细胞外组蛋白是涉及多种危重和炎症性疾病的发生和进展的关键损伤相关分子模式,比如败血症,胰腺炎,创伤,急性肝功能衰竭,急性呼吸窘迫综合征,血管炎和关节炎。在过去的十年里,组蛋白介导的炎症的病理生理学机制,内皮功能障碍,凝血激活,已经系统地阐明了疾病中的神经免疫损伤和器官功能障碍。新兴的临床前证据进一步表明,抗组蛋白策略与它们的中和剂(肝素,类肝素,天然血浆蛋白,小阴离子分子和纳米药物,等。)或体外血液净化技术可以显著缓解组蛋白诱导的有害影响,从而改善组蛋白相关的关键和炎症动物模型的结果。然而,目前缺乏对这些组蛋白靶向治疗策略的有效性和安全性的系统评估.在这次审查中,我们首先更新了对组蛋白诱导的炎症过度的潜在分子机制的最新理解,内皮功能障碍,凝血病,和器官功能障碍。然后,我们总结了肝素组蛋白靶向治疗策略的最新进展,抗组蛋白抗体,组蛋白结合蛋白或分子,和临床前研究中的组蛋白亲和血液吸附。最后,还讨论了改善组蛋白靶向治疗策略的临床翻译的挑战和未来前景,以促进更好地管理组蛋白相关疾病患者。
Extracellular
histones are crucial damage-associated molecular patterns involved in the development and progression of multiple critical and inflammatory diseases, such as sepsis, pancreatitis, trauma, acute liver failure, acute respiratory distress syndrome, vasculitis and arthritis. During the past decade, the physiopathologic mechanisms of histone-mediated hyperinflammation, endothelial dysfunction, coagulation activation, neuroimmune injury and organ dysfunction in diseases have been systematically elucidated. Emerging preclinical evidence further shows that anti-histone strategies with either their neutralizers (heparin, heparinoids, nature plasma proteins, small anion molecules and nanomedicines, etc.) or extracorporeal blood purification techniques can significantly alleviate histone-induced deleterious effects, and thus improve the outcomes of histone-related critical and inflammatory animal models. However, a systemic evaluation of the efficacy and safety of these histone-targeting therapeutic strategies is currently lacking. In this
review, we first update our latest understanding of the underlying molecular mechanisms of histone-induced hyperinflammation, endothelial dysfunction, coagulopathy, and organ dysfunction. Then, we summarize the latest advances in histone-targeting therapy strategies with heparin, anti-histone antibodies, histone-binding proteins or molecules, and histone-affinity hemoadsorption in pre-clinical studies. Finally, challenges and future perspectives for improving the clinical translation of histone-targeting therapeutic strategies are also discussed to promote better management of patients with histone-related diseases.