Secondary Cell Death and the Inflammatory Reaction After Dorsal Hemisection of the Rat Spinal Cord

Abstract

Local spinal cord lesions are often greatly enlarged by secondary damage, a process which leads to massive additional cell death. This process is poorly understood. In order to investigate which types of cells could play a role in increasing the size of the lesion, we have analysed the events occurring at rat spinal cord lesion sites from 1 h to 3 months after partial transection using cell type‐specific markers. One hour after transection, the lesion site was small and corresponded to the zone of primary mechanical damage. Extravasation of blood and an opening of the blood – brain barrier occurred. Rapidly thereafter, at 3 and 6 h, an area of secondary cell death developed around the zone of the primary lesion. This secondary cell death, which was probably largely of the necrotic type, affected neurons, macroglia and microglial cells indiscriminately. It was virtually complete at 12 h. Recruitment of inflammatory cells followed a time course which lagged behind that of secondary cell death. Adhesion of neutrophils to the inside of blood vessels was observed at 3 h. They appeared in large numbers at 6 h at the site of the primary lesion, but not yet in the area of secondary cell death. They were numerous throughout the lesion site at 24 h and then disappeared rapidly. Proliferation and recruitment of macrophages and microglial cells became predominant 2 days after injury. Their density was highest within the lesion site between 4 and 8 days. Very few astrocytes were present in the lesion site during the first week. In contrast, the surrounding area contained numerous activated astrocytes, which began to delineate the lesion site. After 2 weeks, the microglial cells and macrophages progressively disappeared from the lesion site, and a cavity formed. A glial scar surrounded this cavity and consisted of reactive astrocytes and activated microglial cells. The time course of the cellular reactions observed here suggests that secondary damage is not primarily due to destructive effects of neutrophils and macrophages. The inflammatory process after spinal cord transection is qualitatively similar to that observed outside the CNS. Inflammatory cells, which can release cytokines and growth factors, could play important roles in protective reactions of the tissue and glial scar formation.