The recruitment of leukocytes to the sites of inflammation and leukocyte-derived inflammatory mediators contributes to the development of tissue injury associated with inflammatory diseases. The first step in the pathogenesis of inflammatory conditions is adhesion of circulating leukocytes to activated vascular endothelial cell in the inflamed tissues and subsequent transmigration through the endothelial cells. During these processes, leukocytes are activated to secrete a variety of substances such as growth factors, chemokines and cytokines, complement components, proteases, nitric oxide, and reactive oxygen metabolites, which are considered to be one of the primary sources of the tissue injury. Prevention or reduction of leukocyte-endothelial cell adhesion often results in a profound attenuation of the microvasculature and parenchymal cell dysfunction in various animal models of human inflammatory diseases. It has been shown that all aspirin-like non-steroidal anti-inflammatory agents share at least one characteristic in that all of these agents diminish the adhesive interactions required for the accumulation of leukocytes at the site of inflamed tissue. The challenge for future investigations will need to be carefully examined: the relations between leukocyte and endothelial cell interactions, the mechanisms of activation of leukocytes and endothelial cells, and the components of the signaling pathways. Information related to these topics will allow a better understanding of the role of leukocytes in inflammatory tissue injury and the development of novel therapeutic strategies.

The mechanisms which lead to secondary brain damage following transient ischaemia are incompletely defined. As discussed in this hypothesis article, the events which lead to such damage could encompass (a) a perturbed membrane handling of calcium, leading to a slow, gradual increase in the free cytosolic calcium concentration (Ca2+i), with subsequent calcium overload of mitochondria, (b) a sustained reduction of protein synthesis which, in the long run, deprives cells of enzymes or trophic factors essential to their survival, or (c) the initiation of an inherent program for cell death.

Results obtained in ischaemia of brief to intermediate duration demonstrate that the ultimate cell death is heralded by a reduction in the respiratory capacity of isolated mitochondria. However, the results fail to demonstrate whether or not such a reduction precedes deterioration of the bioenergetic state which then precipitates cell death. Cyclosporin A (CsA) has recently been shown to dramatically improve the delayed CA1 damage following transient forebrain ischaemia. Since CsA is known to block a deleterious permeability transition (PT) in mitochondria from several tissues in response to calcium accumulation and oxidative stress, the results on CsA effects in forebrain ischaemia support a mitochondrial origin for the delayed cell death. Furthermore, comparisons with the effects of CsA and α-phenyl-N-tert-butyl nitrone (PBN) in thymocytes and other cells undergoing programmed cell death suggest that delayed neuronal damage occurs by a sequence of events akin to those leading to apoptotic cell death. However, whether cell death is apoptotic or necrotic may depend on the severity of the insult (and its duration). We speculate that the initial ischaemic transient leads to gradual mitochondrial calcium overload, the latter triggering a PT, and apoptotic or necrotic cell death.

Since similar results have been obtained in normoglycaemic animals subjected to ischaemia of intermediate duration, and in animals with preischaemic hyperglycaemia, it seems likely that both increased ischaemia duration and hyperglycaemia accelerate damage to mitochondria in the reperfusion period.

Recent results obtained in transient focal ischaemia of 2 h duration demonstrate that the free radical spin trap PBN reduces infarct size, even when given 1 or 3 h after the start of reperfusion, thus providing a second window of therapeutic possibility. A major effect of the drug is exerted on the recovery of energy metabolism of the tissue since it reduces a secondary deterioration in the bioenergetic state, occurring after 2–4 h of reperfusion. At least in part, the spin trap may exert its effect by reducing microvascular dysfunction caused by oedema and to adhesion of polymorphonuclear (PMN) leucocytes, which give rise to an inflammatory response mediated by cytokines, lipid mediators, or free radicals. This contention is supported by the reduction in focal ischaemic damage by antibodies to adhesion molecules for PMNs. However, it has now been found that the secondary deterioration of the bioenergetic state of core and penumbral tissues are mirrored by corresponding changes in the respiratory functions of isolated mitochondria, suggesting that, also in this type of ischaemia, the mitochondria suffer secondary damage. It is conceivable that a significant fraction of malfunctioning mitochondria emanate from microvascular tissue, explaining why antibodies to adhesion molecules mitigate the ischaemic lesions.

In the past 10 years, the management of brain injury has shown several advances. Besides new diagnostic tools many new tentative approaches have been investigated, such as jugular bulb measurement of oxygen and lactate differences and near-infrared spectroscopy. The latest tool is microdialysis, which uses a probe as an interface to the brain. This method uses internally perfused semi-permeable membrane probes, which allow neurochemical water-soluble substances to be collected outside the brain for further analysis. Since the late 1980s the first results of microdialysis in neurointensive care show that chemical substances such as lactate, glucose, amino acids, metabolites of several biochemical mechanisms and electrolytes are measurable. This heterogeneous approach now waits for validation for clinical use and for the most challenging aspect, the clinical interpretation and use to improve therapy. The aim of this review is to describe the state of the art of this new technique, including our own experiences and concepts.

Subarachnoid haemorrhage (SAH) following cerebral aneurysm rupture or trauma can result in the induction of secondary ischaemic brain damage via a decrease in microvascular perfusion, a disruption of the blood-brain barrier and consequent vasogenic oedema, and the delayed spasm of the major cerebral arteries (i.e. vasospasm). It is increasingly apparent that oxygen radical-induced, iron-catalyzed lipid peroxidation (LP) within the subarachnoid blood and vascular wall plays a key role in the occurrence of these secondary events. Tirilazad mesylate is a potent cytoprotective inhibitor of LP that works by a combination of radical scavenging and membrane stabilizing properties. It has been demonstrated to attenuate the acute and delayed vascular consequences of SAH and to protect the brain against ischaemic insults. Much of its action is mediated by an effect on the vascular endothelium, although it also appears to exert some direct neuroprotection and to inhibit LP in the subarachnoid blood. These actions of tirilazad in experimental SAH are reviewed.

The precise mechanisms underlying secondary brain damage after traumatic injury to the central nervous system (CNS) are not well understood, and delayed neuronal injury may result from pathological changes in neurotransmitter release, synthesis or generation of endogenous autodestructive neurochemicals and/or inflammatory mediators, or alterations in endogenous protective or trophic factors. Recent identification of such factors and the elucidation of the timing of the neurochemical cascade following CNS injury provides a window of opportunity for therapeutic intervention with pharmacological compounds which modify synthesis, release, receptor binding or physiological activity of neurotoxic factors. A number of recent experimental studies have reported that pharmacological modification of the post-traumatic neurochemical milieu can promote functional recovery in a variety of animal models of CNS trauma. This paper summarizes recent work suggesting that pharmacological manipulation of several key neurotransmitter and neurochemical systems can attenuate neuronal damage and improve functional outcome associated with traumatic brain injury.