Persistent accumulation of cyclooxygenase-1—expressing microglial cells and macrophages and transient upregulation by endothelium in human brain injury

Abstract

Object. Secondary damage after central nervous system (CNS) injury is driven in part by oxidative stress and CNS inflammation and is substantially mediated by cyclooxygenases (COXs). To date, the rapidly inducible COX-2 isoform has been primarily linked to inflammatory processes, whereas expression of COX-1 is confined to physiological functions. The authors report the differential localization of COX-1 in human traumatic brain injury (TBI). Methods. Differential cellular COX-1 protein expression profiles were analyzed following TBI in 31 patients and compared with neuropathologically unaltered control brains by using immunohistochemistry. In these patients with TBI, a significant increase of COX-1 protein expression by vessel endothelial and smooth-muscle cells and CD68+ microglia/macrophages was observed to be strictly confined to the lesion. Accumulation of COX-1+ microglia/macrophages in the lesion was already evident 6 hours postinjury, reaching maximal levels after several weeks and remaining elevated at submaximal levels for several months after injury. Furthermore, COX-1+ cell clusters were located in the Virchow—Robin space during the leukocyte infiltration period from Days 4 to 8 after TBI. Double-labeling experiments confirmed coexpression of COX-1 by CD68+ microglia/macrophages. The numbers of COX-1+ vessel endothelial and smooth-muscle cells increased from Day 1, remaining at submaximal levels for months after injury. Conclusions. The prolonged accumulation of COX-1+ microglia/macrophages that were restricted to perilesional areas affected by the acute inflammatory response points to a role of COX-1 in secondary injury. The authors have identified localized, accumulated COX-1 expression as a potential pharmacological target following TBI. Their results challenge the current paradigms of a selective COX-2 role in the postinjury inflammatory response.