After acute brain injury there may be increased intracranial production of cytokines, with activation of inflammatory cascades. We have sought to determine if a transcranial cytokine gradient was demonstrable in paired sera of 32 patients requiring intensive care after acute brain injury. The difference between concentrations of IL-1 beta, IL-6, IL-8 and TNF alpha in jugular venous and arterial serum was measured on admission, and at 24, 48 and 96 h after the primary injury. There were no differences in IL-1 beta, IL-8 or TNF alpha, but median gradients of 6.7 and 11.5 pg ml-1 for IL-6 were demonstrated in the traumatic brain injury (n = 22) and subarachnoid haemorrhage (n = 10) groups, respectively (normal values in serum < 4.7 pg ml-1; P < 0.001 both groups). This suggests that there is significant production of IL-6 by intracranial cells after acute brain injury. Therapy directed towards combatting the negative effects of IL-6 may potentially benefit patients who have sustained an acute brain injury.

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Once thought to be relatively shielded from the immunological and inflammatory processes which occur in the tissues of other body systems after acute injury, the brain participates actively in these processes. As a result of trauma, haemorrhage or ischaemia, injury to the brain releases mediators such as the cytokines which activate inflammation and cause further secondary brain injury. Intensive care physicians can do little to alleviate the gravity of the primary injury, but by understanding the mechanisms responsible for secondary injury, and how these mechanisms may, in future, be altered by drug therapy, they may be able to improve patient management and outcome. A primary brain injury stimulates the cells of the central nervous system (CNS) to produce a variety of mediators. Laboratory and human studies have shown that there are at least three important cytokines which are released both by microglia and astrocytes after injury: interleukin-1␤ (IL-1␤), tumour necrosis factor ␣ (TNF␣) and interleukin-6 (IL-6). 67 68 82 These proteins function as intercellular communication molecules and stimulate the reparative process which is termed gliosis. Gliosis, however, results in further production and release of cytokines by hypertrophied astrocytes and microglial cells, in addition to mediators released by cells of the peripheral immune system, such as polymorphonuclear cells (PMN), which migrate across a "leaky" bloodbrain barrier. The net result may therefore be further damage to brain tissue. The first part of this review focuses on the parts played by these cytokines. Leucocyte adhesion molecules, which are expressed on the surface of leucocytes and endothelial cells, control the migration of leucocytes into tissue. The expression of these molecules after brain injury is linked closely to cytokine production. They mediate toxicity in two ways: by causing leucocyte plugging of micro-vessels and by facilitating the release of toxic oxygen-derived free radicals by PMN which migrate into brain tissue as a result of adhesion molecule activity. The second part of this review focuses on the parts played by the adhesion molecules, intercellular adhesion molecule (ICAM)-1, E-selectin, L-selectin, P-selectin and the integrins in brain injury, and on the evidence linking the cytokines to adhesion molecule upregulation. Finally, we shall discuss if anti-cytokine or anti-adhesion molecule therapy may improve outcome after acute brain injury.