de Gaetano Monica, McEvoy Caitriona, Andrews Darrell, Cacace Antonino, Hunter Jonathan, Brennan Eoin, Godson Catherine
UCD Diabetes Complications Research Centre, Conway Institute and UCD School of Medicine, University College Dublin, Dublin, Ireland.
Renal Transplant Program, University Health Network, Toronto, ON, Canada.
Front Pharmacol. 2018 Dec 19;9:1488. doi: 10.3389/fphar.2018.01488. eCollection 2018.
Diabetes and its associated chronic complications present a healthcare challenge on a global scale. Despite improvements in the management of chronic complications of the micro-/macro-vasculature, their growing prevalence and incidence highlights the scale of the problem. It is currently estimated that diabetes affects 425 million people globally and it is anticipated that this figure will rise by 2025 to 700 million people. The vascular complications of diabetes including diabetes-associated atherosclerosis and kidney disease present a particular challenge. Diabetes is the leading cause of end stage renal disease, reflecting fibrosis leading to organ failure. Moreover, diabetes associated states of inflammation, neo-vascularization, apoptosis and hypercoagulability contribute to also exacerbate atherosclerosis, from the metabolic syndrome to advanced disease, plaque rupture and coronary thrombosis. Current therapeutic interventions focus on regulating blood glucose, glomerular and peripheral hypertension and can at best slow the progression of diabetes complications. Recently advanced knowledge of the pathogenesis underlying diabetes and associated complications revealed common mechanisms, including the inflammatory response, insulin resistance and hyperglycemia. The major role that inflammation plays in many chronic diseases has led to the development of new strategies aiming to promote the restoration of homeostasis through the "resolution of inflammation." These strategies aim to mimic the spontaneous activities of the 'specialized pro-resolving mediators' (SPMs), including endogenous molecules and their synthetic mimetics. This review aims to discuss the effect of SPMs [with particular attention to lipoxins (LXs) and resolvins (Rvs)] on inflammatory responses in a series of experimental models, as well as evidence from human studies, in the context of cardio- and reno-vascular diabetic complications, with a brief mention to diabetic retinopathy (DR). These data collectively support the hypothesis that endogenously generated SPMs or synthetic mimetics of their activities may represent lead molecules in a new discipline, namely the 'resolution pharmacology,' offering hope for new therapeutic strategies to prevent and treat, specifically, diabetes-associated atherosclerosis, nephropathy and retinopathy.
糖尿病及其相关慢性并发症在全球范围内对医疗保健构成挑战。尽管在微血管/大血管慢性并发症的管理方面有所改善，但其不断上升的患病率和发病率凸显了问题的严重程度。目前估计，全球有4.25亿人受糖尿病影响，预计到2025年这一数字将增至7亿人。糖尿病的血管并发症，包括糖尿病相关的动脉粥样硬化和肾脏疾病，构成了特别的挑战。糖尿病是终末期肾病的主要原因，反映了纤维化导致器官衰竭。此外，糖尿病相关的炎症、新生血管形成、细胞凋亡和高凝状态也会加剧动脉粥样硬化，从代谢综合征到晚期疾病、斑块破裂和冠状动脉血栓形成。目前的治疗干预措施侧重于调节血糖、肾小球和外周高血压，充其量只能减缓糖尿病并发症的进展。最近，对糖尿病及其相关并发症发病机制的深入了解揭示了一些共同机制，包括炎症反应、胰岛素抵抗和高血糖。炎症在许多慢性疾病中所起的主要作用促使人们开发新的策略，旨在通过“炎症消退”促进内环境稳态的恢复。这些策略旨在模拟“特殊促消退介质”（SPM）的自发活性，包括内源性分子及其合成模拟物。本综述旨在讨论SPM（特别关注脂氧素（LXs）和消退素（Rvs））在一系列实验模型中的炎症反应作用，以及人体研究的证据，涉及心血管和肾脏糖尿病并发症，并简要提及糖尿病视网膜病变（DR）。这些数据共同支持这样一种假设，即内源性产生的SPM或其活性的合成模拟物可能代表新学科“消退药理学”中的先导分子，为预防和治疗糖尿病相关的动脉粥样硬化、肾病和视网膜病变的新治疗策略带来希望。
