Balk Stefanie, Panier Franziska, Brandner Sebastian, Coras Roland, Blümcke Ingmar, Ekici Arif B, Sembill Jochen A, Schwab Stefan, Huttner Hagen B, Sprügel Maximilian I
Department of Neurology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schwabachanlage 6, 91054 Erlangen, Germany.
Department of Neurosurgery, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schwabachanlage 6, 91054 Erlangen, Germany.
Biomolecules. 2025 Jan 22;15(2):164. doi: 10.3390/biom15020164.
Intracerebral hemorrhage leads to immediate brain injury due to local mechanical damage, on which current treatment approaches are focused, but it also induces secondary brain injury. The purpose of this study is to characterize blood components, degradation products and their effects in secondary brain injury. Immunocyto- and immunohistochemistry, Fluorescence-Activated Cell Sorting, WST-1 assays and RNA sequencing were applied using human cell cultures and human ex vivo brain tissue slices. Brain tissue was immediately collected, cooled and sliced during neurosurgical operations to perform experiments on living tissue slices of the human brain. Among the blood degradation products, free iron (Fe and Fe), but not hemoglobin, induced detrimental effects on pericyte function and survival (78.5% vs. 94.3%; -value < 0.001). RNA sequencing revealed ferroptosis as the underlining cellular mechanism, mediated via GPX-4 (log2 fold change > 1.0, -value < 1.08 × 10) in pathway analysis and eventually resulting in oxidative cell death. Pericytes located at cerebral capillary branching sites were specifically affected by ferroptosis, leading to capillary disruption and vasoconstriction, which were partially prevented by ferrostatin-1. Free iron induces the pericyte-dependent disruption of cerebral capillary function and represents a therapeutic target to attenuate secondary injury after intracerebral hemorrhage.
脑出血由于局部机械损伤会导致即刻脑损伤，目前的治疗方法主要针对这一点，但它也会引发继发性脑损伤。本研究的目的是对血液成分、降解产物及其在继发性脑损伤中的作用进行特征描述。使用人类细胞培养物和人类离体脑组织切片进行免疫细胞化学和免疫组织化学、荧光激活细胞分选、WST-1检测及RNA测序。在神经外科手术过程中立即收集、冷却并切片脑组织，以对人类大脑的活组织切片进行实验。在血液降解产物中，游离铁（Fe²⁺和Fe³⁺）而非血红蛋白，对周细胞功能和存活产生有害影响（78.5%对94.3%；P值<0.001）。RNA测序揭示铁死亡是潜在的细胞机制，在通路分析中通过GPX-4介导（log2倍数变化>1.0，P值<1.08×10⁻⁴），最终导致氧化性细胞死亡。位于脑毛细血管分支部位的周细胞受到铁死亡的特异性影响，导致毛细血管破坏和血管收缩，而铁抑素-1可部分预防这种情况。游离铁诱导依赖周细胞的脑毛细血管功能破坏，是减轻脑出血后继发性损伤的一个治疗靶点。
