Sreenivas Bk Anirudh, Simakurthy Sriram, Shanmugam P Mahesh, Nath Sangeeta, Raju Trichur R
Manipal Institute of Regenerative Medicine, Bangalore, Manipal Academy of Higher Education, Manipal, India.
Sankara Eye Hospital, Hyderabad, Bengaluru, India.
Exp Eye Res. 2025 Jun 9;258:110482. doi: 10.1016/j.exer.2025.110482.
Proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR) are vision-threatening retinal diseases characterized by pathological fibrosis and epiretinal membrane (ERM) formation. While PDR is primarily driven by chronic hyperglycemia associated with diabetes, PVR typically arises secondary to retinal detachment or ocular trauma, both conditions share common mechanisms with respect to fibrosis and inflammation. These mechanisms are orchestrated by a complex interplay of inflammatory cytokines, growth factors, and extracellular matrix (ECM) remodeling. Fibrosis and inflammation play central roles in both diseases. Transforming growth factor-beta (TGF-β) is a key profibrotic cytokine that induces epithelial-to-mesenchymal transition (EMT) in retinal pigment epithelial (RPE) cells and endothelial-to-mesenchymal transition (EndoMT) in vascular endothelial cells, driving fibrotic membrane formation. Additional growth factors such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and connective tissue growth factor (CTGF) further contribute to fibroproliferative membrane formation in PVR and fibrovascular membrane formation in PDR. This process is also exacerbated by pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and various interleukins, which amplify cellular activation and ECM deposition. Emerging evidence also highlights the modulatory roles of exosomes, long non-coding RNA, microRNAs, and metabolic alterations in shaping the fibrotic microenvironment. This review also outlines current treatment modalities in both diseases, including surgical and adjuvant-based approaches. However, these therapeutic approaches are only validated in pre-clinical animal models, which often do not replicate human conditions. Lower efficiency and the need for repetitive applications make prognosis very difficult. Moreover, patient-to-patient variability in disease manifestation and lack of a definite biomarker also add to the complexity. Emerging therapeutics shift focus towards personalized medicine with modulations at the gene and cell levels to achieve better clinical efficiency. A deeper understanding of the shared microenvironmental drivers of fibrosis and inflammation in PDR and PVR may pave way for more effective and targeted therapies to prevent vision loss in these devastating retinal disorders.
增殖性糖尿病视网膜病变（PDR）和增殖性玻璃体视网膜病变（PVR）是威胁视力的视网膜疾病，其特征为病理性纤维化和视网膜前膜（ERM）形成。虽然PDR主要由糖尿病相关的慢性高血糖驱动，但PVR通常继发于视网膜脱离或眼外伤，这两种情况在纤维化和炎症方面具有共同机制。这些机制由炎性细胞因子、生长因子和细胞外基质（ECM）重塑的复杂相互作用所调控。纤维化和炎症在这两种疾病中都起着核心作用。转化生长因子-β（TGF-β）是一种关键的促纤维化细胞因子，可诱导视网膜色素上皮（RPE）细胞发生上皮-间充质转化（EMT）以及血管内皮细胞发生内皮-间充质转化（EndoMT），从而驱动纤维化膜的形成。其他生长因子，如血管内皮生长因子（VEGF）、血小板衍生生长因子（PDGF）和结缔组织生长因子（CTGF），进一步促进了PVR中纤维增殖膜的形成以及PDR中纤维血管膜的形成。促炎细胞因子，包括肿瘤坏死因子-α（TNF-α）和各种白细胞介素，也会加剧这一过程，它们会放大细胞活化和ECM沉积。新出现的证据还强调了外泌体、长链非编码RNA、微小RNA和代谢改变在塑造纤维化微环境中的调节作用。本综述还概述了这两种疾病目前的治疗方式，包括手术和基于辅助治疗的方法。然而，这些治疗方法仅在临床前动物模型中得到验证，而这些模型往往无法复制人类的情况。效率较低以及需要重复应用使得预后非常困难。此外，疾病表现的个体差异以及缺乏明确的生物标志物也增加了复杂性。新兴疗法将重点转向个性化医疗，在基因和细胞水平上进行调控，以实现更好的临床疗效。深入了解PDR和PVR中纤维化和炎症的共同微环境驱动因素，可能为预防这些毁灭性视网膜疾病导致的视力丧失提供更有效、更有针对性的治疗方法。
