Del Pozo Aarón, Villa María, Vargas Carlos, Castejón David, Fernández-Valle M Encarnación, Gutiérrez-Rodríguez Ana, Martínez-Orgado José
Biomedical Research Foundation, Hospital Clínico San Carlos - IdISSC, 28040, Madrid, Spain.
ICTS Bioimagen Complutense (BioImaC), Complutense University, 28040, Madrid, Spain.
Pediatr Res. 2023 Jan;93(1):78-88. doi: 10.1038/s41390-022-02062-3. Epub 2022 Apr 15.
We aimed to characterize a preclinical model of intraventricular hemorrhage-induced brain damage (IVH-BD) in extremely low birth weight newborns (ELBWN), to identify potential therapeutic targets based on its pathophysiology.
IVH was induced in 1-day-old (P1) Wistar rats by left periventricular injection of clostridium collagenase (PVCC). At P6, P14, and P45 IVH-BD (area of damage, motor and cognitive deficits, Lactate/N-acetylaspartate ratio), white matter injury (WMI: ipsilateral hemisphere and corpus callosum atrophy, oligodendroglial population and myelin basic protein signal reduction), blood-brain barrier (BBB) dysfunction (occludin and Mfsd2a expression, Gadolinium leakage) and inflammation (TNFα, TLR4, NFkB, and MMP9 expression; immune cell infiltration), excitotoxicity (Glutamate/N-acetylaspartate), and oxidative stress (protein nitrosylation) were assessed. Sham animals were similarly studied.
IVH-BD leads to long-term WMI, resulting in motor and cognitive impairment, thus reproducing IVH-BD features in ELBWN. BBB dysfunction with increased permeability was observed at P6 and P14, coincident with an increased inflammatory response with TLR4 overexpression, increased TNFα production, and increased immune cell infiltration, as well as increased excitotoxicity and oxidative stress.
This model reproduced some key hallmarks of IVH-BD in ELBWN. Inflammation associated with BBB dysfunction appears as relevant therapeutic target to prevent IVH-BD-induced WMI.
Paraventricular injection of clostridium collagenase (PVCC) to 1-day-old Wistar rats uniquely reproduced the neuroimaging, histologic and functional characteristics of intraventricular hemorrhage-induced brain damage (IVH-BD) in extremely low birth weight newborns (ELBWN). PVCC-induced IVH triggered a prolonged inflammatory response associated with blood-brain barrier increased permeability, which in turn facilitates the infiltration of inflammatory cells. Thus, PVCC led to white matter injury (WMI) resulting in long-term motor and cognitive impairment. This model offers a valuable tool to obtain further insight into the mechanisms of IVH-BD in ELBWN and proposes some key therapeutic targets.
我们旨在描述极低出生体重新生儿（ELBWN）脑室内出血所致脑损伤（IVH-BD）的临床前模型，基于其病理生理学确定潜在的治疗靶点。
通过左脑室周围注射梭菌胶原酶（PVCC）诱导1日龄（P1）的Wistar大鼠发生IVH。在P6、P14和P45时评估IVH-BD（损伤面积、运动和认知缺陷、乳酸/ N-乙酰天门冬氨酸比值）、白质损伤（WMI：同侧半球和胼胝体萎缩、少突胶质细胞数量和髓鞘碱性蛋白信号降低）、血脑屏障（BBB）功能障碍（闭合蛋白和Mfsd2a表达、钆渗漏）以及炎症（TNFα、TLR4、NFkB和MMP9表达；免疫细胞浸润）、兴奋性毒性（谷氨酸/ N-乙酰天门冬氨酸）和氧化应激（蛋白质亚硝化）。对假手术动物进行类似研究。
IVH-BD导致长期WMI，进而引起运动和认知障碍，从而再现了ELBWN中的IVH-BD特征。在P6和P14时观察到BBB功能障碍且通透性增加，同时伴有炎症反应增强，TLR4过表达、TNFα产生增加、免疫细胞浸润增加，以及兴奋性毒性和氧化应激增加。
该模型再现了ELBWN中IVH-BD的一些关键特征。与BBB功能障碍相关的炎症似乎是预防IVH-BD所致WMI的相关治疗靶点。
向1日龄Wistar大鼠脑室周围注射梭菌胶原酶（PVCC）独特地再现了极低出生体重新生儿（ELBWN）脑室内出血所致脑损伤（IVH-BD）的神经影像学、组织学和功能特征。PVCC诱导的IVH引发了与血脑屏障通透性增加相关的长期炎症反应，这反过来又促进了炎症细胞的浸润。因此，PVCC导致白质损伤（WMI），从而导致长期的运动和认知障碍。该模型为进一步深入了解ELBWN中IVH-BD的机制提供了有价值的工具，并提出了一些关键的治疗靶点。
