Early Versus Late Onset of Multiple Organ Failure Is Associated With Differing Patterns of Plasma Cytokine Biomarker Expression and Outcome After Severe Trauma

Maier, Bernd Oliver; Lefering, Rolf; Lehnert, Mark; Laurer, Helmut; Steudel, W. I.; Neugebauer, Edmund; Marzi, Ingo

doi:10.1097/shk.0b013e318123e64e

Cited by 163 publications

(131 citation statements)

References 27 publications

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“…Furthermore, the initial serum levels (days 0-1) of sTNF-R p55 and sTNF-R p75 have good predictive value (0.75 and 0.72, respectively) for the development of late MOF. 146 Diagnosis of TBI in polytrauma patients using current biomarkers can be challenging. As previously described, several of the putative biomarkers of injury suffer from a lack of specificity in that they can be released into the serum by conditions not due to brain injury.…”

Section: Biomarkers For Polytraumamentioning

confidence: 99%

Biomarkers for the Diagnosis, Prognosis, and Evaluation of Treatment Efficacy for Traumatic Brain Injury

et al. 2010

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Section: Biomarkers For Polytraumamentioning

confidence: 99%

Biomarkers for the Diagnosis, Prognosis, and Evaluation of Treatment Efficacy for Traumatic Brain Injury

et al. 2010

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“…[1][2][3][4][5][6][7][8][9] Many studies have begun to assess these changes in the reactivity of the immune system following trauma. [10][11][12][13][14][15] Immunologic studies are greatly supported through the wide variety of transgenic and knockout mice available for in vivo modeling; these strains aid in detailed investigations to assess the molecular pathways involved in the immunologic responses. [16][17][18][19][20][21] The challenge in experimental murine trauma modeling is long term investigation, as fracture fixation techniques in mice, can be complex and not easily reproducible.…”

Section: Introductionmentioning

confidence: 99%

Pseudofracture: An Acute Peripheral Tissue Trauma Model

Darwiche

Kobbe²,

Pfeifer³

et al. 2011

JoVE

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Following trauma there is an early hyper-reactive inflammatory response that can lead to multiple organ dysfunction and high mortality in trauma patients; this response is often accompanied by a delayed immunosuppression that adds the clinical complications of infection and can also increase mortality. [1][2][3][4][5][6][7][8][9] Many studies have begun to assess these changes in the reactivity of the immune system following trauma. [10][11][12][13][14][15] Immunologic studies are greatly supported through the wide variety of transgenic and knockout mice available for in vivo modeling; these strains aid in detailed investigations to assess the molecular pathways involved in the immunologic responses. [16][17][18][19][20][21] The challenge in experimental murine trauma modeling is long term investigation, as fracture fixation techniques in mice, can be complex and not easily reproducible. [22][23][24][25][26][27][28][29][30] This pseudofracture model, an easily reproduced trauma model, overcomes these difficulties by immunologically mimicking an extremity fracture environment, while allowing freedom of movement in the animals and long term survival without the continual, prolonged use of anaesthesia. The intent is to recreate the features of long bone fracture; injured muscle and soft tissue are exposed to damaged bone and bone marrow without breaking the native bone.The pseudofracture model consists of two parts: a bilateral muscle crush injury to the hindlimbs, followed by injection of a bone solution into these injured muscles. The bone solution is prepared by harvesting the long bones from both hindlimbs of an age-and weight-matched syngeneic donor. These bones are then crushed and resuspended in phosphate buffered saline to create the bone solution.Bilateral femur fracture is a commonly used and well-established model of extremity trauma, and was the comparative model during the development of the pseudofracture model. Among the variety of available fracture models, we chose to use a closed method of fracture with soft tissue injury as our comparison to the pseudofracture, as we wanted a sterile yet proportionally severe peripheral tissue trauma model. 31 Hemorrhagic shock is a common finding in the setting of severe trauma, and the global hypoperfusion adds a very relevant element to a trauma model. [32][33][34][35][36] The pseudofracture model can be easily combined with a hemorrhagic shock model for a multiple trauma model of high severity. 37 Protocol

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“…Multiple studies have shown that IL-6 is a biomarker for adverse outcomes in settings such as trauma/hemorrhage and sepsis and specifically of poor outcome in trauma [18,19]. This was reflected in our own clinical cohort, since we could segregate survivors from non-survivors based on plasma IL-6 levels.…”

Section: Discussionmentioning

confidence: 99%

“…MCP-1 also appeared to coordinate stress-induced production of mediators including IL-6 (see above), and IL-6 has been identified consistently as a marker of negative outcomes in T/HS [18,19]. Accordingly, we next evaluated the potential of plasma MCP-1 levels as a biomarker for morbidity in a separate cohort of survivors of blunt trauma.…”

Section: Mcp-1 Is a Central Component Of The Dynamic Multidimensionamentioning

confidence: 99%

Central role for MCP-1/CCL2 in injury-induced inflammation revealed by in vitro, in silico, and clinical studies

Zamora

Ziraldo

Namas

et al. 2013

Journal of Critical Care

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The translation of in vitro findings to clinical outcomes is often elusive. Trauma/hemorrhagic shock (T/HS) results in hepatic hypoxia that drives inflammation. We hypothesize that in silico methods would help bridge in vitro hepatocyte data and clinical T/HS, in which the liver is a primary site of inflammation. Primary mouse hepatocytes were cultured under hypoxia (1% O 2 ) or normoxia (21% O 2 ) for 1-72 h, and both the cell supernatants and protein lysates were assayed for 18 inflammatory mediators by Luminex TM technology. Statistical analysis and data-driven modeling were employed to characterize the main components of the cellular response. Statistical analyses, hierarchical and k-means clustering, Principal Component Analysis, and Dynamic Network Analysis suggested MCP-1/CCL2 and IL-1a as central coordinators of hepatocyte-mediated inflammation in C57BL/6 mouse hepatocytes. Hepatocytes from MCP-1-null mice had altered dynamic inflammatory networks. Circulating MCP-1 levels segregated human T/HS survivors from non-survivors. Furthermore, T/HS survivors with elevated early levels of plasma MCP-1 post-injury had longer total lengths of stay, longer intensive care unit lengths of stay, and prolonged requirement for mechanical ventilation vs. those with low plasma MCP-1. This study identifies MCP-1 as a main driver of the response of hepatocytes in vitro and as a biomarker for clinical outcomes in T/HS, and suggests an experimental and computational framework for discovery of novel clinical biomarkers in inflammatory diseases.

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Early Versus Late Onset of Multiple Organ Failure Is Associated With Differing Patterns of Plasma Cytokine Biomarker Expression and Outcome After Severe Trauma

Cited by 163 publications

References 27 publications

Biomarkers for the Diagnosis, Prognosis, and Evaluation of Treatment Efficacy for Traumatic Brain Injury

Biomarkers for the Diagnosis, Prognosis, and Evaluation of Treatment Efficacy for Traumatic Brain Injury

Pseudofracture: An Acute Peripheral Tissue Trauma Model

Central role for MCP-1/CCL2 in injury-induced inflammation revealed by in vitro, in silico, and clinical studies

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