Hewitt Benjamin J, Ali Myah, Hubbard Jessica, Hill Lisa J, Botfield Hannah
Biomedical Sciences, School of Infection, Inflammation and Immunology, College of Medicine and Health University of Birmingham Birmingham United Kingdom.
Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health University of Birmingham Birmingham United Kingdom.
J Am Heart Assoc. 2025 Jul 15;14(14):e037890. doi: 10.1161/JAHA.124.037890. Epub 2025 Jul 1.
Stroke is a leading cause of death, with patients often experiencing significant disability. Stroke is classified as ischemic, caused by the occlusion of a blood vessel leading to reduction in cerebral blood flow, or hemorrhagic, resulting from the rupture of a vessel that causes bleeding into the brain. Transforming growth factor β1 (TGF-β1), a pleiotropic cytokine, has been investigated in stroke due to its diverse effects on proliferation, extracellular matrix deposition, and inflammation. This systematic review examined the role of TGF-β1 in preclinical studies of ischemic and hemorrhagic stroke.
A search of PubMed, Web of Science, and Scopus databases identified animal studies examining TGF-β1 signaling as an outcome or intervention. A total of 89 studies were included: 68 on ischemic stroke and 21 on hemorrhagic stroke. Studies were assessed for bias following the SYRCLE (Systematic Review Centre for Laboratory Animal Experimentation) guidelines, followed by extraction of methodology and the role of TGF-β1.
Compliance with SYRCLE guidelines was found to be low, and the methodological approaches to stroke models were variable. A range of interventions were shown to modify TGF-β1 expression or signaling, with exogenous TGF-β1 improving outcomes in all ischemic stroke studies. TGF-β1 was found to play a protective role in 76% of ischemic stroke studies but was only protective in 33% of hemorrhagic stroke studies, with likely involvement in fibrosis development in the latter.
Our findings suggest a marked difference in TGF-β1 function between these types of stroke, and it is hypothesized that blood cytotoxicity following hemorrhagic stroke may generate more sustained TGF-β1 expression than that seen in ischemic stroke. This may lead to TGF-β1-mediated fibrosis and hydrocephalus, as opposed to the neuroprotective role played by the same molecule following ischemic stroke. These findings highlight the possible clinical utility of exogenous TGF-β1 therapies after ischemic stroke, and TGF-β1 inhibitors after hemorrhagic stroke, to reduce morbidity and disability caused by these events.
中风是主要的死亡原因之一，患者常伴有严重残疾。中风分为缺血性中风，由血管阻塞导致脑血流量减少引起；以及出血性中风，由血管破裂导致血液流入大脑引起。转化生长因子β1（TGF-β1）是一种多效性细胞因子，因其对细胞增殖、细胞外基质沉积和炎症具有多种作用，已在中风研究中受到关注。本系统评价探讨了TGF-β1在缺血性和出血性中风临床前研究中的作用。
检索PubMed、Web of Science和Scopus数据库，确定以TGF-β1信号传导为研究结果或干预措施的动物研究。共纳入89项研究：68项关于缺血性中风，21项关于出血性中风。按照SYRCLE（实验动物实验系统评价中心）指南评估研究的偏倚，随后提取研究方法以及TGF-β1的作用。
发现符合SYRCLE指南的程度较低，中风模型的方法学途径各不相同。一系列干预措施可改变TGF-β1的表达或信号传导，外源性TGF-β1在所有缺血性中风研究中均改善了预后。在76%的缺血性中风研究中发现TGF-β1具有保护作用，但在出血性中风研究中仅33%具有保护作用，后者可能与纤维化发展有关。
我们的研究结果表明，TGF-β1在这两种类型中风中的功能存在显著差异，据推测，出血性中风后的血液细胞毒性可能会产生比缺血性中风中更持久的TGF-β1表达。这可能导致TGF-β1介导的纤维化和脑积水，与缺血性中风后同一分子发挥的神经保护作用相反。这些研究结果凸显了缺血性中风后外源性TGF-β1疗法以及出血性中风后TGF-β1抑制剂在降低这些事件所致发病率和残疾方面的潜在临床应用价值。
