Cai Zhengwei, Pang Yi, Lin Shuying, Rhodes Philip G
Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Brain Res. 2003 Jun 13;975(1-2):37-47. doi: 10.1016/s0006-8993(03)02545-9.
Increasing data provide support for the hypothesis that inflammatory cytokines mediate inflammation-induced injury to developing white matter. In the present study, roles of tumor necrosis factor-alpha (TNFalpha) and interleukin-1 beta (IL-1beta) in mediating lipopolysaccharide (LPS)-induced brain injury were investigated by co-administration of LPS with IL-1 receptor antagonist (IL-1ra) or TNFalpha antibody in the 5-day-old rat brain. Intracerebral injection of LPS and other agents was performed in a stereotaxic apparatus at the location of 1.0 mm posterior and 1.0 mm lateral to the bregma, and 2.0 mm deep to the skull surface at the left hemisphere. Brain injury was examined in brain sections 3 and 11 days after LPS injection. LPS-induced inflammatory responses were evidenced by great increases in TNFalpha and IL-1beta concentrations in the neonatal rat brain 6 h after LPS injection. White matter rarefaction was observed in 71% (five out of seven) of the rat brains 3 days after LPS injection and bilateral ventricle dilation was found in 71% (five out of seven) of the P8 rat brains and in 100% of the P16 rat brains (four out of four). These alterations were not found in the control rat brains. No apparent histological changes in gray matter were observed in the LPS-injected rat brains. LPS injection also resulted in injuries to oligodendrocytes (OLs) and hypomyelination, as indicated by reduced immunostaining for O4 and myelin basic protein (MBP). Increased astrogliosis, as indicated by increased glial fibrillary acidic protein (GFAP) immunostaining, was also observed in the LPS-injected, but not the control rat brain. Co-administration of LPS with IL-1ra, but not with TNFalpha antibody, significantly attenuated LPS-induced white matter injury, as indicated by decreases in ventricle dilation, white matter rarefaction, GFAP positive staining and by improved O4 and MBP immunostaining. Co-administration of LPS with IL-1ra significantly reduced LPS-induced elevation of caspase-3 activity in the rat brain. While TNFalpha antibody had no effect on LPS-induced elevation of caspase-3 activity, co-administration of LPS with TNFalpha antibody partially, but significantly, decreased LPS-stimulated increase in IL-1beta in the neonatal rat brain. These data suggest that IL-1beta may play an important role in mediating LPS-induced brain injury and TNFalpha may have complicated, probably dual, effects in LPS-induced brain injury.
越来越多的数据支持这样一种假说，即炎性细胞因子介导炎症诱导的发育中白质损伤。在本研究中，通过在5日龄大鼠脑内将脂多糖（LPS）与白细胞介素-1受体拮抗剂（IL-1ra）或肿瘤坏死因子-α（TNFα）抗体联合给药，研究了TNFα和白细胞介素-1β（IL-1β）在介导LPS诱导的脑损伤中的作用。在立体定位仪中于左半球前囟后1.0 mm、外侧1.0 mm且颅骨表面深2.0 mm处进行脑内注射LPS和其他药物。在LPS注射后3天和11天检查脑切片中的脑损伤情况。LPS注射后6小时新生大鼠脑内TNFα和IL-1β浓度大幅升高，证明了LPS诱导的炎症反应。LPS注射后3天，71%（7只中的5只）大鼠脑出现白质稀疏，P8大鼠脑的71%（7只中的5只）以及P16大鼠脑的100%（4只中的4只）出现双侧脑室扩张。对照大鼠脑中未发现这些改变。LPS注射的大鼠脑灰质未观察到明显的组织学变化。LPS注射还导致少突胶质细胞（OLs）损伤和髓鞘形成减少，O4和髓鞘碱性蛋白（MBP）免疫染色降低表明了这一点。LPS注射的大鼠脑内，胶质纤维酸性蛋白（GFAP）免疫染色增加表明星形胶质细胞增生增加，而对照大鼠脑未出现这种情况。LPS与IL-1ra联合给药，但不与TNFα抗体联合给药，显著减轻了LPS诱导的白质损伤，脑室扩张、白质稀疏、GFAP阳性染色减少以及O4和MBP免疫染色改善表明了这一点。LPS与IL-1ra联合给药显著降低了LPS诱导的大鼠脑内半胱天冬酶-3活性升高。虽然TNFα抗体对LPS诱导的半胱天冬酶-3活性升高没有影响，但LPS与TNFα抗体联合给药部分但显著降低了LPS刺激的新生大鼠脑内IL-1β增加。这些数据表明，IL-1β可能在介导LPS诱导的脑损伤中起重要作用，而TNFα在LPS诱导的脑损伤中可能具有复杂的、可能是双重的作用。
