Lipoksin A4 (LXA4) Diyabetik Retinopati (DR) İçin Bir Tedavi Olarak

Özet (abstract)

Diabetic retinopathy (DR) is common in those who have long-standing uncontrolled hyperglycemia. DR may result in retinal detachment, vitreal hemorrhage, neovascular glaucoma, and macular edema or capillary nonperfusion and may be associated with microcirculatory dysfunction in other organs as well. Vision loss due to DR can be reduced, prevented, or postponed by control of diabetes and blood pressure and its early detection and treatment. DR Is an Inflammatory Condition In DR, degeneration of retinal capillaries occurs, resulting in retinal ischemia, which leads to neovascularization. DR is an inflammatory condition since it is associated with (i) enhanced vitreal and plasma concentrations of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), (ii) leukostasis, (iii) increased vascular permeability, (iv) activation of nuclear factor-κB (NF-κB), (v) enhanced expression of inducible nitric oxide (NO) synthase (iNOS), cyclooxygenase-2 (COX-2), and intracellular adhesion molecule-1 (ICAM-1), and (vi) excess generation of vascular endothelial growth factor (VEGF),[1] which are all pro-inflammatory markers. Placental growth factor (PlGF), a member of the VEGF family, is expressed by endothelial cells (ECs) and retinal pigment epithelial cells (RPEs).[2] It (PlGF) binds to fms-like tyrosine kinase-1 (FLT1) and soluble FLT1, a circulating form of FLT1, which results in synergistic effects of PlGF and VEGF.[3] PlGF heterodimers with VEGF result in pro-angiogenic action on ECs. DR retinas have higher expression of PlGF that is localized to endothelial and perivascular regions of neovascular membranes. PlGF is produced by human RPE cells in response to hypoxia and is higher in aqueous and vitreous humor in DR. Higher PlGF protein expression is seen in diabetic vascular ECs. Hyperglycemia activated hypoxia-inducible factor (HIF) 1α–VEGF pathway and increased expression of VEGFR1–3, phospho (p)-VEGFR1, p-VEGFR2, and p-endothelial nitric oxide synthase, which are inhibited in the retinas of diabetic PlGF-/- mice, suggesting that PlGF is needed for the development of DR, but PlGF alone is not sufficient to produce all features of DR. Prevention of DR needs Akt activation and HIF1α-VEGF pathway inhibition.[4] Thus, suppression of pro-inflammatory cytokines, decreasing vascular permeability by stabilizing vascular ECs and pericytes, suppression of nuclear factor kappa B (NF-κB), iNOS, COX-2, ICAM-1, and VEGF (including PlGF) can prevent DR. Role of Prostaglandins (PGs) in DR Retina, and in particular retinal pigment epithelium (RPE), is rich in docosahexaenoic acid (DHA, 22:6 n-3) and arachidonic acid (AA) (20:4 n-6) (DHA > AA)[5] that are essential for RPE function. DHA and AA prevent RPE degeneration induced by oxidative stress.[6] DHA enhances pigment epithelial-derived factor (PEDF) generation, a cytoprotective molecule, that blocks oxidative stress induced damage.[7] Pericytes and ECs that are needed for the blood-retinal barrier function are disrupted in diabetes. Hyperglycemia enhances protein kinase C-δ (PKC-δ) expression, which prevents platelet-derived growth factor (PDGF) signaling to Akt (a serine/threonine kinase) as a result of pericyte cell death. Vascular angiogenesis seen in DR is due to loss of pericytes, increased VEGF expression, activation of PKC-β (protein kinase -beta) in ECs, and loss of the junctional complex.[1] Enhanced generation of pro-inflammatory prostaglandin E2 (PGE2) and leukotrienes (LTs) and decreased production of anti-inflammatory lipoxin A4 (LXA4), resolvins, protectins, and maresins is known to occur in DR.[8] These observations suggest that restoring the imbalance between pro- and anti-inflammatory eicosanoids (these include PGs, leukotrienes, thromboxanes, and other metabolites formed from AA, DHA, and eicosapentaenoic acid [EPA]) may suppress DR (see Figs. 1 and 2 for metabolism of AA, EPA, and DHA). One method of restoring this imbalance to normal could be local injections/instillation of LXA4, resolvins, protectins, and maresins.Figure 1: Scheme showing the metabolism of AA. It is evident from the scheme that there is a close interaction(s) between LOX and COX enzymes and products. AA = arachidonic acid, COX = cyclooxygenase-2, LOX = lipoxygenaseFigure 2: Scheme showing the metabolism of essential fatty acids and their role in inflammation. Hyperglycemia enhances the production of IL-6, TNF-α, and VEGF by infiltrating immunocytes, retinal vascular endothelial cells, etc. Hyperglycemia decreases the activities of desaturases, resulting in decreased formation of GLA, DGLA, AA, EPA, and DHA, the precursors of PGE1, PGI2, LXA4, resolvins, protectins, and maresins that are anti-inflammatory in nature. Hyperglycemia also causes enhanced activity of COX-2, resulting in increased production of PGE2, leukotrienes (LTs), and thromboxanes (TXs) that have pro-inflammatory actions and enhance platelet aggregation and augment retinal ischemia. Corticosteroids block the activities of desaturases, COX-2, and LOX and thus inhibit the formation of PGE2, LTs, and TXs that initially suppress inflammation. But continuous use of steroids results in a deficiency of GLA, DGLA, AA, EPA, and DHA, leading to reduced formation of PGE1, PGI2, LXA4, resolvins, protectins, and maresins that are needed to suppress inappropriate inflammation and enhance tissue regeneration. AA = arachidonic acid, COX = cyclooxygenase-2, DHA = docosahexaenoic acid, EPA = eicosapentaenoic acid, IL-6 = interleukin-6, LOX = lipoxygenase, LXA4 = lipoxin A4, TNF-α = tumor necrosis factor-alpha, PGE1 = prostaglandin E1, VEGF = vascular endothelial growth factor, PGI2 = Prostacyclin, DGLA = Dihomo-gamma-linolenic acidNeuroprotectin D1 (NPD1) counteracts H2O2/tumor necrosis factor-α/oxidative-stress-triggered apoptosis of RPE.[9] Previously, we observed that plasma and vitreal content of brain-derived neurotrophic factors (BDNFs) and lipoxin A4 are low, whereas IL-6 and VEGF are increased in DR.[10] Altered Essential Fatty Acids (EFAs) Metabolism Occurs in DM and DR It was reported that plasma phospholipid concentrations of AA, EPA, and DHA, the precursors of LXA4, resolvins, protectins, and maresins, are decreased in those with type 1 and type 2 Diabetes mellitus (DM).[11,12] Transgenic fat-1 mice that have high plasma and tissue concentrations of n-3 fatty acids and low AA levels are resistant to type 1 and high-fat-induced type 2 DM because they have high levels of pancreatic tissue LXA4 (derived from AA) and 18-hydroxyeicosapentaenoic acid (18-HEPE, which is derived from EPA). Furthermore, diabetic animals have decreased activities of desaturases in both retina and liver, enhanced activity of COX-2, 5-lipoxygenase (5-LOX) and 12-LOX enzymes in the retina, decreased plasma concentrations of Gamma-linolenic acid (GLA) and AA with no change in EPA and DHA,[12,13] and increased plasma concentrations of PGE2, hydroxyeicosatetraenoic acids (HETEs), and LTs (derived from AA).[13] In addition, diabetic animals and patients with type 2 DM have low plasma and tissue concentrations of LXA4 (and possibly, resolvins, protectins, and maresins).[10] PGE2 and 12-HETE have pro-inflammatory actions, while 18-HEPE and LXA4 possess anti-inflammatory actions. Based on these results, it is reasonable to suggest that LXA4 is critical not only to prevent DM (both type 1 and type 2) but also DR. LXA4 inhibits EC proliferation, free radical generation, and the production of VEGF and PDGF, while promoting BDNF generation. BDNF has anti-diabetic, cyto- and neuroprotective actions.[14] AA, EPA, and DHA and Their Metabolites in DR EPA, DHA, and AA prevent neovascular age-related macular degeneration (AMD) and regulate retinal vaso-obliteration and neovascularization.[15] EPA and DHA-derived NPD1, resolvin D1, and resolvin E1 prevent neovascularization by inhibiting TNF-α.[16] We showed that plasma and vitreal concentrations of LXA4 and BDNF are low in DR.[10] LXA4 and BDNF are potent anti-diabetic molecules that interact and potentiate each other’s synthesis and action.[1,16] Thus, PGE2, 12-HETE, 18-HEPE, LXA4, resolvins, protectins and maresins, BDNF, cytokines, and VEGF have a critical role in DR. Anti-TNF-α therapy currently employed for DR is in tune with the fact that plasma and vitreal VEGF levels are increased in DR. LXA4 suppresses VEGF production, COX-2, and NF-κB expression and has potent anti-inflammatory actions.[16] It is suggested that LXA4 is useful to prevent and manage DR. Similar protective action may also reside with resolvins, protectins, and maresins since they are anti-inflammatory in nature and enhance LXA4 production.[16] AA, DHA, LXA4, Resolvins, and Protectins are Safe to Administer A single dose of intravitreal injections of 50 µg/50 µL, 25 µg/50 µL, and 5 µg/50 µL of DHA is safe in rabbits with no adverse events.[17] LXA4 is neuroprotective. Reduced retinal ALOX15 expression decreases the generation of LXA4, resolvins (RvDs), and reduced resolvins enhances the progression of retinitis pigmentosa.[18] Resolvin D1 enhances the production of LXA4 and BDNF.[16] LXA4 reduced alkali-induced corneal inflammation, neovascularization, and augmented the tissue repair process without any side effects.[19] Conclusions and Therapeutic Implications It is evident from the preceding discussion that DR is an inflammatory condition. AA and DHA are needed for RPE functional integrity and prevent retinal degeneration. Maintaining the delicate balance between pro- and anti-inflammatory molecules (cytokines, PGs, leukotrienes, lipoxins, resolvins, protectins, and adhesion molecules) is critical to maintain both retinal structural integrity and function and prevent DR. These observations suggest that DR is an LXA4 deficiency disorder. Hence, it is proposed that intravitreal injection of LXA4 can be employed as a therapeutic option to prevent and manage DR and other retinal conditions such as AMD, macular edema, and RP. In addition, LXA4 could be of significant benefit in keratitis, uveitis, and to augment the healing of corneal ulcers. Hence, the potential use of local application of LXA4 (resolvins, protectins, and maresins) for keratitis and corneal ulcers may be attempted. In this context, it is noteworthy that LXA4 has been tried experimentally in the treatment of arthritis, asthma, and other pulmonary and cardiovascular diseases that are also pro-inflammatory conditions. This implies that LXA4 is of significant benefit in the prevention and treatment of several pro-inflammatory conditions, including DR. Contributions UND is the sole contributor to this work and manuscript (including concept, design, definition of intellectual content, literature search, data acquisition, data analysis, statistical analysis, manuscript preparation, manuscript editing, and manuscript review).

Yazarların özeti; kaynağından alınmıştır. Indian Journal of Ophthalmology, 2026 · DOI ↗