Role of Secretion and Bulk Flow of Brain Interstitial Fluid in Brain Volume Regulation

In systemic tissues, net fluid shifts across the capillary wall and drainage of interstitial fluid (ISF) into the lymphatics are important mechanisms of ISF volume regulation. The situation in the central nervous system is more complex in that (1) cerebral ISF is separated from blood by the blood-brain barrier, (2) there are no lymphatics, and (3) the ependymal and pial surfaces of the brain are in contact with another extracellular fluid, the cerebrospinal fluid (CSF). In this paper evidence is presented supporting a model of brain ISF volume regulation proposed by Bradbury.'.' The model, illustrated in FIGURE 1, is based on ISF secretion at the blood-brain barrier coupled with shifts of extracellular fluid between brain and CSF. Interstitial fluid is separated from blood by the highly impermeable blood-brain barrier, whereas it is connected to CSF by a series of patent extracellular channels. Interstitial fluid volume will be influenced by net exchanges across both of these interfaces. According to the model, ISF is produced at the blood-brain barrier by the process of secretion, whereas volume shifts between brain and the surrounding CSF are via bulk flow. The direction and rate of bulk flow will be a function of the hydrostatic pressure gradient between brain ISF and CSF (Paf-P,8f). In normal brain, it is proposed that ISF volume is maintained constant despite continual secretion of ISF through drainage into CSF. Although not confirmed experimentally, it is assumed that ISF drainage is driven by an appropriate hydrostatic pressure gradient, i.e., P,sr>P,r, generated by the secretion of ISF. Reversal of this gradient, through an increase in Paf and/or a decrease in P,,r, will lead to a reversal of flow. In normal brain, retrograde flow of CSF into brain will expand ISF, causing interstitial edema, whereas in situations where ISF volume is reduced, retrograde flow provides a mechanism for restoring ISF volume to normal. In this paper we summarize evidence from this laboratory in favor of the proposed model of ISF volume regulation. Specifically, this evidence indicates that: ( 1 ) ISF drains continuously from the parenchyma in normal brain and the rate of drainage provides an estimate of the rate of ISF secretion at the blood-brain barrier; (2) elevation of plasma osmolality, which shrinks the brain and lowers brain ISF pressure: leads to a reversal of ISF flow with bulk flow of CSF into brain; and (3) brain volume regulation during this hyperosmotic stress can be explained quantitatively on the basis of ISF secretion and retrograde flow of CSF into brain (i.e., on the basis of the proposed model). In addition, new evidence is presented, indicating a shift of fluid within the osmotically dehydrated brain from ISF into brain cells.