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Acta Ophthalmologica May 2010Diabetic macular oedema (DMO) is an important cause of vision loss in patients with diabetes mellitus. The underlying mechanisms of DMO, on both macrocellular and... (Review)
Review
Diabetic macular oedema (DMO) is an important cause of vision loss in patients with diabetes mellitus. The underlying mechanisms of DMO, on both macrocellular and microcellular levels, are discussed in this review. The pathophysiology of DMO can be described as a process whereby hyperglycaemia leads to overlapping and inter-related pathways that play a role not only in the initial vascular events, but also in the continued tissue insult that leads to chronic DMO. On a macrocellular level, DMO is believed to be in part caused by alterations in hydrostatic pressure, oxygen tension, oncotic pressure and shear stress. Three key components of the microvascular pathways include angiogenic factor expression, inflammation and oxidative stress. These molecular mediators, acting in conjunction with macrocellular factors, which are all stimulated in part by the hyperglycaemia and hypoxia, can have a direct endothelial effect leading to hyperpermeability, disruption of vascular endothelial cell junctions, and leukostasis. The interactions, signalling events and feedback loops between the various molecules are complicated and are not completely understood. However, by attempting to understand the pathways involved in DMO, we can help guide new treatment options targeted towards specific factors or mediators.
Topics: Blood Glucose; Blood-Retinal Barrier; Diabetes Mellitus; Diabetic Retinopathy; Humans; Hyperglycemia; Macular Edema; Retina
PubMed: 20222885
DOI: 10.1111/j.1755-3768.2008.01501.x -
Frontiers in Immunology 2013We have shown previously that diabetes causes increases in retinal arginase activity that are associated with impairment of endothelial cell (EC)-dependent vasodilation...
We have shown previously that diabetes causes increases in retinal arginase activity that are associated with impairment of endothelial cell (EC)-dependent vasodilation and increased formation of the peroxynitrite biomarker nitrotyrosine. Arginase blockade normalizes vasodilation responses and reduces nitrotyrosine formation, suggesting that overactive arginase contributes to diabetic retinopathy by reducing NO and increasing oxidative stress. We tested this hypothesis by studies in streptozotocin-induced diabetic mice and high glucose (HG) treated retinal ECs. Our results show that arginase activity is increased in both diabetic retinas and HG-treated retinal ECs as compared with the controls. Western blot shows that both arginase isoforms are present in retinal vessels and ECs and arginase I is increased in the diabetic vessels and HG-treated retinal ECs. Nitrate/nitrite levels are significantly increased in diabetic retinas, indicating an increase in total NO products. However, levels of nitrite, an indicator of bioavailable NO, are reduced by diabetes. Imaging analysis of NO formation in retinal sections confirmed decreases in NO formation in diabetic retinas. The decrease in NO is accompanied by increased [Formula: see text] formation and increased leukocyte attachment in retinal vessels. Studies in knockout mice show that arginase gene deletion enhances NO formation, reduces [Formula: see text] and prevents leukostasis in the diabetic retinas. HG treatment of retinal ECs also reduces NO release, increases oxidative stress, increases ICAM-1, and induces EC death. Arginase inhibitor treatment reverses these effects. In conclusion, diabetes- and HG-induced signs of retinal vascular activation and injury are associated with increased arginase activity and expression, decreased bioavailable NO, and increased [Formula: see text] formation. Blockade of the arginase pathway prevents these alterations, suggesting a primary role of arginase in the pathophysiological process.
PubMed: 23840196
DOI: 10.3389/fimmu.2013.00173 -
Medicina (Kaunas, Lithuania) Sep 2022: Acute hematologic malignancies are a group of heterogeneous blood diseases with a high mortality rate, mostly due to acute respiratory failure (ARF). Acute respiratory... (Review)
Review
: Acute hematologic malignancies are a group of heterogeneous blood diseases with a high mortality rate, mostly due to acute respiratory failure (ARF). Acute respiratory distress syndrome (ARDS) is one form of ARF which represents a challenging clinical condition. The paper aims to review current knowledge regarding the variable pathogenic mechanisms, as well as therapeutic options for ARDS in acute hematologic malignancy patients. : We provide an overview of ARDS in patients with acute hematologic malignancy, from an etiologic perspective. We searched databases such as PubMed or Google Scholar, including articles published until June 2022, using the following keywords: ARDS in hematologic malignancy, pneumonia in hematologic malignancy, drug-induced ARDS, leukostasis, pulmonary leukemic infiltration, pulmonary lysis syndrome, engraftment syndrome, diffuse alveolar hemorrhage, TRALI in hematologic malignancy, hematopoietic stem cell transplant ARDS, radiation pneumonitis. We included relevant research articles, case reports, and reviews published in the last 18 years. The main causes of ARDS in acute hematologic malignancy are: pneumonia-associated ARDS, leukostasis, leukemic infiltration of the lung, pulmonary lysis syndrome, drug-induced ARDS, radiotherapy-induced ARDS, diffuse alveolar hemorrhage, peri-engraftment respiratory distress syndrome, hematopoietic stem cell transplantation-related ARDS, transfusion-related acute lung injury. The short-term prognosis of ARDS in acute hematologic malignancy relies on prompt diagnosis and treatment. Due to its etiological heterogeneity, precision-based strategies should be used to improve overall survival. Future studies should focus on identifying the relevance of such etiologic-based diagnostic strategies in ARDS secondary to acute hematologic malignancy.
Topics: Hematologic Neoplasms; Humans; Leukemic Infiltration; Leukostasis; Lung; Lung Diseases; Respiratory Distress Syndrome
PubMed: 36143892
DOI: 10.3390/medicina58091215 -
Scientific Reports Aug 2017To investigate the effect of glucose transporter-1 (GLUT1) inhibition on diabetic retinopathy, we divided forty-eight mice into scrambled siRNA, diabetic scrambled...
To investigate the effect of glucose transporter-1 (GLUT1) inhibition on diabetic retinopathy, we divided forty-eight mice into scrambled siRNA, diabetic scrambled siRNA, and GLUT1 siRNA (intravitreally injected) groups. Twenty-one weeks after diabetes induction, we calculated retinal glucose concentrations, used electroretinography (ERG) and histochemical methods to assess photoreceptor degeneration, and conducted immunoblotting, leukostasis and vascular leakage assays to estimate microangiopathy. The diabetic scrambled siRNA and GLUT1 siRNA exhibited higher glucose concentrations than scrambled siRNA, but GLUT1 siRNA group concentrations were only 50.05% of diabetic scrambled siRNA due to downregulated GLUT1 expression. The diabetic scrambled siRNA and GLUT1 siRNA had lower ERG amplitudes and ONL thicknesses than scrambled siRNA. However, compared with diabetic scrambled siRNA, GLUT1 siRNA group amplitudes and thicknesses were higher. Diabetic scrambled siRNA cones were more loosely arranged and had shorter outer segments than GLUT1 siRNA cones. ICAM-1 and TNF-α expression levels, adherent leukocyte numbers, fluorescence leakage areas and extravasated Evans blue in diabetic scrambled siRNA were higher than those in scrambled siRNA. However, these parameters in the GLUT1 siRNA were lower than diabetic scrambled siRNA. Together, these results demonstrate that GLUT1 siRNA restricted glucose transport by inhibiting GLUT1 expression, which decreased retinal glucose concentrations and ameliorated diabetic retinopathy.
Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Electroretinography; Glucose; Glucose Transporter Type 1; Intercellular Adhesion Molecule-1; Intravitreal Injections; Male; Mice; Oncogene Proteins; RNA, Small Interfering; Retina; Transcriptional Regulator ERG; Treatment Outcome; Tumor Necrosis Factor-alpha
PubMed: 28785055
DOI: 10.1038/s41598-017-07942-x -
Cureus May 2018We present a case of a subacute headache related to leukostasis secondary to accelerated chronic myeloid leukemia (CML), which required white blood cell (WBC) reduction...
We present a case of a subacute headache related to leukostasis secondary to accelerated chronic myeloid leukemia (CML), which required white blood cell (WBC) reduction in the emergency department. A 28-year-old male presented to the emergency department with a chronic headache found to be secondary to leukostasis from accelerated CML with a white blood cell count of 801,000 and 9% blasts. He had bilateral retinal hemorrhage and a headache associated with elevated intracranial pressure. Hydroxyurea and allopurinol were initiated in the emergency department and the patient was eventually transitioned to a tyrosine kinase inhibitor as outpatient therapy. Headaches are a frequent cause of emergency department visits, and this case illustrates another possible etiology of headache requiring emergent intervention.
PubMed: 30027015
DOI: 10.7759/cureus.2623 -
Vascular Expression of Permeability-Resistant Occludin Mutant Preserves Visual Function in Diabetes.Diabetes Jul 2021Diabetic retinopathy is one of the leading causes of vision loss and blindness. Extensive preclinical and clinical evidence exists for both vascular and neuronal...
Diabetic retinopathy is one of the leading causes of vision loss and blindness. Extensive preclinical and clinical evidence exists for both vascular and neuronal pathology. However, the relationship of these changes in the neurovascular unit and impact on vision remains to be determined. Here, we investigate the role of tight junction protein occludin phosphorylation at S490 in modulating barrier properties and its impact on visual function. Conditional vascular expression of the phosphorylation-resistant Ser490 to Ala (S490A) form of occludin preserved tight junction organization and reduced vascular endothelial growth factor (VEGF)-induced permeability and edema formation after intraocular injection. In the retinas of streptozotocin-induced diabetic mice, endothelial-specific expression of the S490A form of occludin completely prevented diabetes-induced permeability to labeled dextran and inhibited leukostasis. Importantly, vascular-specific expression of the occludin mutant completely blocked the diabetes-induced decrease in visual acuity and contrast sensitivity. Together, these results reveal that occludin acts to regulate barrier properties downstream of VEGF in a phosphorylation-dependent manner and that loss of inner blood-retinal barrier integrity induced by diabetes contributes to vision loss.
Topics: Animals; Blood-Retinal Barrier; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Leukostasis; Mice; Mice, Inbred C57BL; Occludin; Permeability; Phosphorylation; Streptozocin; Vascular Endothelial Growth Factor A; Visual Acuity
PubMed: 33883214
DOI: 10.2337/db20-1220 -
British Journal of Pharmacology Mar 2018The kinin B receptor contributes to vascular inflammation and blood-retinal barrier breakdown in diabetic retinopathy (DR). We investigated the changes in expression,...
BACKGROUND AND PURPOSE
The kinin B receptor contributes to vascular inflammation and blood-retinal barrier breakdown in diabetic retinopathy (DR). We investigated the changes in expression, cellular localization and vascular inflammatory effect of B receptors in retina of streptozotocin diabetic rats.
EXPERIMENTAL APPROACH
The distribution of B receptors on retinal cell types was investigated by immunocytochemistry. Effects of B receptor agonist, R-838, and antagonist, R-954, on retinal leukocyte adhesion, gene expression of kinin and VEGF systems, B receptor immunoreactivity, microgliosis and capillary leakage were measured. Effect of B receptor siRNA on gene expression was also assessed.
KEY RESULTS
mRNA levels of the kinin and VEGF systems were significantly enhanced at 2 weeks in streptozotocin (STZ)-retina compared to control-retina and were further increased at 6 weeks. B receptor mRNA levels remained increased at 6 months. B receptor immunolabelling was detected in vascular layers of the retina, on glial and ganglion cells. Intravitreal R-838 amplified B and B receptor gene expression, B receptor levels (immunodetection), leukostasis and vascular permeability at 2 weeks in STZ-retina. Topical application (eye drops) of R-954 reversed these increases in B receptors, leukostasis and vascular permeability. Intravitreal B receptor siRNA inhibited gene expression of kinin and VEGF systems in STZ-retina. Microgliosis was unaffected by R-838 or R-954 in STZ-retina.
CONCLUSION AND IMPLICATIONS
Our results support the detrimental role of B receptors on endothelial and glial cells in acute and advanced phases of DR. Topical application of the B receptor antagonist R-954 seems a feasible therapeutic approach for the treatment of DR.
Topics: Administration, Ophthalmic; Animals; Bradykinin; Capillary Permeability; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Gene Expression Regulation; Leukostasis; Male; RNA, Messenger; RNA, Small Interfering; Rats; Rats, Wistar; Receptor, Bradykinin B1; Retina; Streptozocin
PubMed: 29285756
DOI: 10.1111/bph.14138 -
Molecular Vision Jun 2007Spontaneously diabetic Torii (SDT) rats, an animal model of type 2 diabetes, have a low incidence of neovascular formation and an absence of non-perfused areas in their...
PURPOSE
Spontaneously diabetic Torii (SDT) rats, an animal model of type 2 diabetes, have a low incidence of neovascular formation and an absence of non-perfused areas in their retinas at the proliferative stage that presents tractional retinal detachment with fibrous proliferation. The aim of this study was to determine whether leukostasis is present in the retina, to evaluate the levels of pigment epithelium-derived factor (PEDF) and intracellular adhesion molecule-1 (ICAM-1) levels in the blood of SDT rats, and to examine the effects of PEDF on leukostasis.
METHODS
SDT rats, streptozotocin-induced diabetic (STZ) rats, and control Sprague-Dawley (SD) rats were studied. The index of leukostasis in the retina was determined immunohistochemically by counting the number of labeled adherent leukocytes. The levels of PEDF and the soluble intracellular adhesion molecule (sICAM)-1 in the plasma were measured. To investigate the effect of PEDF and vascular endothelial growth factor (VEGF) on leukostasis, the adhesion of monocytes to human umbilical vein endothelial cells (HUVECs) was assayed in vitro.
RESULTS
SDT and STZ diabetic rats showed a significant increase of retinal leukostasis compared to that of control SD rats, but SDT rats had noteworthy lower levels of leukostasis than STZ rats in long term experiments. The sICAM-1 levels and PEDF expression were up-regulated in both STZ and SDT rats, but the SDT rats showed significantly higher levels of PEDF than STZ rats. In vitro studies showed that exposure of HUVECs to VEGF increased the number of adhering monocytes, and PEDF inhibited the VEGF-induced leukostasis in a dose-dependent manner.
CONCLUSIONS
The inhibition of the VEGF-induced leukostasis by PEDF is most likely responsible for the low incidence of capillary occlusion and retinal neovascularization in SDT rats.
Topics: Animals; Blood; Cell Adhesion; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Endothelial Cells; Eye Proteins; Humans; Intercellular Adhesion Molecule-1; Leukostasis; Monocytes; Nerve Growth Factors; Rats; Rats, Mutant Strains; Rats, Sprague-Dawley; Serpins; Severity of Illness Index; Solubility; Umbilical Veins; Vascular Endothelial Growth Factor A
PubMed: 17653050
DOI: No ID Found -
Nature Communications Feb 2020Neovascular age-related macular degeneration and diabetic retinopathy are prevalent causes of vision loss requiring frequent intravitreous injections of...
Neovascular age-related macular degeneration and diabetic retinopathy are prevalent causes of vision loss requiring frequent intravitreous injections of VEGF-neutralizing proteins, and under-treatment is common and problematic. Here we report incorporation of sunitinib, a tyrosine kinase inhibitor that blocks VEGF receptors, into a non-inflammatory biodegradable polymer to generate sunitinib microparticles specially formulated to self-aggregate into a depot. A single intravitreous injection of sunitinib microparticles potently suppresses choroidal neovascularization in mice for six months and in another model, blocks VEGF-induced leukostasis and retinal nonperfusion, which are associated with diabetic retinopathy progression. After intravitreous injection in rabbits, sunitinib microparticles self-aggregate into a depot that remains localized and maintains therapeutic levels of sunitinib in retinal pigmented epithelium/choroid and retina for more than six months. There is no intraocular inflammation or retinal toxicity. Intravitreous injection of sunitinib microparticles provides a promising approach to achieve sustained suppression of VEGF signaling and improve outcomes in patients with retinal vascular diseases.
Topics: Animals; Choroidal Neovascularization; Female; Humans; Male; Mice; Mice, Inbred C57BL; Rabbits; Receptors, Vascular Endothelial Growth Factor; Retinal Diseases; Sunitinib; Swine; Swine, Miniature; Vascular Endothelial Growth Factor A
PubMed: 32019921
DOI: 10.1038/s41467-020-14340-x -
Scientific Reports Dec 2016The objective of the present study was to assess the effect of elevating epoxygenated fatty acids on retinal vascular inflammation. To stimulate inflammation we utilized...
The objective of the present study was to assess the effect of elevating epoxygenated fatty acids on retinal vascular inflammation. To stimulate inflammation we utilized TNFα, a potent pro-inflammatory mediator that is elevated in the serum and vitreous of diabetic patients. In TNFα-stimulated primary human retinal microvascular endothelial cells, total levels of epoxyeicosatrienoic acids (EETs), but not epoxydocosapentaenoic acids (EDPs), were significantly decreased. Exogenous addition of 11,12-EET or 19,20-EDP when combined with 12-(3-adamantane-1-yl-ureido)-dodecanoic acid (AUDA), an inhibitor of epoxide hydrolysis, inhibited VCAM-1 and ICAM-1 expression and protein levels; conversely the diol product of 19,20-EDP hydrolysis, 19,20-DHDP, induced VCAM1 and ICAM1 expression. 11,12-EET and 19,20-EDP also inhibited leukocyte adherence to human retinal microvascular endothelial cell monolayers and leukostasis in an acute mouse model of retinal inflammation. Our results indicate that this inhibition may be mediated through an indirect effect on NFκB activation. This is the first study demonstrating a direct comparison of EET and EDP on vascular inflammatory endpoints, and we have confirmed a comparable efficacy from each isomer, suggesting a similar mechanism of action. Taken together, these data establish that epoxygenated fatty acid elevation will inhibit early pathology related to TNFα-induced inflammation in retinal vascular diseases.
Topics: 8,11,14-Eicosatrienoic Acid; Adamantane; Animals; Cells, Cultured; Disease Models, Animal; Down-Regulation; Endothelial Cells; Epoxy Compounds; Fatty Acids, Unsaturated; Humans; Intercellular Adhesion Molecule-1; Lauric Acids; Male; Mice; Retinal Vasculitis; Retinal Vessels; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1
PubMed: 27966642
DOI: 10.1038/srep39211