早产儿脑部持续炎症和白质损伤：来自一种新型绵羊慢性炎症模型的见解

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology Pub Date : 2025-07-24 DOI:10.1016/j.expneurol.2025.115397

Abdul Razak , Amy E. Sutherland , Yen Pham , Tamara Yawno , Ilias Nitsos , Lindsay Zhou , Tegan A. White , Charmaine Rock , Rod W. Hunt , Atul Malhotra , Beth J. Allison , Suzanne L. Miller , Courtney A. McDonald

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引用次数: 0

摘要

背景：早产脑损伤涉及持续性炎症，使其成为潜在的治疗靶点。目前的大型动物模型关注的是短期结果，限制了对长期影响的理解。我们开发了一种炎症性早产脑损伤的绵羊模型，以评估相当于人类婴儿早期脑瘫诊断的长期神经病理学。方法胎羊在妊娠期(d) 90 ~ 91（足月148d）进行实验：一组给予脂多糖(LPS 200 ng；N = 9)分别在96d、97d和98d（妊娠0.65，人脑发育~ 25-26周），对照组接受生理盐水治疗（N = 8）。在138d诱导出生，在出生后24 h内对羔羊实施安乐死。评估大脑皮层下（SCWM）、脑室周围（PVWM）和皮层（CWM）白质、脑室下区（SVZ）和胼胝体（CC）的白质损伤、小胶质细胞/巨噬细胞活化和星形胶质增生。结果产前给药LPS与PVWM （P = 0.04）、SCWM （P = 0.01）和CWM （P = 0.006）的持续小胶质细胞/巨噬细胞活化相关。此外，LPS暴露与PVWM （P = 0.02）、SCWM （P = 0.001）和CWM （P = 0.0001）中少突胶质细胞数量减少有关，并且与CWM (CNPase, P <；0.0001和MBP， P = 0.04), SVZ （MBP, P = 0.05）。在星形胶质细胞增生和微出血方面没有观察到差异。我们证明，在炎症诱导的宫内早产脑损伤的大型动物模型中，长期持续的炎症发生，并伴有明显的白质损伤，包括少突胶质细胞的丢失和多个白质区域髓鞘形成的减少。该模型为持续早产儿脑损伤临床相关模型中有希望的治疗方法和行为评估的长期评估铺平了道路。

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Persistent inflammation and white matter damage in the preterm brain: Insights from a novel ovine model of chronic inflammation

Background

Preterm brain injury involves persistent inflammation, making it a potential therapeutic target. Current large animal models focus on short-term outcomes, limiting understanding of long-term effects. We developed an ovine model of inflammation-induced preterm brain injury to assess long-term neuropathology at an age equivalent to early cerebral palsy diagnosis in human infants.

Methods

Fetal sheep were instrumented at gestational day (d) 90–91 (term is 148d): one group received lipopolysaccharide (LPS 200 ng; n = 9) on 96d, 97d, and 98d (0.65 gestation, ∼25–26 weeks human brain development), and a control group received saline (n = 8). Birth was induced on 138d, and lambs were euthanised within 24 h of birth. Brains were evaluated for white matter injury, microglial/macrophage activation and astrogliosis in the subcortical (SCWM), periventricular (PVWM), and cortical (CWM) white matter, subventricular zone (SVZ), and corpus callosum (CC).

Results

Antenatal LPS administration was associated with significant persistent microglial/macrophage activation in the PVWM (P = 0.04), SCWM (P = 0.01), and CWM (P = 0.006). Furthermore, LPS exposure was associated with reduced oligodendrocyte cell number in the PVWM (P = 0.02), SCWM (P = 0.001), and CWM (P = 0.0001), and reduced nyelination in CWM (CNPase, P < 0.0001 and MBP, P = 0.04) and SVZ (MBP, P = 0.05). No difference in astrogliosis or microhaemorrhages was observed.

Conclusion

We demonstrated that in a large animal model of inflammation-induced intrauterine preterm brain injury, long-term persistent inflammation occurs, along with significant white matter injury, including loss of oligodendrocytes and reduced myelination in multiple white matter regions. This model paves the way for long-term evaluation of promising therapeutics and behavioral assessment in this clinically relevant model of persistent preterm brain injury.

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来源期刊

Experimental Neurology 医学-神经科学

CiteScore

10.10

自引率

3.80%

发文量

258

审稿时长

42 days

期刊介绍： Experimental Neurology, a Journal of Neuroscience Research, publishes original research in neuroscience with a particular emphasis on novel findings in neural development, regeneration, plasticity and transplantation. The journal has focused on research concerning basic mechanisms underlying neurological disorders.