Department of Anesthesiology, Center for Translational Research in Neurodegenerative Disease and McKnight Brain Institute, College of Medicine, University of Florida, 1275 Center Drive, Biomed Sci J493, Gainesville, FL, 32610, USA.
Departments of Neurosurgery, Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA.
Mol Neurobiol. 2020 Jan;57(1):159-178. doi: 10.1007/s12035-019-01766-8. Epub 2019 Oct 16.
Emergency visits, hospitalizations, and deaths due to traumatic brain injury (TBI) have increased significantly over the past few decades. While the primary early brain trauma is highly deleterious to the brain, the secondary injury post-TBI is postulated to significantly impact mortality. The presence of blood, particularly hemoglobin, and its breakdown products and key binding proteins and receptors modulating their clearance may contribute significantly to toxicity. Heme, hemin, and iron, for example, cause membrane lipid peroxidation, generate reactive oxygen species, and sensitize cells to noxious stimuli resulting in edema, cell death, and increased morbidity and mortality. A wide range of other mechanisms such as the immune system play pivotal roles in mediating secondary injury. Effective scavenging of all of these pro-oxidant and pro-inflammatory metabolites as well as controlling maladaptive immune responses is essential for limiting toxicity and secondary injury. Hemoglobin metabolism is mediated by key molecules such as haptoglobin, heme oxygenase, hemopexin, and ferritin. Genetic variability and dysfunction affecting these pathways (e.g., haptoglobin and heme oxygenase expression) have been implicated in the difference in susceptibility of individual patients to toxicity and may be target pathways for potential therapeutic interventions in TBI. Ongoing collaborative efforts are required to decipher the complexities of blood-related toxicity in TBI with an overarching goal of providing effective treatment options to all patients with TBI.
在过去的几十年中，外伤性脑损伤（TBI）导致的急诊就诊、住院和死亡人数显著增加。虽然早期原发性脑损伤对大脑有高度的危害性，但据推测，TBI 后的继发性损伤会显著影响死亡率。血液的存在，特别是血红蛋白及其分解产物以及调节其清除的关键结合蛋白和受体，可能会对毒性产生重大影响。例如，血红素、胆绿素和铁会导致膜脂质过氧化、产生活性氧物质，并使细胞对有害刺激敏感，从而导致水肿、细胞死亡以及发病率和死亡率增加。其他广泛的机制，如免疫系统，在介导继发性损伤中发挥着关键作用。有效清除所有这些促氧化剂和促炎代谢物，并控制适应性免疫反应，对于限制毒性和继发性损伤至关重要。血红蛋白代谢由关键分子如触珠蛋白、血红素加氧酶、血红素结合蛋白和铁蛋白介导。影响这些途径的遗传变异和功能障碍（例如，触珠蛋白和血红素加氧酶的表达）与个体患者对毒性的易感性差异有关，并且可能是 TBI 潜在治疗干预的目标途径。需要开展持续的合作努力来阐明 TBI 中与血液相关的毒性的复杂性，其总体目标是为所有 TBI 患者提供有效的治疗选择。
