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Diabetic macular edema, retinopathy and age-related macular degeneration as inflammatory conditions

View Article: PubMed Central - PubMed

ABSTRACT

Diabetic macular edema (DME) and diabetic retinopathy (DR) are complications affecting about 25% of all patients with long-standing type 1 and type 2 diabetes mellitus and are a major cause of significant decrease in vision and quality of life. Age-related macular degeneration (AMD) is not uncommon, and diabetes mellitus affects the incidence and progression of AMD through altering hemodynamics, increasing oxidative stress, accumulating advanced glycation end products, etc. Recent studies suggest that DME, DR and AMD are inflammatory conditions characterized by a breakdown of the blood-retinal barrier, inflammatory processes and an increase in vascular permeability. Key factors that seem to have a dominant role in DME, DR and AMD are angiotensin II, prostaglandins and the vascular endothelial growth factor and a deficiency of anti-inflammatory bioactive lipids. The imbalance between pro- and anti-inflammatory eicosanoids and enhanced production of pro-angiogenic factors may initiate the onset and progression of DME, DR and AMD. This implies that bioactive lipids that possess anti-inflammatory actions and suppress the production of angiogenic factors could be employed in the prevention and management of DME, DR and AMD.

No MeSH data available.


Related in: MedlinePlus

Scheme showing possible sequence of events that lead to the development of DME, DR and AMD. Hyperglycemia causes activation of leukocytes, macrophages and lymphocytes, resulting in increased production of reactive oxygen species (ROS) and pro-inflammatory IL-6, TNF-α, macrophage migration inhibitory factor (MIF) and other cytokines. These cytokines also enhance ROS production and enhance the production and release of pro-inflammatory eicosanoids ((prostaglandins (PGs), leukotrienes (LTs) and thromboxanes (TXs)) by activating cell membrane bound phospholipase A2 (PLA2) that induces the release of polyunsaturated fatty acids: arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are precursors of PGs, LTs and TXs. IL-6, TNF-α, MIF, PGs, LTs and TXs enhance the expression of adhesion molecules, which leads to adhesion of leukocytes to endothelial cells, resulting in endothelial dysfunction due to the action of ROS released by adherent leukocytes on endothelial cells. Eicosanoids, cytokines, ROS and endothelial dysfunction can cause breakdown of the blood-retinal barrier, resulting in increased vascular permeability and fluid accumulation in the retinal tissue via special water fluxes. This leads to retinal ischemia and increased production of VEGF and pathological angiogenesis, events that result in the initiation and progression of retinal edema, macular degeneration and DR. Increased production of IL-6, TNF-α, MIF, and eicosanoids also induces enhanced production of VEGF and iNOS, which have pro-inflammatory actions and so are capable of producing endothelial dysfunction, retinal ischemia and pathological angiogenesis. Leukocytes are activated, and when diabetes is associated with hypertension there could be enhanced production of angiotensin-II, which has pro-inflammatory actions. Angiotensin-II is capable of enhancing ROS generation by leukocytes and stimulates increased production of IL-6, TNF-α and MIF and pro-inflammatory eicosanoids. Under normal physiological conditions, AA, EPA and DHA can also give rise to the formation of anti-inflammatory lipoxins (LXs), resolvins (RVs), protectins (PRs) and maresins (MaRs), which suppress leukocyte activation, ROS generation, PGs, LTs and TXs, formation of angiotensin-II, VEGF production and activation of iNOS. These events would ultimately result in suppression of inflammation and preservation of the blood retinal barrier and prevention of retinal ischemia and thus amelioration of DME, DR and AMD. Lipoxins, resolvins and protectins enhance the production of CO, a vasodilator and anti-inflammatory gas that also has cytoprotective properties. CO can suppress the production of ROS. PEDF produced by retinal pigment epithelial cells has anti-inflammatory, cytoprotective and anti-oxidant properties and is capable of protecting retinal cells and thus preventing DME, AMD and DR. Hyperglycemia suppresses the production of PEDF and thus may initiate the onset of DME, DR and AMD. It is not yet known whether PEDF can enhance the formation of lipoxins, resolvins and protectins and vice versa, though this is a distinct possibility. PEDF suppresses the formation of ROS, IL-6, TNF-α and MIF and expression of adhesion molecules and preserves the blood retinal barrier. BDNF is another neurotrophic factor that preserves retinal cell integrity, enhances formation of lipoxins, resolvins, protectins and maresins and prevents DME, DR and AMD. For details see the text
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Figure 0005: Scheme showing possible sequence of events that lead to the development of DME, DR and AMD. Hyperglycemia causes activation of leukocytes, macrophages and lymphocytes, resulting in increased production of reactive oxygen species (ROS) and pro-inflammatory IL-6, TNF-α, macrophage migration inhibitory factor (MIF) and other cytokines. These cytokines also enhance ROS production and enhance the production and release of pro-inflammatory eicosanoids ((prostaglandins (PGs), leukotrienes (LTs) and thromboxanes (TXs)) by activating cell membrane bound phospholipase A2 (PLA2) that induces the release of polyunsaturated fatty acids: arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are precursors of PGs, LTs and TXs. IL-6, TNF-α, MIF, PGs, LTs and TXs enhance the expression of adhesion molecules, which leads to adhesion of leukocytes to endothelial cells, resulting in endothelial dysfunction due to the action of ROS released by adherent leukocytes on endothelial cells. Eicosanoids, cytokines, ROS and endothelial dysfunction can cause breakdown of the blood-retinal barrier, resulting in increased vascular permeability and fluid accumulation in the retinal tissue via special water fluxes. This leads to retinal ischemia and increased production of VEGF and pathological angiogenesis, events that result in the initiation and progression of retinal edema, macular degeneration and DR. Increased production of IL-6, TNF-α, MIF, and eicosanoids also induces enhanced production of VEGF and iNOS, which have pro-inflammatory actions and so are capable of producing endothelial dysfunction, retinal ischemia and pathological angiogenesis. Leukocytes are activated, and when diabetes is associated with hypertension there could be enhanced production of angiotensin-II, which has pro-inflammatory actions. Angiotensin-II is capable of enhancing ROS generation by leukocytes and stimulates increased production of IL-6, TNF-α and MIF and pro-inflammatory eicosanoids. Under normal physiological conditions, AA, EPA and DHA can also give rise to the formation of anti-inflammatory lipoxins (LXs), resolvins (RVs), protectins (PRs) and maresins (MaRs), which suppress leukocyte activation, ROS generation, PGs, LTs and TXs, formation of angiotensin-II, VEGF production and activation of iNOS. These events would ultimately result in suppression of inflammation and preservation of the blood retinal barrier and prevention of retinal ischemia and thus amelioration of DME, DR and AMD. Lipoxins, resolvins and protectins enhance the production of CO, a vasodilator and anti-inflammatory gas that also has cytoprotective properties. CO can suppress the production of ROS. PEDF produced by retinal pigment epithelial cells has anti-inflammatory, cytoprotective and anti-oxidant properties and is capable of protecting retinal cells and thus preventing DME, AMD and DR. Hyperglycemia suppresses the production of PEDF and thus may initiate the onset of DME, DR and AMD. It is not yet known whether PEDF can enhance the formation of lipoxins, resolvins and protectins and vice versa, though this is a distinct possibility. PEDF suppresses the formation of ROS, IL-6, TNF-α and MIF and expression of adhesion molecules and preserves the blood retinal barrier. BDNF is another neurotrophic factor that preserves retinal cell integrity, enhances formation of lipoxins, resolvins, protectins and maresins and prevents DME, DR and AMD. For details see the text

Mentions: It is known that PUFAs and their anti-inflammatory products lipoxins, resolvins, protectins and maresins inhibit the production of IL-6 and TNF-α and suppress the expression of ICAM-1 and VCAM and induce resolution of the inflammatory process [98–105]. This implies that presence of appropriate amounts of PUFAs (including AA) and formation of their anti-inflammatory products lipoxins, resolvins, protectins and maresins serve as negative feedback inhibitors of pro-inflammatory IL-6, IL-2 and TNF-α formation and action and thus suppress inflammatory events and restore homeostasis. In addition, PUFAs and lipoxins, resolvins, protectins and maresins suppress whereas pro-inflammatory prostaglandins (especially PGE2 and PGE1) enhance VEGF production [106–114]. It was reported that epoxy metabolites of DHA formed due to the action of cytochrome P450 activity inhibit VEGF- and fibroblast growth factor 2-induced angiogenesis in vivo, and suppress endothelial cell migration and protease production in vitro via a VEGF receptor 2-dependent mechanism [114]. It is likely that similar epoxy metabolites formed from AA and EPA may also inhibit VEGF production and action. These results suggest that several metabolites of AA, EPA and DHA that have both pro- and anti-inflammatory actions can either enhance or suppress the production and action of VEGF. This indicates that maintaining a delicate balance between these pro- and anti-inflammatory products of AA, EPA and DHA and their action on VEGF, and pro- and anti-inflammatory cytokines ultimately determines either continuation or persistence of inflammation and suppression of inflammation and restoration of homeostasis (see Figures 4 and 5). These results imply that it is not just the presence of adequate concentrations of AA, EPA and DHA that is essential to suppress inflammation and restore normalcy but it is essential for the formation of appropriate amounts of their anti-inflammatory lipoxins, resolvins, protectins, maresins and epoxy metabolites to trigger the anti-inflammatory process and resolve inflammation. In view of this, activities of Δ6 and Δ5 desaturases (which are essential to metabolize essential fatty acids LA and ALA to their respective long-chain products: AA and EPA and DHA, respectively), COX-2 and 5-, 12- and 15-lipoxygenases (which are needed for the formation of lipoxins, resolvins, protectins and maresins) and cytochrome P450 activity (to form relevant epoxy metabolites) (see Figures 1–3), several co-factors needed for the activities of these enzymes and their genetic polymorphisms may play a significant role in the pathobiology of DME, DR and AMD by influencing the formation of AA, EPA and DHA, lipoxins, resolvins, protectins, maresins and epoxy metabolites of AA, EPA and DHA.


Diabetic macular edema, retinopathy and age-related macular degeneration as inflammatory conditions
Scheme showing possible sequence of events that lead to the development of DME, DR and AMD. Hyperglycemia causes activation of leukocytes, macrophages and lymphocytes, resulting in increased production of reactive oxygen species (ROS) and pro-inflammatory IL-6, TNF-α, macrophage migration inhibitory factor (MIF) and other cytokines. These cytokines also enhance ROS production and enhance the production and release of pro-inflammatory eicosanoids ((prostaglandins (PGs), leukotrienes (LTs) and thromboxanes (TXs)) by activating cell membrane bound phospholipase A2 (PLA2) that induces the release of polyunsaturated fatty acids: arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are precursors of PGs, LTs and TXs. IL-6, TNF-α, MIF, PGs, LTs and TXs enhance the expression of adhesion molecules, which leads to adhesion of leukocytes to endothelial cells, resulting in endothelial dysfunction due to the action of ROS released by adherent leukocytes on endothelial cells. Eicosanoids, cytokines, ROS and endothelial dysfunction can cause breakdown of the blood-retinal barrier, resulting in increased vascular permeability and fluid accumulation in the retinal tissue via special water fluxes. This leads to retinal ischemia and increased production of VEGF and pathological angiogenesis, events that result in the initiation and progression of retinal edema, macular degeneration and DR. Increased production of IL-6, TNF-α, MIF, and eicosanoids also induces enhanced production of VEGF and iNOS, which have pro-inflammatory actions and so are capable of producing endothelial dysfunction, retinal ischemia and pathological angiogenesis. Leukocytes are activated, and when diabetes is associated with hypertension there could be enhanced production of angiotensin-II, which has pro-inflammatory actions. Angiotensin-II is capable of enhancing ROS generation by leukocytes and stimulates increased production of IL-6, TNF-α and MIF and pro-inflammatory eicosanoids. Under normal physiological conditions, AA, EPA and DHA can also give rise to the formation of anti-inflammatory lipoxins (LXs), resolvins (RVs), protectins (PRs) and maresins (MaRs), which suppress leukocyte activation, ROS generation, PGs, LTs and TXs, formation of angiotensin-II, VEGF production and activation of iNOS. These events would ultimately result in suppression of inflammation and preservation of the blood retinal barrier and prevention of retinal ischemia and thus amelioration of DME, DR and AMD. Lipoxins, resolvins and protectins enhance the production of CO, a vasodilator and anti-inflammatory gas that also has cytoprotective properties. CO can suppress the production of ROS. PEDF produced by retinal pigment epithelial cells has anti-inflammatory, cytoprotective and anti-oxidant properties and is capable of protecting retinal cells and thus preventing DME, AMD and DR. Hyperglycemia suppresses the production of PEDF and thus may initiate the onset of DME, DR and AMD. It is not yet known whether PEDF can enhance the formation of lipoxins, resolvins and protectins and vice versa, though this is a distinct possibility. PEDF suppresses the formation of ROS, IL-6, TNF-α and MIF and expression of adhesion molecules and preserves the blood retinal barrier. BDNF is another neurotrophic factor that preserves retinal cell integrity, enhances formation of lipoxins, resolvins, protectins and maresins and prevents DME, DR and AMD. For details see the text
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5016593&req=5

Figure 0005: Scheme showing possible sequence of events that lead to the development of DME, DR and AMD. Hyperglycemia causes activation of leukocytes, macrophages and lymphocytes, resulting in increased production of reactive oxygen species (ROS) and pro-inflammatory IL-6, TNF-α, macrophage migration inhibitory factor (MIF) and other cytokines. These cytokines also enhance ROS production and enhance the production and release of pro-inflammatory eicosanoids ((prostaglandins (PGs), leukotrienes (LTs) and thromboxanes (TXs)) by activating cell membrane bound phospholipase A2 (PLA2) that induces the release of polyunsaturated fatty acids: arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are precursors of PGs, LTs and TXs. IL-6, TNF-α, MIF, PGs, LTs and TXs enhance the expression of adhesion molecules, which leads to adhesion of leukocytes to endothelial cells, resulting in endothelial dysfunction due to the action of ROS released by adherent leukocytes on endothelial cells. Eicosanoids, cytokines, ROS and endothelial dysfunction can cause breakdown of the blood-retinal barrier, resulting in increased vascular permeability and fluid accumulation in the retinal tissue via special water fluxes. This leads to retinal ischemia and increased production of VEGF and pathological angiogenesis, events that result in the initiation and progression of retinal edema, macular degeneration and DR. Increased production of IL-6, TNF-α, MIF, and eicosanoids also induces enhanced production of VEGF and iNOS, which have pro-inflammatory actions and so are capable of producing endothelial dysfunction, retinal ischemia and pathological angiogenesis. Leukocytes are activated, and when diabetes is associated with hypertension there could be enhanced production of angiotensin-II, which has pro-inflammatory actions. Angiotensin-II is capable of enhancing ROS generation by leukocytes and stimulates increased production of IL-6, TNF-α and MIF and pro-inflammatory eicosanoids. Under normal physiological conditions, AA, EPA and DHA can also give rise to the formation of anti-inflammatory lipoxins (LXs), resolvins (RVs), protectins (PRs) and maresins (MaRs), which suppress leukocyte activation, ROS generation, PGs, LTs and TXs, formation of angiotensin-II, VEGF production and activation of iNOS. These events would ultimately result in suppression of inflammation and preservation of the blood retinal barrier and prevention of retinal ischemia and thus amelioration of DME, DR and AMD. Lipoxins, resolvins and protectins enhance the production of CO, a vasodilator and anti-inflammatory gas that also has cytoprotective properties. CO can suppress the production of ROS. PEDF produced by retinal pigment epithelial cells has anti-inflammatory, cytoprotective and anti-oxidant properties and is capable of protecting retinal cells and thus preventing DME, AMD and DR. Hyperglycemia suppresses the production of PEDF and thus may initiate the onset of DME, DR and AMD. It is not yet known whether PEDF can enhance the formation of lipoxins, resolvins and protectins and vice versa, though this is a distinct possibility. PEDF suppresses the formation of ROS, IL-6, TNF-α and MIF and expression of adhesion molecules and preserves the blood retinal barrier. BDNF is another neurotrophic factor that preserves retinal cell integrity, enhances formation of lipoxins, resolvins, protectins and maresins and prevents DME, DR and AMD. For details see the text
Mentions: It is known that PUFAs and their anti-inflammatory products lipoxins, resolvins, protectins and maresins inhibit the production of IL-6 and TNF-α and suppress the expression of ICAM-1 and VCAM and induce resolution of the inflammatory process [98–105]. This implies that presence of appropriate amounts of PUFAs (including AA) and formation of their anti-inflammatory products lipoxins, resolvins, protectins and maresins serve as negative feedback inhibitors of pro-inflammatory IL-6, IL-2 and TNF-α formation and action and thus suppress inflammatory events and restore homeostasis. In addition, PUFAs and lipoxins, resolvins, protectins and maresins suppress whereas pro-inflammatory prostaglandins (especially PGE2 and PGE1) enhance VEGF production [106–114]. It was reported that epoxy metabolites of DHA formed due to the action of cytochrome P450 activity inhibit VEGF- and fibroblast growth factor 2-induced angiogenesis in vivo, and suppress endothelial cell migration and protease production in vitro via a VEGF receptor 2-dependent mechanism [114]. It is likely that similar epoxy metabolites formed from AA and EPA may also inhibit VEGF production and action. These results suggest that several metabolites of AA, EPA and DHA that have both pro- and anti-inflammatory actions can either enhance or suppress the production and action of VEGF. This indicates that maintaining a delicate balance between these pro- and anti-inflammatory products of AA, EPA and DHA and their action on VEGF, and pro- and anti-inflammatory cytokines ultimately determines either continuation or persistence of inflammation and suppression of inflammation and restoration of homeostasis (see Figures 4 and 5). These results imply that it is not just the presence of adequate concentrations of AA, EPA and DHA that is essential to suppress inflammation and restore normalcy but it is essential for the formation of appropriate amounts of their anti-inflammatory lipoxins, resolvins, protectins, maresins and epoxy metabolites to trigger the anti-inflammatory process and resolve inflammation. In view of this, activities of Δ6 and Δ5 desaturases (which are essential to metabolize essential fatty acids LA and ALA to their respective long-chain products: AA and EPA and DHA, respectively), COX-2 and 5-, 12- and 15-lipoxygenases (which are needed for the formation of lipoxins, resolvins, protectins and maresins) and cytochrome P450 activity (to form relevant epoxy metabolites) (see Figures 1–3), several co-factors needed for the activities of these enzymes and their genetic polymorphisms may play a significant role in the pathobiology of DME, DR and AMD by influencing the formation of AA, EPA and DHA, lipoxins, resolvins, protectins, maresins and epoxy metabolites of AA, EPA and DHA.

View Article: PubMed Central - PubMed

ABSTRACT

Diabetic macular edema (DME) and diabetic retinopathy (DR) are complications affecting about 25% of all patients with long-standing type 1 and type 2 diabetes mellitus and are a major cause of significant decrease in vision and quality of life. Age-related macular degeneration (AMD) is not uncommon, and diabetes mellitus affects the incidence and progression of AMD through altering hemodynamics, increasing oxidative stress, accumulating advanced glycation end products, etc. Recent studies suggest that DME, DR and AMD are inflammatory conditions characterized by a breakdown of the blood-retinal barrier, inflammatory processes and an increase in vascular permeability. Key factors that seem to have a dominant role in DME, DR and AMD are angiotensin II, prostaglandins and the vascular endothelial growth factor and a deficiency of anti-inflammatory bioactive lipids. The imbalance between pro- and anti-inflammatory eicosanoids and enhanced production of pro-angiogenic factors may initiate the onset and progression of DME, DR and AMD. This implies that bioactive lipids that possess anti-inflammatory actions and suppress the production of angiogenic factors could be employed in the prevention and management of DME, DR and AMD.

No MeSH data available.


Related in: MedlinePlus