Search

Inflammatory cellular responses to brain injury are promoted by proinflammatory messengers. Cyclooxygenases (prostaglandin endoperoxide H synthases [PGH]) are key enzymes in the conversion of arachidonic acid into prostanoids, which mediate immunomodulation, mitogenesis, apoptosis, blood flow, secondary injury (lipid peroxygenation), and inflammation. Here, we report COX-1 expression following brain injury. In control brains, COX-1 expression was localized rarely to brain microglia/macrophages. One to 5 days after injury, we observed a highly significant (p < 0.0001) increase in COX-1+ microglia/macrophages at perilesional areas and in the developing core with a delayed culmination of cell accumulation at day 7, correlating with phagocytic activity. There, cell numbers remained persistently elevated up to 21 days following injury. Further, COX-1+ cells were located in perivascular Virchow-Robin spaces also reaching maximal numbers at day 7. Lesion-confined COX-1+ vessels increased in numbers from day 1, reaching the maximum at days 5-7. Double-labeling experiments confirmed coexpression of COX-1 by ED-1+ and OX-42+ microglia/ macrophages. Transiently after injury, most COX-1+ microglia/macrophages coexpress the activation antigen OX-6 (MHC class II). However, the prolonged accumulation of COX-1+, ED-1+ microglia/macrophages in lesional areas enduring the acute postinjury inflammatory response points to a role of COX-1 in the pathophysiology of secondary injury. We have identified localized, accumulated COX-1 expression as a potential pharmacological target in the treatment of brain injury. Our results suggest that therapeutic approaches based on long-term blocking including COX-1, might be superior to selective COX-2 blocking to suppress the local synthesis of prostanoids.

In brain injury, the primary trauma is followed by a cascade of cellular and molecular mechanisms resulting in secondary injury and scar formation. Astrogliosis and expression of transforming growth factor beta (TGF-beta) are key components of scar formation. A cytokine mediating the effects of TGF-beta is connective tissue growth factor (CTGF), a fibrogenic peptide encoded by an immediate early gene with suggested roles in tissue regeneration and aberrant deposition of extracellular matrix. In order to investigate CTGF in traumatic lesions, we evaluated 20 human brains with traumatic brain injury (TBI) and 18 rat brains with stab wound injury. Compared to remote areas and unaltered control brains, CTGF+ cells accumulated in border zones of the traumatic lesion site (p < 0.0001). In the direct peri-lesional rim, CTGF expression was confined to invading vimentin+, GFAP- fibroblastoid cells, endothelial and smooth muscle cells of laminin+ vessels, and GFAP+ reactive astrocytes. In the direct peri-lesional rim, CTGF+ astrocytes (>80%) co-expressed the activation associated intermediate filaments nestin and vimentin. In injured rat brains, numbers of CTGF+ cells peaked at day 3 and 7 and decreased to almost base level 3 weeks postinjury, whereas in humans, CTGF+ cells remained persistently elevated up to 6 months (p < 0.0001). The restricted accumulation of CTGF+-reactive astrocytes and CTGF+ fibroblastoid cells lining the adjacent laminin+ basal lamina suggests participation of these cells in scar formation. Furthermore, peri-lesional upregulation of endothelial CTGF expression points to a role in blood-brain barrier function and angiogenesis. In addition, CTGF appears to be a sensitive marker of early astrocyte activation.

The induction of heat shock protein 72 (hsp72) has been described in various experimental models of brain injury. The present study examined hsp72 expression patterns within the rodent cerebral cortex in experimental paradigms designed to mimic two mechanisms of damage produced by penetration of the cerebral cortex: (1) tissue tearing from the missile track and (2) diffuse excitotoxicity during temporary cavitation and shock wave formation. Adult male Spaque-Dawley rats received controlled penetration (stab) or injection of the NMDA receptor excitotoxin, quinolinic acid (QA), into the frontal cortex and were killed 1-24 h later. Tissue from the lesioned, sham-operated, or contralateral uninjected cortex was processed for Western and immunocytochemical analyses of hsp72 protein expression. By 12 h, both controlled penetration and excitotoxic brain injuries produced significant increases in hsp72 immunoreactivity, which decreased toward control levels at 24 h. However, the severity and regional distribution of hsp72 expression varied between the two models. Specifically, the controlled penetration injury produced many hsp72-expressing cells near the needle track, while immunoreactive cells within the QA-injected cortex were found in the periphery of the lesion site. Morphological assessment of brain sections subjected to dual-labeling procedures demonstrated that cells expressing hsp72 were primarily neuronal in both models of injury. These results suggest that although controlled penetration and diffuse excitotoxicity may induce similar temporal and cellular patterns of hsp72 expression, the spatial location of hsp72-immunoreactive cells may differ between the two models.