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(Stroke. 2002;33:795.)
© 2002 American Heart Association, Inc.

Original Contributions

Hypoxic-Ischemic Injury Induces Macrophage Inflammatory Protein-1 Expression in Immature Rat Brain

Rita M. Cowell, BS; Haiyan Xu, MS; John M. Galasso, PhD Faye S. Silverstein, MD

From the Departments of Pediatrics and Neurology (H.X., F.S.S.), Neuroscience Program (R.M.C., F.S.S.), and Medical School (J.M.G., F.S.S.), University of Michigan, Ann Arbor, Mich.

Correspondence to Faye S. Silverstein, MD, 8301 MSRB III, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-0646. E-mail fsilvers{at}med.umich.edu

Background and Purpose— Macrophage inflammatory protein (MIP)-1 is a well-characterized monocyte chemoattractant; its role in regulating monocyte and microglial recruitment and activation in the injured neonatal brain is unknown. We evaluated the impact of acute hypoxic-ischemic (HI) brain injury on the expression of MIP-1 in neonatal rat brain.

Methods— To elicit forebrain ischemic injury, 7-day-old (P7) rats underwent right carotid ligation, followed by 2.5 hours of 8% oxygen exposure. We used an enzyme-linked immunosorbent assay and immunohistochemistry to detect MIP-1; double-labeling immunofluorescence assays were analyzed with confocal microscopy to identify cellular sources of MIP-1. Immunocytochemistry assays were also used to detect 2 MIP-1 receptors, CCR1 and CCR5.

Results— We found marked increases in tissue concentrations of MIP-1 in the HI cerebral hemisphere, peaking from 8 to 72 hours after lesioning. Immunocytochemistry assays revealed that MIP-1 was constitutively expressed in physiologically activated microglia; from 8 to 120 hours after lesioning, MIP-1 immunoreactive monocytes and microglia accumulated in the lesion territory. In immunoreactive cells, MIP-1 was diffusely distributed throughout the cytoplasm at early post-HI time intervals; by 72 hours, MIP-1 immunoreactivity was typically concentrated adjacent to the nucleus, a pattern indicative of active MIP-1 production. In P7 to P12 brain, many cells expressed MIP-1 receptors; both CCR1 and CCR5 immunoreactivity were localized to endothelium and ependyma; CCR1-immunoreactive astrocytes and neurons and CCR5-immunoreactive microglia were also identified.

Conclusions— These data implicate MIP-1 as a mediator of the complex and sustained inflammatory response initiated by perinatal HI braininjury.

Key Words: astrocytes • chemokines • endothelium • neonate • receptors, chemokine • rats

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