Research ReportDynamic changes of inflammatory markers in brain after hemorrhagic stroke in humans: A postmortem study
Introduction
Intracerebral hemorrhage (ICH) is one of the most common and devastating types of stroke. ICH causes secondary brain damage through various pathways, including inflammation-related mechanisms, the local release of reactive oxygen species (ROS), and activation of proteolytic enzymes (Wang & Doré, 2007, Xi et al., 2006). Nuclear factor-kappa B (NF-κB) is exquisitely sensitive to ROS and is rapidly activated in perihematomal brain after ICH in rats (Hickenbottom et al., 1999, Wagner, 2007). Activation of NF-κB leads to rapid and coordinated induction of proteolytic enzymes and release of proinflammatory cytokines and chemokines (Wagner, 2007). Most preclinical studies have indicated that proteolytic enzyme matrix metalloproteinase (MMP)-9 has a detrimental role (Rosenberg & Navratil, 1997, Wang & Tsirka, 2005, Xue et al., 2009). In addition, several clinical studies have assessed blood MMP-9 levels in patients with acute spontaneous ICH and found that the increase in blood MMP-9 levels within 12 or 24 h after stroke onset is associated with subsequent enlargement of the hematoma, perihematomal edema, and deterioration of neurologic function (Abilleira et al., 2003, Alvarez-Sabin et al., 2004, Castellazzi et al., 2010, Silva et al., 2005). In our own studies using a blood model of ICH in rats, we found that NF-κB activation and expression of macrophage inflammatory protein (MIP)-2 and MMP-9 were increased at 3 h and reached a maximum at 2 days after ICH (Wu et al., 2008, Wu et al., 2009).
To date, relatively little ICH histopathologic data have been obtained from human post-mortem specimens (Wang and Doré, 2007). There are no reports regarding NF-κB or MIP-2, and only two reports on MMP-9 in human ICH brain (Rosell et al., 2006, Tejima et al., 2007). The purpose of this histopathologic case-control study was to characterize the dynamic changes of the protein expression of NF-κB/p65 subunit, MIP-2, and MMP-9 by immunohistochemistry in postmortem brains of patients with and without ICH.
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Histologic examination
In the postmortem human brain tissue, normal morphology of hippocampal CA1 neurons was observed in the brain sections from the control group (Fig. 1A); few morphologic changes were observed in hippocampal CA1 neurons at 2 h after ICH (Fig. 1B). At 24 h, obvious histopathologic changes were observed (Fig. 1C). Some neurons were pyknotic and triangular. Some neurons exhibited nuclear swelling and incomplete cellular structures. The inflammatory cells that had infiltrated the area were mainly
Discussion
We systematically assessed the protein expression of NF-κB/p65, MIP-2, and MMP-9 to elucidate the changes that occur after ICH in a histopathologic study of patients with and without ICH. By using immunohistochemistry, we found that NF-κB/p65, MIP-2, and MMP-9 protein expression increased on the injured side of the hippocampus over the course of 2 h to 5 days after ICH. The expression of these three markers was also upregulated, although to a lesser extent, on the uninjured side of the
Collection of human brain tissue
All specimens were from the brain bank in the Department of Neuropathology, the First Hospital of Harbin Medical University, China. Sections of formaldehyde-fixed human brains were obtained from 30 fatal cases of ICH (age at death, 36–70 years; 20 male; 10 female; Table 2). Patients with hematoma secondary to head injury, congenital or acquired coagulation abnormalities, known acute or chronic infections, inflammatory or malignant diseases, or immunosuppressive treatment were excluded from the
Acknowledgments
This work was supported by the Natural Science Foundation of Heilongjiang ProvinceZJY0705 and the Foundation of the First Clinical Hospital of Harbin Medical UniversityY08-009 (HW); and AHA09BGIA2080137 and NIHK01AG031926 (JW).
We thank Claire Levine for assistance with this manuscript.
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These authors contributed equally to the work.