This research will investigate to what extent the reparative potential of macrophages exists within the traumatically injured spinal cord. Historically, macrophages have been considered inflammatory scavenger cells in the CNS, capable only of removing cellular debris at sites of injury or infection. Now, many functions have been attributed to these cells including the ability to promote blood vessel growth, myelination, and neurite sprouting/regeneration. Unfortunately, these same cells can promote demyelination and cell injury. How and under what conditions macrophages effect such a broad range of biological functions is not clear, but may result from changes in the lesion microenvironment. It is the major hypothesis of this proposal that the inherent ability of macrophages to promote tissue repair and functional recovery changes as a function of time after spinal cord injury (SCI) and is negatively influenced by the accumulation of blood-borne elements (cells and proteins) at the injury site. Using radiation bone marrow chimeric rats in combination with macrophage and complement-depletion protocols, we will examine how these vascular constituents influence resident (microglia) and recruited (blood-derived) macrophage activation and function. Specifically, the neurotrophic and oxidative capacity of each macrophage subpopulation will be evaluated in vivo using immunohistochemistry and in vitro using cytokines and other factors present in the injury site to trigger macrophage effector functions. Cells exhibiting neurotrophic secretory profiles will be transplanted into injured rat spinal cords to test their ability to promote regeneration and functional recovery. By learning more about the factors that influence macrophage function in the injured CNS, we may be able to harness the innate reparative potential of the inflammatory response (specifically macrophages) to promote functional regeneration. Moreover, we will be determining the feasibility of manipulating an intrinsic component of the injury site to promote tissue repair. Such an approach may be biologically and clinically advantageous and could eliminate the need for chronic drug therapy.
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