Toll-like receptor activation as a biomarker in traumatically injured patients


© 2018 Elsevier Inc. Background: Surgical insult and trauma have been shown to cause dysregulation of the immune and inflammatory responses. Interaction of damage-associated molecular patterns (DAMPs) with toll-like receptors (TLRs) initiates innate immune response and systemic inflammatory responses. Given that surgical patients produce high levels of circulating damage-associated molecular patterns, we hypothesized that plasma-activated TLR activity would be correlated to injury status and could be used to predict pathological conditions involving tissue injury. Methods: An observational study was performed using samples from a single-institution prospective tissue and data repository from a Level-1 trauma center. In vitro TLR 2, 3, 4, and 9 activation was determined in a TLR reporter assay after isolation of plasma from peripheral blood. We determined correlations between plasma-activated TLR activity and clinical course measures of severity. Results: Eighteen patients were enrolled (median Injury Severity Score 15 [interquartile range 10, 23.5]). Trauma resulted in significant elevation in circulation high mobility group box 1 as well as increase of plasma-activated TLR activation (2.8-5.4-fold) compared to healthy controls. There was no correlation between circulating high mobility group box 1 and trauma morbidity; however, the plasma-activated TLR activity was correlated with acute physiology and chronic health evaluation II scores (R square = 0.24-0.38, P < 0.05). Patients who received blood products demonstrated significant increases in the levels of plasma-activated TLRs 2, 3, 4, and 9 and had a trend toward developing systemic inflammatory response syndrome. Conclusions: Further studies examining TLR modulation and signaling in surgical patients may assist in predictive risk modeling and reduction in morbidity and mortality.






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Publication Info

Darrabie, Marcus D, Jennifer Cheeseman, Alexander T Limkakeng, Joseph Borawski, Bruce A Sullenger, Eric A Elster, Allan D Kirk, Jaewoo Lee, et al. (2018). Toll-like receptor activation as a biomarker in traumatically injured patients. Journal of Surgical Research, 231. pp. 270–277. 10.1016/j.jss.2018.05.059 Retrieved from

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Alexander Tan Limkakeng

Professor of Emergency Medicine

Dr. Alexander T. Limkakeng, Jr., MD, MHSc, FACEP is a Professor of Emergency Medicine, Vice Chair of Clinical Research, Director of the Acute Care Research Team, and Director of the Resident Research Fellowship for the Department of Emergency Medicine in the Duke University School of Medicine in Durham, North Carolina.

Dr. Limkakeng has served as chair of the American College of Emergency Physicians (ACEP) Research Committee, and been the Course Director of the ACEP Research Forum from 2016-2018, the largest emergency medical research platform in the nation. He is also the Assistant Director of ACEP’s Emergency Medicine Basic Research Skills course. He was elected to the Nominating Committee of the Society of Academic Emergency Medicine.

As a researcher, Dr. Limkakeng has led multiple clinical trials and interdepartmental sponsored projects and is author on over 100 peer-reviewed manuscripts. These include studies in emergency conditions such as COVID-19, traumatic brain injury, hypertension, heart failure, thrombosis, stroke, envenomations, and septic shock. His research has been funded by grants and contracts totaling over $9 million dollars. He has lectured internationally on acute coronary syndrome, responsible conduct of research, design of clinical trials, and precision medicine in emergency care. He has led Duke’s involvement in NIH-funded research networks and in industry-funded work that led to FDA approval for multiple high-sensitivity cardiac troponin assays and point-of-care COVID-19 diagnostic tests. He has servesd as Co-PI for the Duke U24 Hub in the NIH Early Phase Pain Investigation Clinical Network (EPPIC-Net) (1U24NS114416) and now serves as a co-PI on the Duke U24 Hub award (1U24NS129498) in the NIH Strategies to Innovate Emergency Care Clinical Trials (SIREN) Network and in the NIH NINDS Strokenet network (1U24NS135250)

His personal research interest is finding new ways to diagnose acute coronary syndrome. In particular, he is interested in novel biomarkers and precision medicine approaches to this problem. The common element throughout this work is a focus on time-sensitive health conditions.

Joseph Brian Borawski

Assistant Professor of Emergency Medicine

Bruce Alan Sullenger

Joseph W. and Dorothy W. Beard Distinguished Professor of Experimental Surgery

The main focus of my translational research laboratory is to develop RNA based therapeutic agents for the potential treatment of a range of diseases. To this end, we have and will continue to take advantage of the fact that RNA is not just a passive carrier of genetic instructions inside of cells during the conversion of information from DNA to RNA to protein. Rather, RNA is an extremely versatile biological macromolecule. Certian RNAs can bind to specific protiens with high affinities, while others can for catalytic centers and perform enzymatic reactions. These facets of RNA coupled with the ease with which RNA can be manipulated in vitro make it a very powerful and unique therapeutic agent whose potential is largely untapped. Durring our endeavors, we plan to work closely with the members of the Molecular Therapeutics program as well as other faculty at the Duke University Medical Center to expedite the development and testing of these therapeutics.

The specific aims of my laboratory are:

1. To isolate and characterize RNA and DNA aptamers which block therapeutically relavent proteins such as those involved in cardiovascular diseases and immune modulation.

2. To develop RNA-based tumor targeting strategies for delivering siRNAs and miRNAs to tumor cells.

3. To reprogram cells using mRNA delivery.

4. To explore novel methods to control inflammation.

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