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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Pediatrics, Oregon Health & Science University, Portland, Oregon, United States of America.
Matthew W
MW
Hagen
Department of Pediatrics, Oregon Health & Science University, Portland, Oregon, United States of America.
Art
A
Riddle
Department of Pediatrics, Oregon Health & Science University, Portland, Oregon, United States of America.
Evelyn
E
McClendon
Department of Pediatrics, Oregon Health & Science University, Portland, Oregon, United States of America.
Xi
X
Gong
Department of Pediatrics, Oregon Health & Science University, Portland, Oregon, United States of America.
Daniel
D
Shaver
Department of Pediatrics, Oregon Health & Science University, Portland, Oregon, United States of America.
Taasin
T
Srivastava
Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Justin M
JM
Dean
Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Ji-Zhong
JZ
Bai
Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Tania M
TM
Fowke
Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Alistair J
AJ
Gunn
New Zealand Genomics Ltd./Bioinformatics Institute, School of Biological Sciences, University of Auckland, Auckland, New Zealand.
Daniel F
DF
Jones
Division of Neuroscience, Oregon National Primate Research Center, Beaverton, Oregon, United States of America; Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, Oregon, United States of America.
Larry S
LS
Sherman
Department of Pathology, Oregon Health & Science University, Portland, Oregon, United States of America.
Marjorie R
MR
Grafe
Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, Oregon, United States of America.
A Roger
AR
Hohimer
Department of Pediatrics, Oregon Health & Science University, Portland, Oregon, United States of America; Department of Neurology, Oregon Health & Science University, Portland, Oregon, United States of America.
Stephen A
SA
Back
D000818:Animals; D000831:Animals, Newborn; D015815:Cell Adhesion Molecules / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005260:Female; D005333:Fetus / Q000378:metabolism / Q000473:pathology; D006820:Hyaluronic Acid / Q000378:metabolism; D006821:Hyaluronoglucosaminidase / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000473:pathology*; D009336:Necrosis / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D012756:Sheep; D066127:White Matter / Q000293:injuries* / Q000473:pathology*
D015815:Cell Adhesion Molecules; D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase; C066852:hyaluronidase PH-20