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Inducible Protein-10, a Potential Driver of Neurally Controlled Interleukin-10 and Morbidity in Human Blunt Trauma*

Zaaqoq, Akram M. MD1; Namas, Rami MD2,3; Almahmoud, Khalid MD2; Azhar, Nabil BS2; Mi, Qi PhD4; Zamora, Ruben PhD2,3; Brienza, David M. PhD3,5,6; Billiar, Timothy R. MD2,3; Vodovotz, Yoram PhD2,3

doi: 10.1097/CCM.0000000000000248
Clinical Investigations

Objective: Blunt trauma and traumatic spinal cord injury induce systemic inflammation that contributes to morbidity. Dysregulated neural control of systemic inflammation postinjury is likely exaggerated in patients with traumatic spinal cord injury. We used in silico methods to discern dynamic inflammatory networks that could distinguish systemic inflammation in traumatic spinal cord injury from blunt trauma.

Design: Retrospective study.

Settings: Tertiary care institution.

Patients: Twenty-one severely injured thoracocervical traumatic spinal cord injury patients and matched 21 severely injured blunt trauma patients without spinal cord injury.

Intervention: None.

Measurements and Main Results: Serial blood samples were obtained from days 1 to 14 postinjury. Twenty-four plasma inflammatory mediators were quantified. Statistical significance between the two groups was determined by two-way analysis of variance. Dynamic Bayesian network inference was used to suggest dynamic connectivity and central inflammatory mediators. Circulating interleukin-10 was significantly elevated in thoracocervical traumatic spinal cord injury group versus non–spinal cord injury group, whereas interleukin-1β, soluble interleukin-2 receptor-α, interleukin-4, interleukin-5, interleukin-7, interleukin-13, interleukin-17, macrophage inflammatory protein 1α and 1β, granulocyte-macrophage colony-stimulating factor, and interferon-γ were significantly reduced in traumatic spinal cord injury group versus non–spinal cord injury group. Dynamic Bayesian network suggested that post-spinal cord injury interleukin-10 is driven by inducible protein-10, whereas monocyte chemotactic protein-1 was central in non–spinal cord injury dynamic networks. In a separate validation cohorts of 356 patients without spinal cord injury and 85 traumatic spinal cord injury patients, individuals with plasma inducible protein-10 levels more than or equal to 730 pg/mL had significantly prolonged hospital and ICU stay and days on mechanical ventilator versus patients with plasma inducible protein-10 level less than 730 pg/mL.

Conclusion: This is the first study to compare the dynamic systemic inflammatory responses of traumatic spinal cord injury patients versus patients without spinal cord injury, suggesting a key role for inducible protein-10 in driving systemic interleukin-10 and morbidity and highlighting the potential utility of in silico tools to identify key inflammatory drivers.

1Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA.

2Department of Surgery, University of Pittsburgh, Pittsburgh, PA.

3Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA.

4Department of Sports Medicine and Nutrition, University of Pittsburgh, Pittsburgh, PA.

5Department of Rehabilitation Science and Technology, University of Pittsburgh, Pittsburgh, PA.

6Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA.

* See also p. 1566.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Table S2 can be viewed here: Supplemental Digital Content 2, http://links.lww.com/CCM/A867.

Dr. Almahmoud received support for article research from National Institutes of Health (NIH). Dr. Mi received grant support from the NIH (grant P50-GM-53789-08) and support for article research from NIH. Dr. Brienza received support for article research from the Department of Education. His institution received grant support from National Institute on Disability and Rehabilitation Research (NIDRR) (grant H133E070024). Dr. Billiar is employed by UPMC, received textbook royalties from McGraw-Hill, received support for development of educational presentations (SAB member), has stock options with Immunetrics Medinos, and received support for article research from NIH. His institution received grant support from NIH. Dr. Vodovotz has stock options with Immunetrics and received support for article research from NIH and NIDRR. His institution received grant support from NIH (grant P50-GM-53789) and NIDRR (grant H133E070024). The remaining authors disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: vodovotzy@upmc.edu

© 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins