Hagen Matthew W, Riddle Art, McClendon Evelyn, Gong Xi, Shaver Daniel, Srivastava Taasin, Dean Justin M, Bai Ji-Zhong, Fowke Tania M, Gunn Alistair J, Jones Daniel F, Sherman Larry S, Grafe Marjorie R, Hohimer A Roger, Back Stephen A
Department of Pediatrics, Oregon Health & Science University, Portland, Oregon, United States of America.
Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
PLoS One. 2014 Nov 12;9(11):e112800. doi: 10.1371/journal.pone.0112800. eCollection 2014.
Although the spectrum of white matter injury (WMI) in preterm infants is shifting from cystic necrotic lesions to milder forms, the factors that contribute to this changing spectrum are unclear. We hypothesized that recurrent hypoxia-ischemia (rHI) will exacerbate the spectrum of WMI defined by markers of inflammation and molecules related to the extracellular matrix (hyaluronan (HA) and the PH20 hyaluronidase) that regulate maturation of the oligodendrocyte (OL) lineage after WMI.
We employed a preterm fetal sheep model of in utero moderate hypoxemia and global severe but not complete cerebral ischemia that reproduces the spectrum of human WMI. The response to rHI was compared against corresponding early or later single episodes of HI. An ordinal rating scale of WMI was compared against an unbiased quantitative image analysis protocol that provided continuous histo-pathological outcome measures for astrogliosis and microglial activation. Late oligodendrocyte progenitors (preOLs) were quantified by stereology. Analysis of hyaluronan and the hyaluronidase PH20 defined the progressive response of the extracellular matrix to WMI.
rHI resulted in a more severe spectrum of WMI with a greater burden of necrosis, but an expanded population of preOLs that displayed reduced susceptibility to cell death. WMI from single episodes of HI or rHI was accompanied by elevated HA levels and increased labeling for PH20. Expression of PH20 in fetal ovine WMI was confirmed by RT-PCR and RNA-sequencing.
rHI is associated with an increased risk for more severe WMI with necrosis, but reduced risk for preOL degeneration compared to single episodes of HI. Expansion of the preOL pool may be linked to elevated hyaluronan and PH20.
尽管早产儿白质损伤（WMI）的谱系正在从囊性坏死性病变转变为更轻微的形式，但导致这种谱系变化的因素尚不清楚。我们假设反复缺氧缺血（rHI）会加剧由炎症标志物和与细胞外基质相关的分子（透明质酸（HA）和PH20透明质酸酶）所定义的WMI谱系，这些分子在WMI后调节少突胶质细胞（OL）谱系的成熟。
我们采用了一种早产胎羊模型，该模型在子宫内造成中度低氧血症和全身性严重但并非完全性的脑缺血，可重现人类WMI的谱系。将对rHI的反应与相应的早期或晚期单次HI发作进行比较。将WMI的序数评分量表与一种无偏定量图像分析方案进行比较，该方案为星形胶质细胞增生和小胶质细胞激活提供连续的组织病理学结果测量。晚期少突胶质前体细胞（preOLs）通过体视学进行定量。对透明质酸和透明质酸酶PH20的分析确定了细胞外基质对WMI的渐进性反应。
rHI导致更严重的WMI谱系，坏死负担更大，但preOLs群体扩大，对细胞死亡的易感性降低。单次HI或rHI发作引起的WMI伴随着HA水平升高和PH20标记增加。通过RT-PCR和RNA测序证实了PH20在胎羊WMI中的表达。
与单次HI发作相比，rHI与更严重的伴有坏死的WMI风险增加相关，但preOLs退变风险降低。preOLs库的扩大可能与透明质酸和PH20升高有关。
