Current aspects of pathophysiology and cell dysfunction after severe head injury.

Traumatic brain injury is a major health problem in all developed countries. The main aim of this review is to provide a short update on the most recent advances in our knowledge of the brains response to mechanical injuries, focusing on metabolic, cellular, subcellular, and molecular events that take place in severe head injuries. Knowledge of these events is essential for a better understanding of new pharmacological avenues and non-pharmacological strategies, such as moderate hypothermia, which are being developed to improve the outcome of this silent epidemic. We will focus on several topics that we consider to be the most significant: diffuse axonal injury, ischemia and the cascades it generates, metabolic derangements, excitotoxicity, oxidative stress, and other phenomena that have been included in the term tertiary injuries. Recent evidence has clearly demonstrated that traumatic brain lesions are highly dynamic and that the different lesions observed after closed head injury are not single events but processes set in motion by the mechanical impact. These processes are not finished until an unpredictable time after injury. We will discuss recent evidence showing that in diffuse axonal injury, primary immediate damage can coexist with axons that, although initially intact, may be evolving towards secondary disconnection. The concept of ischemic penumbra and the more recent concept of traumatic penumbra are discussed, together with recent experimental and clinical data that shed light on the non-ischemic forms of brain hypoxia. The role of excitotoxicity in mechanically-induced cell death and the molecular events that excessive release of glutamate induce, including apoptosis and delayed inflammatory processes, are reviewed. Finally, new knowledge on how central nervous system cells regulate their volume, the new family of channel water molecules known as aquaporins and their possible role in the physiopathology of the swollen brain are discussed. Basic and clinical investigations are still needed to translate the huge amount of pathophysiological knowledge acquired in the last decade into effective treatments for these patients.