Role of recurrent hypoxia-ischemia in preterm white matter injury severity

• Published in: PloS one 2014-11, Vol.9 (11), p.e112800-e112800
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Animals, Newborn; Biology and Life Sciences; Brain damage; Cell Adhesion Molecules - metabolism; Cell death; Degeneration; Extracellular matrix; Extracellular Matrix - metabolism; Extracellular Matrix - pathology; Female; Fetus - metabolism; Fetus - pathology; Fetuses; Gangrene; Gene sequencing; Glial stem cells; Gliosis; Health sciences; Human behavior; Hyaluronic acid; Hyaluronic Acid - metabolism; Hyaluronoglucosaminidase - metabolism; Hypoxemia; Hypoxia; Hypoxia-Ischemia, Brain - metabolism; Hypoxia-Ischemia, Brain - pathology; Image analysis; Image processing; Infants; Ischemia; Lesions; Medicine and Health Sciences; Necrosis; Necrosis - metabolism; Necrosis - pathology; Neuropathology; Newborn babies; NMR; Nuclear magnetic resonance; Oligodendroglia - metabolism; Oligodendroglia - pathology; Ovis aries; Pediatrics; Physiology; Polymerase chain reaction; Premature infants; Ribonucleic acid; Risk reduction; RNA; Rodents; Sheep; Stereology; Studies; Substantia alba; Topography; White Matter - injuries; White Matter - pathology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0112800

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.