Shafqat Areez, Abdul Rab Saleha, Ammar Osama, Al Salameh Sulaiman, Alkhudairi Anas, Kashir Junaid, Alkattan Khaled, Yaqinuddin Ahmed
College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
Center of Comparative Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Front Med (Lausanne). 2022 Aug 23;9:995993. doi: 10.3389/fmed.2022.995993. eCollection 2022.
Immune dysfunction is widely regarded as one of the central tenants underpinning the pathophysiology of diabetes mellitus (DM) and its complications. When discussing immunity, the role of neutrophils must be accounted for: neutrophils are the most abundant of the circulating immune cells and are the first to be recruited to sites of inflammation, where they contribute to host defense phagocytosis, degranulation, and extrusion of neutrophil extracellular traps (NETs). NETs are composed of DNA associated with nuclear and cytosolic neutrophil proteins. Although originally reported as an antimicrobial strategy to prevent microbial dissemination, a growing body of evidence has implicated NETs in the pathophysiology of various autoimmune and metabolic disorders. In these disorders, NETs propagate a pathologic inflammatory response with consequent tissue injury and thrombosis. Many diabetic complications-such as stroke, retinopathy, impaired wound healing, and coronary artery disease-involve these mechanisms. Therefore, in this review, we discuss laboratory and clinical data informing our understanding of the role of NETs in the development of these complications. NET markers, including myeloperoxidase, citrullinated histone H3, neutrophil elastase, and cell-free double-stranded DNA, can easily be measured in serum or be detected immunohistochemical/immunocytochemical staining of tissue specimens. Therefore, NET constituents potentially constitute reliable biomarkers for use in the management of diabetic patients. However, no NET-targeting drug is currently approved for the treatment of diabetic complications; a candidate drug will require the outcomes of well-designed, robust clinical trials assessing whether NET inhibition can benefit patients in terms of morbidity, quality of life, health expenditures, and mortality. Therefore, much work remains to be done in translating these encouraging pieces of data into clinical trials for NET-targeting medications to be used in the clinic.
免疫功能障碍被广泛认为是支撑糖尿病（DM）及其并发症病理生理学的核心因素之一。在讨论免疫时，必须考虑中性粒细胞的作用：中性粒细胞是循环免疫细胞中数量最多的，并且是最早被招募到炎症部位的细胞，在那里它们通过吞噬作用、脱颗粒作用以及释放中性粒细胞胞外陷阱（NETs）来参与宿主防御。NETs由与中性粒细胞核蛋白和胞质蛋白相关的DNA组成。尽管最初报道其是一种防止微生物传播的抗菌策略，但越来越多的证据表明NETs参与了各种自身免疫性和代谢性疾病的病理生理学过程。在这些疾病中，NETs引发病理性炎症反应，进而导致组织损伤和血栓形成。许多糖尿病并发症，如中风、视网膜病变、伤口愈合受损和冠状动脉疾病，都涉及这些机制。因此，在本综述中，我们讨论了实验室和临床数据，这些数据有助于我们理解NETs在这些并发症发生发展中的作用。NET标志物，包括髓过氧化物酶、瓜氨酸化组蛋白H3、中性粒细胞弹性蛋白酶和游离双链DNA，可以很容易地在血清中检测到，或者通过组织标本的免疫组织化学/免疫细胞化学染色检测到。因此，NET成分可能构成用于糖尿病患者管理的可靠生物标志物。然而，目前尚无针对NET的药物被批准用于治疗糖尿病并发症；一种候选药物将需要精心设计、强有力的临床试验结果来评估NET抑制是否能在发病率、生活质量、医疗支出和死亡率方面使患者受益。因此，要将这些令人鼓舞的数据转化为针对NET的药物的临床试验，还有很多工作要做。
