About 10% of the survivors of very low-birth-weight infants have cerebral palsy. Cerebral white mater injury is the leading cause of cerebral palsy in preterm infants. Neuroinflammation plays a central role in the initiation of damage to the white matter of the immature brain. The recruiting leukocytes, predominantly macrophages and neutrophils, contribute to neuroinflammation of the white matter injury in preterm infants. Macrophage/microglia and neutrophils are potent mediators of the acute inflammatory response and may promote tissue injury in the brain. The blood-brain barrier (BBB) acts as a pivotal interface for central- and peripheral-driven inflammatory processes in brain injury. The increase of BBB permeability selectively in the white matter may act in concert with neuroinflammatory cells to accentuate white matter injury through leukocyte recruitment into the brain which may worsen white matter injury. Since neuroinflammatory cells and vascular endothelial cells may closely interact with each other in brain injury, there may be a common mechanism linking neuroinflammation and BBB disruption, and white matter injury of the immature brain. CXCL5 (epithelial neutrophil-activating peptide 78 or ENA-78) is produced by a variety of immune and endothelial cells in response to proinflammatory cytokines. CXCL5 and its receptor CXCR2 are produced by macrophages and endothelial cells in the periphery and in the CNS, in order to form a chemotactic gradient to guide leukocytes through the bloodstream to the injured site. Recent studies have found increases of CXCL5 levels in the amniotic fluids with intraamniotic infection and preterm delivery. The mechanism of recruiting leukocytes into the white matter after brain injury in the preterm infants remains unknown. Whether the CXCL5-CXCR2 chemokine axis is the common mechanism of neuroinflammation and BBB disruption that involved in the white matter injury of the immature brain also remains unknown. Our previous study in the postpartum day 2 rat pups (brain maturation status equivalent to very preterm infants less than 30 weeks) demonstrated that lipopolysaccharide (LPS) sensitized hypoxic-ischemia and selectively caused white matter injury in the immature brain. We also showed that LPS-sensitized hypoxic-ischemia caused white matter injury through c-Jun N-terminal kinases (JNK) activation-mediated upregulation of neuroinflammation, BBB leakage and oligodendrocyte progenitor apoptosis. However, the upstream pathway leading to JNK activation in the macrophage/microglia and vascular endothelial cells remains to be determined. Chemokine receptor CXCR2 and its ligands implicated in several neuroinflammatory brain pathologies and in leukocytes recruitment have been proposed as potential therapeutic targets in several inflammatory diseases. Using the established model of white matter injury in P2 pups and the genetically-engineered rat models of CXCL5 (CXCL5 -/- pups and CXCL5 over-expression transgenic pups, in collaboration with Genetic Engineering Murine Model Services, National Core Facility Program for Biotechnology, National Science Council), we hypothesize that the CXCL5/CXCR2/JNK signaling axis is the shared pathway linking neuroinflammation and vascular endothelial damage, and white matter injury of the immature brain.
|Effective start/end date||8/1/14 → 7/31/15|
- white matter injury
- immature brain
- blood-brain barrier