang
- Department of Internal Medicine and Lung Institute of Medical Research Center, Seoul National University College of Medicine, Seoul, Korea
| | - Choon-Taek Lee
- Respiratory Center, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Young Whan Kim
- Department of Internal Medicine and Lung Institute of Medical Research Center, Seoul National University College of Medicine, Seoul, Korea
| | - Sung Koo Han
- Department of Internal Medicine and Lung Institute of Medical Research Center, Seoul National University College of Medicine, Seoul, Korea
| | - Young-Soo Shim
- Department of Internal Medicine and Lung Institute of Medical Research Center, Seoul National University College of Medicine, Seoul, Korea
| | - Chul-Gyu Yoo
- Department of Internal Medicine and Lung Institute of Medical Research Center, Seoul National University College of Medicine, Seoul, Korea
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Vasilescu C, Rossi S, Shimizu M, Tudor S, Veronese A, Ferracin M, Nicoloso MS, Barbarotto E, Popa M, Stanciulea O, Fernandez MH, Tulbure D, Bueso-Ramos CE, Negrini M, Calin GA. MicroRNA fingerprints identify miR-150 as a plasma prognostic marker in patients with sepsis. PLoS One 2009; 4:e7405. [PMID: 19823581 PMCID: PMC2756627 DOI: 10.1371/journal.pone.0007405] [Citation(s) in RCA: 244] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2009] [Accepted: 09/17/2009] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND The physiopathology of sepsis continues to be poorly understood, and despite recent advances in its management, sepsis is still a life-threatening condition with a poor outcome. If new diagnostic markers related to sepsis pathogenesis will be identified, new specific therapies might be developed and mortality reduced. Small regulatory non-coding RNAs, microRNAs (miRNAs), were recently linked to various diseases; the aim of our prospective study was to identify miRNAs that can differentiate patients with early-stage sepsis from healthy controls and to determine if miRNA levels correlate with the severity assessed by the Sequential Organ Failure Assessment (SOFA) score. METHODOLOGY/PRINCIPAL FINDINGS By using genome-wide miRNA profiling by microarray in peripheral blood leukocytes, we found that miR-150, miR-182, miR-342-5p, and miR-486 expression profiles differentiated sepsis patients from healthy controls. We also proved by quantitative reverse transcription-polymerase chain reaction that miR-150 levels were significantly reduced in plasma samples of sepsis patients and correlated with the level of disease severity measured by the SOFA score, but were independent of the white blood counts (WBC). We found that plasma levels of tumor necrosis factor alpha, interleukin-10, and interleukin-18, all genes with sequence complementarity to miR-150, were negatively correlated with the plasma levels of this miRNA. Furthermore, we identified that the plasma levels ratio for miR-150/interleukin-18 can be used for assessing the severity of the sepsis. CONCLUSIONS/SIGNIFICANCE We propose that miR-150 levels in both leukocytes and plasma correlate with the aggressiveness of sepsis and can be used as a marker of early sepsis. Furthermore, we envision miR-150 restoration as a future therapeutic option in sepsis patients.
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Affiliation(s)
- Catalin Vasilescu
- Department of Surgery, Fundeni Clinical Hospital, Bucharest, Romania
| | - Simona Rossi
- Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America
| | - Masayoshi Shimizu
- Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America
| | - Stefan Tudor
- Department of Surgery, Fundeni Clinical Hospital, Bucharest, Romania
| | - Angelo Veronese
- Department of Experimental and Diagnostic Medicine, Interdepartmental Center for Cancer Research, University of Ferrara, Ferrara, Italy
| | - Manuela Ferracin
- Department of Experimental and Diagnostic Medicine, Interdepartmental Center for Cancer Research, University of Ferrara, Ferrara, Italy
| | - Milena S. Nicoloso
- Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America
| | - Elisa Barbarotto
- Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America
| | - Monica Popa
- Department of Surgery, Fundeni Clinical Hospital, Bucharest, Romania
| | - Oana Stanciulea
- Department of Surgery, Fundeni Clinical Hospital, Bucharest, Romania
| | - Michael H. Fernandez
- Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America
| | - Dan Tulbure
- Department of Anesthesiology, Fundeni Clinical Hospital, Bucharest, Romania
| | - Carlos E. Bueso-Ramos
- Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America
| | - Massimo Negrini
- Department of Experimental and Diagnostic Medicine, Interdepartmental Center for Cancer Research, University of Ferrara, Ferrara, Italy
| | - George A. Calin
- Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America
- * E-mail:
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