Protein microarray analysis identifies key cytokines associated with malignant middle cerebral artery infarction.

Zhonghe Zhou,Yaling Han,Cheng Xia,Jinghua Zhang,Xiaoqiu Li,Huisheng Chen

doi:10.1002/brb3.746

Abstract

IntroductionWe aimed to explore potential cytokines involved in the malignant middle cerebral artery infarction (MMI) and elucidate their underlying regulatory mechanisms.MethodsWe first developed a cytokine profile by Quantibody® Human Cytokine Antibody Array7000 using serum samples from eight patients with MMI and eight patients with non‐acute cerebral infarction (NACI). The differentially expressed cytokines were then identified in patients with MMI using two‐tailed Student's t‐test and Fisher's Exact Test compared with patients with NACI. Gene Ontology and pathway enrichment analyses were performed using DAVID. Protein–protein interaction (PPI) network was constructed based on STRING database.ResultsA total of 10 differentially expressed cytokines were identified from 320 unique inflammatory cytokines in serums. Among them, four cytokines, like NCAM1 (neural cell adhesion molecule 1), IGFBP‐6 (insulin‐like growth factor binding protein 6), LYVE1 (lymphatic vessel endothelial hyaluronan receptor 1), and LCN2 (Lipocalin2), were up‐regulated, while another six cytokines, such as TGFB1 (transforming growth factor, beta 1, also known as LAP), EGF (epidermal growth factor), PDGFA (platelet‐derived growth factor alpha polypeptide), MMP‐10 (matrix metallopeptidase 10), IL‐27 (interleukin 27), and CCL2 (chemokine (C‐C motif) receptor 2), were down‐regulated. Moreover, cytokine–cytokine receptor interaction pathway was significantly enriched.ConclusionsOur findings indicate that 10 differentially expressed cytokines, such as NCAM1, LCN2, IGFBP‐6, LYVE1, MMP‐10, IL‐27, PDGFA, EGF, CCL2, and TGFB1 may participate in the development of MMI. Moreover, cytokine–cytokine receptor interaction pathway may be an important mechanism involved in this disease. These differentially expressed cytokines may serve as diagnostic biomarkers or drug targets for MMI.

Highlights

We aimed to explore potential cytokines involved in the malignant middle cerebral artery infarction (MMI) and elucidate their underlying regulatory mechanisms
MMI was diagnosed according to the following criteria: signs on computerized tomography (CT) showed an infarct of at least 50% of the middle cerebral artery territory or infarct volume >145 cm3 on diffusion-weighted images (DWIs); secondary neurological deterioration including consciousness decline was defined by at least 1 point of consciousness item described in the National Institutes of Health Stroke Scale (NIHSS), which was an essential parameter to assess the severity of acute ischemic stroke; patients were hospitalized within 24 hr of disease onset; patients had no history of other brain disorders, such as hemorrhagic cerebral vessel disease, idiopathic epilepsy, intracranial infection, or craniocerebral trauma; and patients had no other infections such as urinary tract infections or pneumonia
We developed cytokine profile using peripheral blood of MMI and non-acute cerebral infarction (NACI) patients and microarray data were analyzed to detect the concentrations of 320s cytokines simultaneously

Summary

| INTRODUCTION

Malignant middle cerebral artery infarction (MMI), a common acute cerebral infarction, is the most devastating form of ischemic stroke with an 80% mortality rate (Huttner and Schwab 2009; Vahedi et al, 2007). It is characterized with large supratentorial infarcts caused by acute occlusion of malignant middle cerebral artery and space- occupying brain edema followed by cerebral herniation (Berrouschot, Sterker, Bettin, K02ster, & Schneider, 1998; Hacke, Schwab, Horn, Spranger, & De GM, 1996). Many approaches, such as thrombolytic drugs, mechanical embolectomy, and angioplasty have been introduced in the therapy of acute cerebral infarction, exploration of effective treatments for MMI remains a great challenge in neurocritical care (Huttner and Schwab 2009). The objective of our study was to explore potential cytokines involved in the MMI and to elucidate their possible regulatory mechanisms in MMI development

| MATERIALS AND METHODS

| DISCUSSION

CONFLICT OF INTEREST

Findings

SIGNIFICANCE STATEMENT