RESUMEN
BACKGROUND: Leukocytes are believed to be involved in delayed cell death following traumatic brain injury (TBI). However, data demonstrating that blood-borne inflammatory cells are present in the injured brain prior to the onset of secondary brain damage have been inconclusive. We therefore investigated both the interaction between leukocytes and the cerebrovascular endothelium using in vivo imaging and the accumulation of leukocytes in the penumbra following experimentally induced TBI. METHODS: Experimental TBI was induced in C57/Bl6 mice (n = 42) using the controlled cortical impact (CCI) injury model, and leukocyte-endothelium interactions (LEI) were quantified using both intravital fluorescence microscopy (IVM) of superficial vessels and 2-photon microscopy of cortical vessels for up to 14 h post-CCI. In a separate experimental group, leukocyte accumulation and secondary lesion expansion were analyzed in mice that were sacrificed 15 min, 2, 6, 12, 24, or 48 h after CCI (n = 48). Finally, leukocyte adhesion was blocked with anti-CD18 antibodies, and the effects on LEI and secondary lesion expansion were determined 16 (n = 12) and 24 h (n = 21), respectively, following TBI. RESULTS: One hour after TBI leukocytes and leukocyte-platelet aggregates started to roll on the endothelium of pial venules, whereas no significant LEI were observed in pial arterioles or in sham-operated mice. With a delay of >4 h, leukocytes and aggregates did also firmly adhere to the venular endothelium. In deep cortical vessels (250 µm) LEIs were much less pronounced. Transmigration of leukocytes into the brain parenchyma only became significant after the tissue became necrotic. Treatment with anti-CD18 antibodies reduced adhesion by 65%; however, this treatment had no effect on secondary lesion expansion. CONCLUSIONS: LEI occurred primarily in pial venules, whereas little or no LEI occurred in arterioles or deep cortical vessels. Inhibiting LEI did not affect secondary lesion expansion. Importantly, the majority of migrating leukocytes entered the injured brain parenchyma only after the tissue became necrotic. Our results therefore suggest that neither intravascular leukocyte adhesion nor the migration of leukocytes into cerebral tissue play a significant role in the development of secondary lesion expansion following TBI.
Asunto(s)
Lesiones Encefálicas/patología , Lesiones Encefálicas/fisiopatología , Adhesión Celular/fisiología , Movimiento Celular/fisiología , Leucocitos/patología , Animales , Leucocitos/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Microcirculación/fisiología , Factores de TiempoRESUMEN
The timing of decompressive craniectomy for the treatment of increased intracranial pressure (ICP) after traumatic brain injury (TBI) is a widely discussed clinical issue. Although we showed recently that early decompression is beneficial following experimental TBI, it remains unclear to what degree decompression craniectomy reduces secondary brain damage and if craniectomy is still beneficial when it is delayed by several hours as often inevitable during daily clinical practice. The aim of the current study was therefore to investigate the influence of craniectomy on secondary contusion expansion and brain edema formation and to determine the therapeutic window of craniectomy. Male C57/Bl6 mice were subjected to controlled cortical impact injury. Contusion volume, brain edema formation, and opening of the blood-brain barrier were investigated 2, 6, 12, and 24 h and 7 days after trauma. The effect of decompression craniectomy on secondary brain damage was studied in control mice (closed skull) and in animals craniotomized immediately or with a delay of 1, 3, or 8 h after trauma. Twenty-four hours after trauma, the time point of maximal lesion expansion (+60% vs. 15 min after trauma) and brain edema formation (+3.0% water content vs. sham), contusion volume in craniotomized mice did not show any secondary expansion; that is, contusion volume was similar to that observed in mice sacrificed immediately after trauma (18.3 +/- 5.3 vs. 22.2 +/- 1.4 mm(3)). Furthermore, brain edema formation was reduced by 52% in craniotomized animals. The beneficial effect of craniectomy was still present even when treatment was delayed by up to 3 h after trauma (p < 0.05). The current study clearly demonstrates that early craniectomy prevents secondary brain damage and significantly reduces brain edema formation after experimental TBI. Evaluation of early craniectomy as a therapeutic option after TBI in humans may therefore be indicated.