Systematic model of peripheral inflammation after subarachnoid hemorrhage

Jude Savarraj

Kaushik Parsha

Georgene Hergenroeder

Liang Zhu

Dong Kim+2 authors

Objective:

To investigate inflammatory processes after aneurysmal subarachnoid hemorrhage (aSAH) with network models.

Methods:

This is a retrospective observational study of serum samples from 45 participants with aSAH analyzed at multiple predetermined time points: <24 hours, 24 to 48 hours, 3 to 5 days, and 6 to 8 days after aSAH. Concentrations of cytokines were measured with a 41-plex human immunoassay kit, and the Pearson correlation coefficients between all possible cytokine pairs were computed. Systematic network models were constructed on the basis of correlations between cytokine pairs for all participants and across injury severity. Trends of individual cytokines and correlations between them were examined simultaneously.

Results:

Network models revealed that systematic inflammatory activity peaks at 24 to 48 hours after the bleed. Individual cytokine levels changed significantly over time, exhibiting increasing, decreasing, and peaking trends. Platelet-derived growth factor (PDGF)-AA, PDGF-AB/BB, soluble CD40 ligand, and tumor necrosis factor-α (TNF-α) increased over time. Colony-stimulating factor (CSF) 3, interleukin (IL)-13, and FMS-like tyrosine kinase 3 ligand decreased over time. IL-6, IL-5, and IL-15 peaked and decreased. Some cytokines with insignificant trends show high correlations with other cytokines and vice versa. Many correlated cytokine clusters, including a platelet-derived factor cluster and an endothelial growth factor cluster, were observed at all times. Participants with higher clinical severity at admission had elevated levels of several proinflammatory and anti-inflammatory cytokines, including IL-6, CCL2, CCL11, CSF3, IL-8, IL-10, CX3CL1, and TNF-α, compared to those with lower clinical severity.

Conclusions:

Combining reductionist and systematic techniques may lead to a better understanding of the underlying complexities of the inflammatory reaction after aSAH.

Supplementary Material

Data Supplement:

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From the University of Texas Health Science Center at Houston.

^{Corresponding author.}

Correspondence to Dr. Choi: ude.cmt.htu@iohC.A.nhamiuH

Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

From the University of Texas Health Science Center at Houston.

Correspondence to Dr. Choi: ude.cmt.htu@iohC.A.nhamiuHGo to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

Received 2016 Aug 19; Accepted 2016 Nov 16.

Abstract

Objective:

To investigate inflammatory processes after aneurysmal subarachnoid hemorrhage (aSAH) with network models.

Methods:

Results:

Conclusions:

Combining reductionist and systematic techniques may lead to a better understanding of the underlying complexities of the inflammatory reaction after aSAH.

Abstract

Aneurysmal subarachnoid hemorrhage (aSAH) affects ≈30,000 people annually and accounts for 10% to 15% of all strokes.¹ Despite improvements in clinical management, morbidity after aSAH remains high. Studies have shown that early elevation of central and peripheral inflammatory cytokines is associated with delayed neurologic deteriorations.² However, such studies typically use methods to examine differences in concentrations of individual cytokines across disease severity or clinical outcomes. They fail to account for the complexities and redundancies that arise from cytokine interactions inherent to the immune reaction.³,⁴ In addition to examining individual cytokines, investigating associations between them can lead to a better understanding of the inflammatory process after aSAH. A systematic approach based on network theory can offer insights into the multifactorial relationships and can delineate the complexities underlying inflammatory processes.⁵

We propose a data-driven model of immune response at different acute time periods after aSAH. The initial time period after aneurysm rupture (<72 hours), also known as the early brain injury phase, has recently become the focus of investigation⁶ because it is implicated in delayed neurologic deterioration and poor outcomes. Uncontrolled inflammation is posited to contribute to clinical worsening during the early brain injury phase, manifesting clinically as poor neurologic status.⁷,⁸ Hence, in addition to the examination of inflammation at different times, we investigate systematic differences across clinical status at admission. While some studies have used similar techniques to model the inflammatory condition in chronic neurologic conditions,⁹ these techniques have not been fully explored in acute aSAH research.

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ACKNOWLEDGMENT

The investigators thank the Vivian L. Smith Center for Neurologic Research and the Neuroscience Research Repository for assistance with obtaining the specimens.

ACKNOWLEDGMENT

GLOSSARY

aSAH	aneurysmal subarachnoid hemorrhage
CSF	colony-stimulating factor
DCI	delayed cerebral ischemia
EGF	epidermal growth factor
FGF-2	fibroblast growth factor-2
FLT3L	FMS-like tyrosine kinase 3 ligand
HH	Hunt-Hess
IFN-α2	interferon-α2
IFNG	type-II interferon family
IL	interleukin
MIP	macrophage inflammatory protein
Pcc	Pearson correlation coefficient
PDGF	platelet-derived growth factor
sCD40L	soluble CD40 ligand
SI	similarity index
TNF	tumor necrosis factor
VEGF	vascular endothelial growth factor

GLOSSARY

Footnotes

Supplemental data at Neurology.org

Footnotes

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