Commonalities between fibrotic and inflammatory mechanisms in proliferative vitreoretinopathy and proliferative...

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.