Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications

Abstract

Focal cerebral ischaemia and post-ischaemic reperfusion cause cerebral capillary dysfunction, resulting in oedema formation and haemorrhagic conversion. There are substantial gaps in understanding the pathophysiology, especially regarding early molecular participants. Here, we review physiological and molecular mechanisms involved. We reaffirm the central role of Starling's principle, which states that oedema formation is determined by the driving force and the capillary "permeability pore". We emphasise that the movement of fluids is largely driven without new expenditure of energy by the ischaemic brain. We organise the progressive changes in osmotic and hydrostatic conductivity of abnormal capillaries into three phases: formation of ionic oedema, formation of vasogenic oedema, and catastrophic failure with haemorrhagic conversion. We suggest a new theory suggesting that ischaemia-induced capillary dysfunction can be attributed to de novo synthesis of a specific ensemble of proteins that determine osmotic and hydraulic conductivity in Starling's equation, and whose expression is driven by a distinct transcriptional program.Correspondence to: Dr J Marc Simard, Department of Neurosurgery, 22 S. Greene St., Suite 12SD, Baltimore, MD 21201−1595, USA msimard@smail.umaryland.edu. Contributors JMS originated the overall concept for this review and wrote the first and second drafts. TAK contributed to and helped edit the first and second drafts, and supplied important citations. MC participated in the original work on the sections on the NC Ca-ATP channel and contributed to the first draft. KVT did the computer analysis of the gene promoter regions. VG engaged in numerous intellectual exchanges with JMS during formulation of concepts for this review.Conflict of interest JMS and MC have applied for a US patent, "A novel non-selective cation channel in neural cells and methods for treating brain swelling" (application number 10/391,561). NIH Public Access

Novel Treatment Targets for Cerebral Edema

“…Although it is not optimal to use historical terms to describe new paradigms, conventional terms remain useful for differentiating the sequential events in edema development. After brain injury, alterations in ionic gradients lead to a step-wise temporal progression from what is known as cytotoxic (cellular) edema to ionic edema, and finally to vasogenic edema [10]. Ischemia leads to the cessation of primary active transport via Na + -K + -adenosinetriphosphatase (ATPase).…”

“…Intracellular accumulation of sodium during the "cytotoxic (cellular) edema" phase derives from a multitude of transporters, including ion channels [10]. These ion transport proteins located in the cell membrane are activated or upregulated by factors associated with ischemia, such as elevated levels of extracellular potassium, alterations in pH, inflammatory mediators (such as cytokines), and excitatory neurotransmitters (such as glutamate).…”

Targeting the Microvasculature in Cerebral Ischemia—Go (or Stop Going) with the Flow

“…Few "protective" agents specifically target the microvasculature in ischemia/hypoxia. After ischemia/hypoxia, the microvasculature is never normal, but suffers one of two broad fates: (1) it can become occluded due to endothelial cell swelling, with no restoration of flow [6] and (2) flow may be partial but impeded due to endothelial cell swelling, with the endothelial cell becoming pathologically dysfunctional [7]. In the first instance, with flow occlusion, no neuroprotectant can be conceived that will reach the neuron to save it.…”

“…In the second instance, impeded flow via abnormal dysfunctional capillaries gives rise to harmful pathological processes. Capillary endothelial cells subjected to ischemia/hypoxia undergo not only swelling (cytotoxic edema), which compromises microcirculatory flow [6], but in addition, they lose the integrity of inter-endothelial tight junctions, which allows extravasation of plasma and promotes the formation of vasogenic edema [7]. Ultimately, complete loss of the structural integrity of capillaries can lead to the formation of petechial hemorrhages and hemorrhagic transformation [7].…”

“…Capillary endothelial cells subjected to ischemia/hypoxia undergo not only swelling (cytotoxic edema), which compromises microcirculatory flow [6], but in addition, they lose the integrity of inter-endothelial tight junctions, which allows extravasation of plasma and promotes the formation of vasogenic edema [7]. Ultimately, complete loss of the structural integrity of capillaries can lead to the formation of petechial hemorrhages and hemorrhagic transformation [7]. If the brain and the organism survive the edema and the hemorrhagic transformation, the activated capillary endothelial cell becomes the gateway for inflammatory cells, which cause additional injury.…”