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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.


Scheme showing the formation of LXA4 from AA, resolvin E1 (RvE1) from EPA and protectin D1 (PD1), resolvin D1 (RvD1) and maresin (MaR1) from DHA
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Figure 0003: Scheme showing the formation of LXA4 from AA, resolvin E1 (RvE1) from EPA and protectin D1 (PD1), resolvin D1 (RvD1) and maresin (MaR1) from DHA

Mentions: The essential fatty acids (EFAs) n-3 α-linolenic acid (ALA) and n-6 linoleic acid (LA) are widely distributed in our diet, and fatty acids are metabolized by the same set of enzymes, Δ6 and Δ5 desaturases and elongases, into their long-chain metabolites, namely: ALA to eicosapentaenoic and docosahexaenoic acids (EPA and DHA respectively) and LA to arachidonic acid (AA) (see Figure 1) [19–21]. All cell membranes incorporate both EFAs and their long-chain metabolites AA, EPA and DHA mainly into their phospholipid (PL) fraction. Various stimuli such as growth factors including epidermal growth factor (EGF) and VEGF, various cytokines and free radicals have the ability to activate phospholipase A2 (PLA2), which is a membrane bound enzyme that induces the release of AA, EPA and DHA to form their respective products. AA, EPA and DHA are metabolized by cyclo-oxygenases (COXs), lipoxygenases (LOXs), and cytochrome P450 (Cyp450) enzymes, which results in the formation of several products (see Figure 2). AA forms a precursor to pro-inflammatory PGs and thromboxanes (TXs) of 2 series and leukotrienes (LTs) of 4 series (though not all prostaglandins formed are pro-inflammatory; for instance, prostacyclin from AA and PGE1 from dihomo-gamma-linolenic acid (DGLA) have anti-inflammatory actions), whereas EPA forms a precursor to 3 series PGs, TXs and 5 series LTs. It is noteworthy that AA can also give rise to lipoxins, which are potent anti-inflammatory molecules. Similarly, EPA gives rise to resolvins and DHA to protectins, which possess significant anti-inflammatory and wound healing properties and show cytoprotective actions. Thus, AA, EPA and DHA, under some well-defined conditions, form specific anti-inflammatory lipoxins, resolvins and protectins, respectively, that protect various cells and tissues against insults and augment recovery of the target tissues and organs to normal and reestablish homeostasis (see Figure 3). Since the retina and brain are rich in AA, DHA and EPA (DHA > AA > EPA), it is reasonable to assume that adequate amounts of lipoxins, resolvins and protectins are formed under normal physiological conditions to protect the retina and other neuronal cells from various insults and diseases [19–21]. This evidence indicates that PUFAs are not only biologically active by themselves but are also capable of giving rise to several biologically active metabolites that play an important role in physiological and pathological processes.


Diabetic macular edema, retinopathy and age-related macular degeneration as inflammatory conditions
Scheme showing the formation of LXA4 from AA, resolvin E1 (RvE1) from EPA and protectin D1 (PD1), resolvin D1 (RvD1) and maresin (MaR1) from DHA
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 0003: Scheme showing the formation of LXA4 from AA, resolvin E1 (RvE1) from EPA and protectin D1 (PD1), resolvin D1 (RvD1) and maresin (MaR1) from DHA
Mentions: The essential fatty acids (EFAs) n-3 α-linolenic acid (ALA) and n-6 linoleic acid (LA) are widely distributed in our diet, and fatty acids are metabolized by the same set of enzymes, Δ6 and Δ5 desaturases and elongases, into their long-chain metabolites, namely: ALA to eicosapentaenoic and docosahexaenoic acids (EPA and DHA respectively) and LA to arachidonic acid (AA) (see Figure 1) [19–21]. All cell membranes incorporate both EFAs and their long-chain metabolites AA, EPA and DHA mainly into their phospholipid (PL) fraction. Various stimuli such as growth factors including epidermal growth factor (EGF) and VEGF, various cytokines and free radicals have the ability to activate phospholipase A2 (PLA2), which is a membrane bound enzyme that induces the release of AA, EPA and DHA to form their respective products. AA, EPA and DHA are metabolized by cyclo-oxygenases (COXs), lipoxygenases (LOXs), and cytochrome P450 (Cyp450) enzymes, which results in the formation of several products (see Figure 2). AA forms a precursor to pro-inflammatory PGs and thromboxanes (TXs) of 2 series and leukotrienes (LTs) of 4 series (though not all prostaglandins formed are pro-inflammatory; for instance, prostacyclin from AA and PGE1 from dihomo-gamma-linolenic acid (DGLA) have anti-inflammatory actions), whereas EPA forms a precursor to 3 series PGs, TXs and 5 series LTs. It is noteworthy that AA can also give rise to lipoxins, which are potent anti-inflammatory molecules. Similarly, EPA gives rise to resolvins and DHA to protectins, which possess significant anti-inflammatory and wound healing properties and show cytoprotective actions. Thus, AA, EPA and DHA, under some well-defined conditions, form specific anti-inflammatory lipoxins, resolvins and protectins, respectively, that protect various cells and tissues against insults and augment recovery of the target tissues and organs to normal and reestablish homeostasis (see Figure 3). Since the retina and brain are rich in AA, DHA and EPA (DHA > AA > EPA), it is reasonable to assume that adequate amounts of lipoxins, resolvins and protectins are formed under normal physiological conditions to protect the retina and other neuronal cells from various insults and diseases [19–21]. This evidence indicates that PUFAs are not only biologically active by themselves but are also capable of giving rise to several biologically active metabolites that play an important role in physiological and pathological processes.

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.