| Summary: | 碩士 === 國立成功大學 === 臨床醫學研究所 === 98 === Cerebral white matter injury (WMI) is the most common form of injury in the preterm infants, and is associated with subsequent neurodevelopmental impairment. Among the survivors of very-low-birth-weight infants, 10% exhibit cerebral palsy, and 50% have cognitive/behavioral deficits. Periventricular leukomalacia (PVL) is the major form of white matter injury, characterized by loss of premyelinating oligodendrocytes (pre-OLs), astrogliosis, and microglial infiltration. Increased CXCL5 expression has been found in preterm infants with intrauterine infection. Using an established model of selective white matter injury in postpartum (P) day 2 rat pups induced by lipopolysaccharide (LPS) followed by hypoxic ischemia (HI), we hypothesized that CXCL5 is involved in the white matter injury of the immature brain.
We found that P2 rat pups had increased CXCL5 expression in the cerebral cortex compared with P7 and P30 rats. All the P3, P7 and P30 rats had very few CXCL5 expression in the white matter. Immunofluorescence showed that CXCL5 was mainly expressed in cortical neurons of P2 pups. Western blots demonstrated increases of CXCL5 levels in the cortex 6 h to 24 h after hypoxia in the LPS+HI pups. Immunohistochemical analysis showed increased CXCL5 immunoreactivity in the white matter 24 h after HI in the LPS+HI group. Immunofluorescence showed that CXCL5 was mainly expressed in the CD11b+ microglia in the white matter and neurons in the cortex.
To confirm that CXCL5 sensitized HI-induced white matter injury, we intracerebroventricularly injected recombinant CXCL5 (2 ug per rat) to P2 rat pups before HI. On P11, the CXCL5+HI but not the NS+HI group had significant decreases of myelin basic protein (MBP) expression, increases of astrocytosis in the white matter, and increases of ventricle size but without neuronal injury in the ipsilateral hemisphere compared with the NS group. The CXCL5 group also had significant decreases of MBP in the white matter. In addition, the CXCL5+HI group had significant increases of blood-brain barrier damage evidenced by increases of extravascular IgG leakage, and increases of microglia and neutrophil infiltration in the white matter than the NS group. The CXCL5 group had more blood-brain barrier damage and upregulated neutrophil but not microglia infiltration in the white matter than the NS group.
In the immature brain, CXCL5 followed by HI upregulates microglia and neutrophils infiltration, and causes white matter injury, while CXCL5 alone predominately induces neutrophil infiltration and also causes white matter injury. Targeting on CXCL5 and its receptor signaling may be an attractive therapeutic strategy to protect against white matter injury in the immature brain.
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