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Journal of Neuroscience, Vol 9, 4416-4429, Copyright © 1989 by Society for Neuroscience
The role of mononuclear phagocytes in wound healing after traumatic injury to adult mammalian brain
D Giulian, J Chen, JE Ingeman, JK George and M Noponen
Department of Neurology, Baylor College of Medicine, Houston, Texas 77031.
We monitor cellular responses to a penetrating wound in the cerebral cortex
of adult rat during the first weeks after injury. Two classes of activated
mononuclear phagocytes containing acetylated low-density lipoprotein
(ac-LDL) receptors appear within hours at the wound site. One type of cell
surrounding the lesion edge had thin, delicate processes and is identical
in appearance to ramified microglia found in developing brain. Within the
lesion, round cells are recognized as blood-borne macrophages when labeled
by intravenous injection of carbon particles. Thus, both process-bearing
reactive microglia and invading macrophages respond to brain trauma. The
greatest number of ac-LDL(+) or nonspecific esterase(+) mononuclear
phagocytes appears 2 days after injury within the wound site and are
associated with a peak production of the cytokine interleukin-1 (IL-1).
Because intracerebral infusion of IL-1 is known to stimulate astrogliosis
and neovascularization (Giulian et al., 1988), we examine the time course
of injury-induced reactive astrogliosis and angiogenesis. A 5-fold increase
in the number of reactive astroglia is found at 3 d and a marked
neovascularization at 5 d after injury. During the first week, mononuclear
phagocytes engulf particles and clear them from the wound site either by
migrating to the brain surface or by entering newly formed brain
vasculature. To investigate further the role of reactive brain mononuclear
phagocytes in CNS injury, we use drugs to inhibit trauma-induced
inflammation. When applied in vivo, chloroquine or colchicine reduce the
number of mononuclear phagocytes in damaged brain, help to block reactive
astrogliosis and neovascularization, and slow the rate of debris clearance
from sites of traumatic injury. In contrast, the glucocorticoid
dexamethasone neither reduces the number of brain inflammatory cells nor
hampers such responses as phagocytosis, astrogliosis, neovascularization,
or debris clearance in vivo. Our observations show that mononuclear
phagocytes play a major role in wound healing after CNS trauma with some
events controlled by secretion of cytokines. Moreover, certain classes of
immunosuppressive drugs may be useful in the treatment of acute brain
injury.
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