actually reside within the spinal cord. Once these cells are activated, they too remove degenerating fiber tracts and other tissue debris by phagocytosis. They also secrete numerous cytokines, free radicals, and growth factors, which, in turn, affect nearby cells in positive and negative ways (Lindholm et al., 1992; Schnell et al., 1999; Anderson, 2002). The growth factors are critical for neuron survival and tissue repair. However, free radicals and proinflammatory cytokines contribute to expansion of the lesion, worsening the impact of the injury. Activation of macrophages and microglia is sustained over the course of weeks.
The role of lymphocytes in spinal cord injuries is somewhat controversial. Some argue that one type of lymphocyte (autoreactive T-lymphocytes) have destructive properties: according to this schema they exacerbate injury to axons and induce demyelination, leading to functional loss (Popovich and Jones, 2003). Others argue that this lymphocyte is not pathological but, rather, confers protection to the myelin-insulated neurons (Schwartz and Kipnis, 2001; Kipnis et al., 2002). Protection of myelin also protects the integrity of the axon that it insulates.
During the acute phase, the mechanical trauma to the spinal cord causes cells to die instantaneously by necrosis, a process of cell swelling and then cell membrane rupture. Within hours, however, another type of cell death assumes center stage: apoptosis. This very active form of death afflicts neurons, oligodendrocytes, astrocytes, and other cells of the spinal cord after injury (Liu et al., 1997; Beattie et al., 2000). Apoptosis has been detected in humans (Emery et al., 1998) and lasts for about one month in animal models (Beattie et al., 2000). With apoptosis, cells do not swell before death; rather, they condense and break apart into small fragments in a very orderly process that requires energy and protein synthesis. These fragments of the apoptotic cell are engulfed by other cells in a process that prevents spillage of the dying cells’ contents and avoids elicitation of an inflammatory response. Necrotic cell death, on the other hand, elicits inflammation and spills out neurotransmitters and other contents that build to levels toxic enough to harm or kill nearby cells.
What triggers apoptosis after spinal cord injury? An answer to this question would immediately open up new targets for treatments that could prevent apoptosis from occurring. A major trigger appears to be the injury-induced rush of calcium into cells (Young, 1992). Calcium influx activates key enzymes inside the cell—the caspases and calpain—that break down proteins in the internal cytoskeleton and membrane of the cell (Ray et al., 2003). With the destruction of its structural integrity, the cell dies. Yet, apoptosis of cortical motor neurons can occur after the axons centimeters