Table 1.
Key inflammatory mediators driving BRB breakdown in diabetic macular edema
| Mediator | Contribution to BRB breakdown |
|---|---|
| Leukocytes | Rich content of readily releasable mediators including cytokines, chemokines, superoxide, and proteolytic enzymes that perpetuate inflammation, damage underlying EC, promote BRB breakdown, and participate in tissue remodeling Expression of Fas ligand directly encourages EC death (neutrophils) |
| Growth factors (VEGF, TGFβ) | Phosphorylation of tight and adherens junctional molecules, leading to breakdown of BRB (VEGF) Activation of ECs, expression of ICAM-1 and VCAM-1, and leukostasis (VEGF) Vascular remodeling via multiple pathways (TGFβ in particular) |
| Oxidative stress (O2−, H2O2,ONOO−) | Radicals cause cell damage and vasodilation, while having inherent signaling qualities, including PKC activation Increases the formation of AGE and lipid mediators Activates production of pro-inflammatory mediators (superoxide/hydrogen peroxide) |
| Cytokines (TNF-α, IL-1β, IL-6, HMGB1) | Stimulate the production and release of further pro-inflammatory mediators Encourage reorganization of junctional proteins, leading to BRB breakdown (IL-6), sometimes in conjunction with leukocyte recruitment (TNF, IL-1β) High local concentrations promote cell death, including ECs and pericytes (TNF, IL-1β) |
| Chemokines (MCP-1, IL-8, SDF-1) | Induce VEGF expression (SDF-1) Direct recruitment of cellular mediators toward the retina, from both the blood and within the tissue (MCP-1, IL-8, SDF-1) Can also directly induce EC junctional reorganization and BRB breakdown (IL-8) |
| Adhesion molecules (ICAM-1, VCAM-1, P-selectin) | Allow attachment of blood leukocytes to ECs, initiating leukostasis and diapedesis |
| AGE | Act on RAGE receptors to initiate mediator production |
| Protein kinases (PKC) | Phosphorylate junctional molecules to induce BRB breakdown (PKC) Induce production/release of many other mediators (PKC) |
| Lipid mediators and eicosanoids (LTB4, PGE1, PGE2, PLA2) | Chemotactic for leukocytes (LTB4) Promote reorganization of EC junctional proteins, leading to BRB breakdown (LTB4, PGE1) Induce vasodilation (PGE2) Promote retinal VEGF, ICAM-1, and TNF-α expression (PLA2) |
| MMP (MMP9) | Digests basement membrane, releasing mediators and also weakening vascular support Proteolytically activate chemokines May aid the diapedesis of leukocytes but damage pericyte layer |
| Hypoxia (low pO2 and high metabolite levels) | Induces production of pro-inflammatory mediators and initiates angiogenesis, both of which encourage BRB breakdown |
Abbreviations: AGE, advanced glycation end-products; BRB, blood–retinal barrier; EC, endothelial cell; HMGB1, high-mobility group box-1 protein; ICAM-1, intercellular adhesion molecule 1; IL, interleukin; LTB4, leukotriene B4; MCP-1, monocyte chemoattractant protein 1; MMP, metalloproteinase; PGE, prostaglandin E; PKC, protein kinase C; PLA2, phospholipase A2; pO2, partial pressure of oxygen; RAGE, receptor for AGE; SDF-1, stromal cell-derived factor 1; TGFβ, transforming growth factor-beta; TNF, tumor necrosis factor; VCAM-1, vascular cell adhesion molecule 1; VEGF, vascular endothelial growth factor.