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

Daniel F Jones,Taasin Srivastava,Tania M Fowke,A Roger Hohimer,Stephen A Back,Matthew W Hagen,Marjorie R Grafe,Larry S Sherman,Evelyn Mcclendon,Ji-Zhong Bai,Art Riddle,Daniel Shaver,Pierre Gressens,Xi Gong,Justin M Dean,Alistair J Gunn

doi:10.1371/journal.pone.0112800

Abstract

ObjectiveAlthough 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.MethodsWe 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.ResultsrHI 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.ConclusionsrHI 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.

Highlights

Ill prematurely born infants are susceptible to hypoxic-ischemic cerebral white matter injury (WMI)
To define the response to recurrent hypoxiaischemia (rHI) relative to single episodes of HI (Fig. 1), we employed several complementary approaches to quantify the severity of WMI in two regions of particular predilection for injury: the frontal and parietal cerebral white matter
Consistent with these findings, there was a significant increase in the number of frontal and parietal macroscopic foci of necrosis in the rHI group relative to the other treatment groups (p = 0.026; Kruskal-Wallis; Bonferroni-corrected post-hoc Mann-Whitney Utest showed a significant increase in the *rHI group vs. late HI group, p = 0.045)

Summary

Introduction

Ill prematurely born infants are susceptible to hypoxic-ischemic cerebral white matter injury (WMI). WMI is the leading cause of cerebral palsy (CP) in survivors of premature birth and contributes to a wide range of life-long neurobehavioral disabilities [1]. This developmental predilection for WMI is related to vascular maturational factors that include disturbances in cerebral auto-regulation [2], as well as an enriched population of late oligodendrocyte progenitors (preOLs) that populate the white matter during a broad high-risk period for injury [3]. The topography of this diffuse WMI is defined by the density and distribution of susceptible preOLs within the ischemic territory [4]

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Results

Discussion

Conclusion