Abstract
The astroglial water channel aquaporin-4 (AQP4) facilitates water movement into and out of brain parenchyma. To investigate the role of AQP4 in meningitis-induced brain edema, Streptococcus pneumoniae was injected into cerebrospinal fluid (CSF) in wild type and AQP4 null mice. AQP4-deficient mice had remarkably lower intracranial pressure (9 +/- 1 versus 25 +/- 5 cm H2O) and brain water accumulation (2 +/- 1 versus 9 +/- 1 microl) at 30 h, and improved survival (80 versus 0% survival) at 60 h, through comparable CSF bacterial and white cell counts. Meningitis produced marked astrocyte foot process swelling in wild type but not AQP4 null mice, and slowed diffusion of an inert macromolecule in brain extracellular space. AQP4 protein was strongly up-regulated in meningitis, resulting in a approximately 5-fold higher water permeability (P(f)) across the blood-brain barrier compared with non-infected wild type mice. Mathematical modeling using measured P(f) and CSF dynamics accurately simulated the elevated lower intracranial pressure and brain water produced by meningitis and predicted a beneficial effect of prevention of AQP4 upregulation. Our findings provide a novel molecular mechanism for the pathogenesis of brain edema in acute bacterial meningitis, and suggest that inhibition of AQP4 function or up-regulation may dramatically improve clinical outcome.
Highlights
Streptococcus pneumoniae is the most common and aggressive meningeal pathogen [1,2,3]
A major complication associated with unfavorable outcome in bacterial meningitis is brain edema, which causes a rise in intracranial pressure potentially leading to brain ischemia, herniation, and death [8, 9]
The model predicted that the majority of the excess water in meningitis entered the brain through up-regulated AQP4 water channels
Summary
Streptococcus pneumoniae (pneumococcus) is the most common and aggressive meningeal pathogen [1,2,3]. As occurs in brain tumors, involves accumulation of excess fluid in the extracellular space of the brain parenchyma because of a leaky blood-brain barrier (BBB).. As occurs in brain tumors, involves accumulation of excess fluid in the extracellular space of the brain parenchyma because of a leaky blood-brain barrier (BBB).1 Both types of brain edema are thought to co-exist in meningitis [8, 9], their relative contributions to brain swelling are not known. AQP4 deletion markedly reduced brain swelling in mouse models of cytotoxic brain edema, including water intoxication and focal cerebral ischemia [16]. AQP4 deletion in mice significantly worsened outcome in mouse models of vasogenic brain edema, including intraparenchymal fluid infusion, focal cortical freeze injury, and brain tumor [19]. Our results have specific implications regarding aquaporin-based therapies of bacterial meningitis
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