Search Results

You are looking at 1 - 8 of 8 items for

  • Author or Editor: Jan M. Schwab x
Clear All Modify Search
Restricted access

Jan M. Schwab, Rudi Beschorner, Richard Meyermann, Fatma Gözalan and Hermann J. Schluesener

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.

Restricted access

Sabine Conrad, Hermann J. Schluesener, Mehdi Adibzahdeh and Jan M. Schwab

Object. The glial scar composed of astrogliosis and extracellular matrix deposition represents a major impediment to axonal regeneration. The authors investigated the role of a novel profibrotic and angiogenic peptide connective tissue growth factor (CTGF [Hcs24/IGFBP-r2P]) in glial scar formation following spinal cord injury (SCI) in rats.

Methods. The effects of SCI on CTGF expression during glial scar maturation 1 day to 1 month post-SCI were investigated using fluorescein-activated cell sorter (FACS) immunohistochemical analysis; these findings were compared with those obtained in sham-operated (control) spinal cords.

The CTGF-positive cells accumulated at the spinal cord lesion site (p < 0.0001) corresponding to areas of glial scar formation. In the perilesional rim, CTGF expression was confined to invading vimentin-positive, glial fibrillary acidic protein (GFAP)—negative fibroblastoid cells, endothelial and smooth-muscle cells of laminin-positive vessels, and GFAP-positive reactive astrocytes. The CTGF-positive astrocytes coexpressed the activation-associated intermediate filaments nestin, vimentin (> 80%), and mesenchymal scar component fibronectin (50%).

Conclusions. The restricted accumulation of CTGF-reactive astrocytes and CTGF-positive fibroblastoid cells lining the laminin-positive basal neolamina suggests participation of these cells in scar formation. In addition, perilesional upregulation of endothelial and smooth-muscle CTGF expression points to a role in blood—brain barrier function modulating edema-induced secondary damage.

Restricted access

Christian A. Mueller, Hermann J. Schluesener, Sabine Conrad, Torsten Pietsch and Jan M. Schwab

Object

Spinal cord injury (SCI) elicits a strong inflammatory response that readily participates in lipid oxygenation, edema formation, apoptotic cell death, and tissue remodeling. Because cytokines determine the postinjury inflammatory milieu, the authors analyzed the expression of the immunomodulatory chemokine interleukin-16 (IL-16) after SCI.

Methods

The authors detected a highly significant, persistent, lesional accumulation of parenchymal IL-16+ microglia/macrophages, which reached a maximal level 3 days postinjury compared with control rats. The majority of cells that demonstrated positive labeling for IL-16 also had positive labeling for ED1 (> 70%) and OX-8/CD8; these cells exhibited the morphological hallmarks of activated microglia/macrophages and pronounced MHC Class II expression. In contrast to IL-16+ED1+ cells, IL-16+ microglia/macrophages that coexpressed OX-8 were exclusively seen in the pannecrotic lesion core. In addition, clustering of IL-16+ cells was observed in perivascular Virchow–Robin-like spaces in areas of the primary injury (lesion core) and in immediately adjacent areas of secondary injury. Furthermore, on Day 3 postinjury, IL-16+ microglia/macrophages were frequently observed in a perineuronal position.

Conclusions

The early lesional accumulation of IL-16+ microglia/macrophages suggests a role for IL-16 in the early postinjury immune response such as recruitment and activation of immune cells, leading to microvessel clustering and secondary damage progression.

Restricted access

Christian A. Mueller, Sabine Conrad, Hermann J. Schluesener, Torsten Pietsch and Jan M. Schwab

Object.

Spinal cord injury (SCI) induces the disruption of neural and vascular structures. In contrast to the emerging knowledge of mechanisms regulating the onset of the postinjury angiogenic response, little is known about counterregulatory signals.

Methods.

Using immunohistochemical methods, the authors investigated the expression of the endogenous angiogenic inhibitor endostatin/collagen XVIII during the tissue remodeling response to SCI.

Results.

After SCI, endostatin/collagen XVIII+ cells accumulated at the lesion site, in pannecrotic regions (especially in areas of cavity formation), at the lesion margin/areas of ongoing secondary damage, and in perivascular Virchow–Robin spaces. In remote areas (> 0.75 cm from the epicenter) a more modest accumulation of endostatin/collagen XVIII+ cells was observed, especially in areas of pronounced Wallerian degeneration. The numbers of endostatin/collagen XVIII+ cells reached their maximum on Day 7 after SCI. The cell numbers remained elevated in both, the lesion and remote regions, compared with control spinal cords for 4 weeks afterwards. In addition to being predominantly confined to ED1+-activated microglia/macrophages within the pannecrotic lesion core, endostatin/collagen XVIII expression was frequently detected by the endothelium/vessel walls. Numbers of lesional endostatin/collagen XVIII+ endothelium/vessel walls were found to increase early by Day 1 postinjury, reaching their maximum on Day 3 and declining subsequently to enhanced (above control) levels 30 days after SCI.

Conclusions.

The authors detected that in comparison to the early expression of neoangiogenic factors, there was a postponed lesional expression of the antiangiogenic endostatin/collagen XVIII. Furthermore, the expression of endostatin/collagen XVIII was localized to areas of neovascular pruning and retraction (cavity formation). The expression of endostatin/collagen XVIII by macrophages in a “late” activated phagocytic mode suggests that this factor plays a role in counteracting the preceding “early” neoangiogenic response after SCI.