Pathological changes in the cellular structures of retina and choroidea in the early stages of alloxan-induced diabetes
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摘要
AIM To investigate the temporal sequence of pathological changes in the cellular structures of retina and choroidea in the early stages of diabetes in laboratory animals.METHODS Experimental type 1 diabetes was modeled by three intraperitoneal injections of an alloxan solution into 30 male nonlinear rats at 16 wk of age. The 30 th and 60 th days from the final alloxan injection were chosen as the endpoints. Light and electron microscopy and morphometric and immunohistochemical studies were performed on histological slices of eyeballs from experimental animals.RESULTS Diabetic disturbances progressed to 60 d of the experiment. Thus, in the retina, a partial destruction of photoreceptors accompanied by interstitial edema was observed. The morphometric analysis revealed a reduction in the thickness of the retina. A reduction in the number of blood vessels of the choroid with disturbances of the endothelial cells and the vascular walls and a persistent reduction in the number of melanocytes were observed. The number of proliferating Ki-67 positive cells decreased, and the number of macrophages increased with diabetes development.CONCLUSION The starting point in the development of destructive changes involves early reduction in the number of melanocytes of the choroidea and alterations in the retinal pigment epithelium.
AIM To investigate the temporal sequence of pathological changes in the cellular structures of retina and choroidea in the early stages of diabetes in laboratory animals.METHODS Experimental type 1 diabetes was modeled by three intraperitoneal injections of an alloxan solution into 30 male nonlinear rats at 16 wk of age. The 30 th and 60 th days from the final alloxan injection were chosen as the endpoints. Light and electron microscopy and morphometric and immunohistochemical studies were performed on histological slices of eyeballs from experimental animals.RESULTS Diabetic disturbances progressed to 60 d of the experiment. Thus, in the retina, a partial destruction of photoreceptors accompanied by interstitial edema was observed. The morphometric analysis revealed a reduction in the thickness of the retina. A reduction in the number of blood vessels of the choroid with disturbances of the endothelial cells and the vascular walls and a persistent reduction in the number of melanocytes were observed. The number of proliferating Ki-67 positive cells decreased, and the number of macrophages increased with diabetes development.CONCLUSION The starting point in the development of destructive changes involves early reduction in the number of melanocytes of the choroidea and alterations in the retinal pigment epithelium.
AIM To investigate the temporal sequence of pathological changes in the cellular structures of retina and choroidea in the early stages of diabetes in laboratory animals.METHODS Experimental type 1 diabetes was modeled by three intraperitoneal injections of an alloxan solution into 30 male nonlinear rats at 16 wk of age. The 30 th and 60 th days from the final alloxan injection were chosen as the endpoints. Light and electron microscopy and morphometric and immunohistochemical studies were performed on histological slices of eyeballs from experimental animals.RESULTS Diabetic disturbances progressed to 60 d of the experiment. Thus, in the retina, a partial destruction of photoreceptors accompanied by interstitial edema was observed. The morphometric analysis revealed a reduction in the thickness of the retina. A reduction in the number of blood vessels of the choroid with disturbances of the endothelial cells and the vascular walls and a persistent reduction in the number of melanocytes were observed. The number of proliferating Ki-67 positive cells decreased, and the number of macrophages increased with diabetes development.CONCLUSION The starting point in the development of destructive changes involves early reduction in the number of melanocytes of the choroidea and alterations in the retinal pigment epithelium.
引文
1 Constantino MI,Molyneaux L,Wu T,Twigg SM,Wong J,Yue DK.Data collection on retinopathy as a public health tool:The Hubble telescope equivalent of looking back in time.J Diabetes Complications 2017;31:721-725[PMID:28161385 DOI:10.1016/j.jdiacomp.2016.12.016]
2 Vujosevic S,Pucci P,Casciano M,Daniele A,Bini S,Berton M,Cavarzeran F,Avogaro A,Lapolla A,Midena E.A decade-long telemedicine screening program for diabetic retinopathy in the north-east of Italy.J Diabetes Complications 2017;31:1348-1353[PMID:28551296 DOI:10.1016/j.jdiacomp.2017.04.010]
3 Das A.Diabetic retinopathy:Battling the global epidemic.Indian JOphthalmol 2016;64:2-3[PMID:26953017 DOI:10.4103/0301-4738.178155]
4 Yau JW,Rogers SL,Kawasaki R,Lamoureux EL,Kowalski JW,Bek T,Chen SJ,Dekker JM,Fletcher A,Grauslund J,Haffner S,Hamman RF,Ikram MK,Kayama T,Klein BE,Klein R,Krishnaiah S,Mayurasakorn K,O’Hare JP,Orchard TJ,Porta M,Rema M,Roy MS,Sharma T,Shaw J,Taylor H,Tielsch JM,Varma R,Wang JJ,Wang N,West S,Xu L,Yasuda M,Zhang X,Mitchell P,Wong TY;Meta-Analysis for Eye Disease(META-EYE)Study Group.Global prevalence and major risk factors of diabetic retinopathy.Diabetes Care 2012;35:556-564[PMID:22301125DOI:10.2337/dc11-1909]
5 Chen M,Stitt A.Animal Models of Diabetic Retinopathy.In:Chan CC,editor.Animal Models of Ophthalmic Diseases.Cham:Springer International Publishing,2016:67-83[DOI:10.1007/978-3-319-19434-9_5]
6 Stitt AW,Lois N,Medina RJ,Adamson P,Curtis TM.Advances in our understanding of diabetic retinopathy.Clin Sci(Lond)2013;125:1-17[PMID:23485060 DOI:10.1042/CS20120588]
7 Du??I,Fica S,Ion DA.The Association between Insulin Resistance and Proliferative Retinopathy in Type 1 Diabetes.Rom J Intern Med 2015;53:261-266[PMID:26710502 DOI:10.1515/rjim-2015-0034]
8 Kandarakis SA,Piperi C,Topouzis F,Papavassiliou AG.Emerging role of advanced glycation-end products(AGEs)in the pathobiology of eye diseases.Prog Retin Eye Res 2014;42:85-102[PMID:24905859 DOI:10.1016/j.preteyeres.2014.05.002]
9 Stem M,Boynton G,Thompson A,Khan NW,Jackson GR,Pop-Busui R,Gardner TW.Inner retinal sensory neuropathy in persons with type 1 diabetes mellitus.Invest Ophthalmol Vis Sci 2014;55:4426-4426
10 Antonetti DA,Klein R,Gardner TW.Diabetic retinopathy.N Engl J Med 2012;366:1227-1239[PMID:22455417 DOI:10.1056/NEJMra1005073]
11 Kern TS.Contributions of inflammatory processes to the develop-ment of the early stages of diabetic retinopathy.Exp Diabetes Res2007;2007:95103[PMID:18274606 DOI:10.1155/2007/95103]
12 Madsen-Bouterse SA,Kowluru RA.Oxidative stress and diabetic retinopathy:pathophysiological mechanisms and treatment perspectives.Rev Endocr Metab Disord 2008;9:315-327[PMID:18654858 DOI:10.1007/s11154-008-9090-4]
13 Barber AJ,Lieth E,Khin SA,Antonetti DA,Buchanan AG,Gardner TW.Neural apoptosis in the retina during experimental and human diabetes.Early onset and effect of insulin.J Clin Invest1998;102:783-791[PMID:9710447 DOI:10.1172/JCI2425]
14 Roy S,Kern TS,Song B,Stuebe C.Mechanistic Insights into Pathological Changes in the Diabetic Retina:Implications for Targeting Diabetic Retinopathy.Am J Pathol 2017;187:9-19[PMID:27846381 DOI:10.1016/j.ajpath.2016.08.022]
15 Barber AJ,Gardner TW,Abcouwer SF.The significance of vascular and neural apoptosis to the pathology of diabetic retinopathy.Invest Ophthalmol Vis Sci 2011;52:1156-1163[PMID:21357409 DOI:10.1167/iovs.10-6293]
16 Barber AJ.A new view of diabetic retinopathy:a neurode-generative disease of the eye.Prog Neuropsychopharmacol Biol Psychiatry 2003;27:283-290[PMID:12657367 DOI:10.1016/S0278-5846(03)00023-X]
17énzs?ly A,SzabóA,Kántor O,Dávid C,Szalay P,SzabóK,Szélá,Németh J,Lukátsá.Pathologic alterations of the outer retina in streptozotocin-induced diabetes.Invest Ophthalmol Vis Sci 2014;55:3686-3699[PMID:24845643 DOI:10.1167/iovs.13-13562]
18 Zampetaki A,Willeit P,Burr S,Yin X,Langley SR,Kiechl S,Klein R,Rossing P,Chaturvedi N,Mayr M.Angiogenic microRNAs Linked to Incidence and Progression of Diabetic Retinopathy in Type 1 Diabetes.Diabetes 2016;65:216-227[PMID:26395742 DOI:10.2337/db15-0389]
19 Schorr SG,Hammes HP,Müller UA,Abholz HH,Landgraf R,Bertram B.The Prevention and Treatment of Retinal Complica-tions in Diabetes.Dtsch Arztebl Int 2016;113:816-823[PMID:28073426 DOI:10.3238/arztebl.2016.0816]
20 Ford JA,Lois N,Royle P,Clar C,Shyangdan D,Waugh N.Current treatments in diabetic macular oedema:systematic review and meta-analysis.BMJ Open 2013;3:pii:e002269[PMID:23457327 DOI:10.1136/bmjopen-2012-002269]
21 El Rami H,Barham R,Sun JK,Silva PS.Evidence-Based Treatment of Diabetic Retinopathy.Semin Ophthalmol 2017;32:67-74[PMID:27700224 DOI:10.1080/08820538.2016.1228397]
22 Lechner J,O’Leary OE,Stitt AW.The pathology associated with diabetic retinopathy.Vision Res 2017;139:7-14[PMID:28412095DOI:10.1016/j.visres.2017.04.003]
23 Rajalakshmi R,Prathiba V,Mohan V.Does tight control of systemic factors help in the management of diabetic retinopathy?Indian J Ophthalmol 2016;64:62-68[PMID:26953026 DOI:10.4103/0301-4738.178146]
24 Danilova IG,Sarapultsev PA,Medvedeva SU,Gette IF,Bulavintceva TS,Sarapultsev AP.Morphological restructuring of myocardium during the early phase of experimental diabetes mellitus.Anat Rec(Hoboken)2015;298:396-407[PMID:25251897 DOI:10.1002/ar.23052]
25 Radenkovi?M,Stojanovi?M,Prostran M.Experimental diabetes induced by alloxan and streptozotocin:The current state of the art.J Pharmacol Toxicol Methods 2016;78:13-31[PMID:26596652DOI:10.1016/j.vascn.2015.11.004]
26 Lenzen S.The mechanisms of alloxan-and streptozotocin-induced diabetes.Diabetologia 2008;51:216-226[PMID:18087688 DOI:10.1007/s00125-007-0886-7]
27 Szkudelski T.The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas.Physiol Res 2001;50:537-546[PMID:11829314]
28 Gelashvily OA.Variant of periodization of biologically similar stages of human and rat`s ontogenesis(in Russian).Saratov J Med Sci Res 2008;4:125-126
29 Karpischev AI.Medical laboratory technology(in Russian).St.Petersburg:Intermedika,2002
30 Yakovleva GE.The enzymes in clinical biochemistry(in Russian).Novosibirsk:Vector-Best,2005
31 Jeppsson JO,Kobold U,Barr J,Finke A,Hoelzel W,Hoshino T,Miedema K,Mosca A,Mauri P,Paroni R,Thienpont L,Umemoto M,Weykamp C;International Federation of Clinical Chemistry and Laboratory Medicine(IFCC).Approved IFCC reference method for the measurement of HbA1c in human blood.Clin Chem Lab Med 2002;40:78-89[PMID:11916276 DOI:10.1515/CCLM.2002.016]
32 Kumar GL,Rudbeck L.Education guide.Immunohistoche-mical(IHC)staining methods.California:Dako North America,Carpinteria,2009:224.Available from:URL:http://www.kanidis.gr/common/files/ANOSOISTOCHIMIA/DETECTION/ihc_staining_methods_5ed.pdf
33 Taylor PR,Martinez-Pomares L,Stacey M,Lin HH,Brown GD,Gordon S.Macrophage receptors and immune recognition.Annu Rev Immunol 2005;23:901-944[PMID:15771589 DOI:10.1146/annurev.immunol.23.021704.115816]
34 Brochhausen C,Schmitt VH,Mamilos A,Schmitt C,Planck CN,Rajab TK,Hierlemann H,Kirkpatrick CJ.Expression of CD68positive macrophages in the use of different barrier materials to prevent peritoneal adhesions-an animal study.J Mater Sci Mater Med 2017;28:15[PMID:27995493 DOI:10.1007/s10856-016-5821-3]
35 Weakley BS.A beginner’s handbook in biological transmission electron microscopy.Edinburg:Churchill Livingstone,1981:264
36 Robinson R,Barathi VA,Chaurasia SS,Wong TY,Kern TS.Update on animal models of diabetic retinopathy:from molecular approaches to mice and higher mammals.Dis Model Mech 2012;5:444-456[PMID:22730475 DOI:10.1242/dmm.009597]
37 Capit?o M,Soares R.Angiogenesis and Inflammation Crosstalk in Diabetic Retinopathy.J Cell Biochem 2016;117:2443-2453[PMID:27128219 DOI:10.1002/jcb.25575]
38 Park SH,Park JW,Park SJ,Kim KY,Chung JW,Chun MH,Oh SJ.Apoptotic death of photoreceptors in the streptozotocin-induced diabetic rat retina.Diabetologia 2003;46:1260-1268[PMID:12898017 DOI:10.1007/s00125-003-1177-6]
39 Nickla DL,Wallman J.The multifunctional choroid.Prog Retin Eye Res 2010;29:144-168[PMID:20044062 DOI:10.1016/j.pret eyeres.2009.12.002]
40 Hua R,Li Q,Wong IY,Ning H,Wang H.Choroidal microvascular proliferation secondary to diabetes mellitus.Oncotarget 2017;8:2034-2036[PMID:28008140 DOI:10.18632/oncotarget.14020]
41 Melancia D,Vicente A,Cunha JP,Abeg?o Pinto L,Ferreira J.Diabetic choroidopathy:a review of the current literature.Graefes Arch Clin Exp Ophthalmol 2016;254:1453-1461[PMID:27109344 DOI:10.1007/s00417-016-3360-8]
42 Adini I,Ghosh K,Adini A,Chi ZL,Yoshimura T,Benny O,Connor KM,Rogers MS,Bazinet L,Birsner AE,Bielenberg DR,D’Amato RJ.Melanocyte-secreted fibromodulin promotes an angiogenic microenvironment.J Clin Invest 2014;124:425-436[PMID:24355922 DOI:10.1172/JCI69404]
43 Cherepanoff S,McMenamin P,Gillies MC,Kettle E,Sarks SH.Bruch’s membrane and choroidal macrophages in early and advanced age-related macular degeneration.Br J Ophthalmol 2010;94:918-925[PMID:19965817 DOI:10.1136/bjo.2009.165563]
44 Aveleira CA,Lin CM,Abcouwer SF,Ambrósio AF,Antonetti DA.TNF-αsignals through PKCζ/NF-κB to alter the tight junction complex and increase retinal endothelial cell permeability.Diabetes2010;59:2872-2882[PMID:20693346 DOI:10.2337/db09-1606]
45 Nita M,Grzybowski A,Ascaso FJ,Huerva V.Age-related macular degeneration in the aspect of chronic low-grade inflammation(pathophysiological parainflammation).Mediators Inflamm 2014;2014:930671[PMID:25214719 DOI:10.1155/2014/930671]
46 Aizu Y,Oyanagi K,Hu J,Nakagawa H.Degeneration of retinal neuronal processes and pigment epithelium in the early stage of the streptozotocin-diabetic rats.Neuropathology 2002;22:161-170[PMID:12416555 DOI:10.1046/j.1440-1789.2002.00439.x]
47 Rizzolo LJ.Barrier properties of cultured retinal pigment epi-thelium.Exp Eye Res 2014;126:16-26[PMID:24731966 DOI:10.1016/j.exer.2013.12.018]
48 Grant WM,Schuman JS.Toxicology of the Eye:Effects on the Eyes and Visual System from Chemicals,Drugs,Metals and Minerals,Plants,Toxins,and Venoms;Also,Systemic Side Effects from Eye med(4th edition).Springfield,Ill.,USA:Charles CThomas Pub Ltd.,1993:1608
49 Koskenoja M.Alloxan diabetes in the pregnant mouse.Its effect on the offspring and particularly on their eyes.Acta Ophthalmol Suppl 1961;Suppl 68:1-92[PMID:14458651]
50 Emanuelli G.Retinal ultrastructural alterations induced by alloxan in the rat(In Italian).Rass Ital Ottalmol 1964;33:62-70
2 Vujosevic S,Pucci P,Casciano M,Daniele A,Bini S,Berton M,Cavarzeran F,Avogaro A,Lapolla A,Midena E.A decade-long telemedicine screening program for diabetic retinopathy in the north-east of Italy.J Diabetes Complications 2017;31:1348-1353[PMID:28551296 DOI:10.1016/j.jdiacomp.2017.04.010]
3 Das A.Diabetic retinopathy:Battling the global epidemic.Indian JOphthalmol 2016;64:2-3[PMID:26953017 DOI:10.4103/0301-4738.178155]
4 Yau JW,Rogers SL,Kawasaki R,Lamoureux EL,Kowalski JW,Bek T,Chen SJ,Dekker JM,Fletcher A,Grauslund J,Haffner S,Hamman RF,Ikram MK,Kayama T,Klein BE,Klein R,Krishnaiah S,Mayurasakorn K,O’Hare JP,Orchard TJ,Porta M,Rema M,Roy MS,Sharma T,Shaw J,Taylor H,Tielsch JM,Varma R,Wang JJ,Wang N,West S,Xu L,Yasuda M,Zhang X,Mitchell P,Wong TY;Meta-Analysis for Eye Disease(META-EYE)Study Group.Global prevalence and major risk factors of diabetic retinopathy.Diabetes Care 2012;35:556-564[PMID:22301125DOI:10.2337/dc11-1909]
5 Chen M,Stitt A.Animal Models of Diabetic Retinopathy.In:Chan CC,editor.Animal Models of Ophthalmic Diseases.Cham:Springer International Publishing,2016:67-83[DOI:10.1007/978-3-319-19434-9_5]
6 Stitt AW,Lois N,Medina RJ,Adamson P,Curtis TM.Advances in our understanding of diabetic retinopathy.Clin Sci(Lond)2013;125:1-17[PMID:23485060 DOI:10.1042/CS20120588]
7 Du??I,Fica S,Ion DA.The Association between Insulin Resistance and Proliferative Retinopathy in Type 1 Diabetes.Rom J Intern Med 2015;53:261-266[PMID:26710502 DOI:10.1515/rjim-2015-0034]
8 Kandarakis SA,Piperi C,Topouzis F,Papavassiliou AG.Emerging role of advanced glycation-end products(AGEs)in the pathobiology of eye diseases.Prog Retin Eye Res 2014;42:85-102[PMID:24905859 DOI:10.1016/j.preteyeres.2014.05.002]
9 Stem M,Boynton G,Thompson A,Khan NW,Jackson GR,Pop-Busui R,Gardner TW.Inner retinal sensory neuropathy in persons with type 1 diabetes mellitus.Invest Ophthalmol Vis Sci 2014;55:4426-4426
10 Antonetti DA,Klein R,Gardner TW.Diabetic retinopathy.N Engl J Med 2012;366:1227-1239[PMID:22455417 DOI:10.1056/NEJMra1005073]
11 Kern TS.Contributions of inflammatory processes to the develop-ment of the early stages of diabetic retinopathy.Exp Diabetes Res2007;2007:95103[PMID:18274606 DOI:10.1155/2007/95103]
12 Madsen-Bouterse SA,Kowluru RA.Oxidative stress and diabetic retinopathy:pathophysiological mechanisms and treatment perspectives.Rev Endocr Metab Disord 2008;9:315-327[PMID:18654858 DOI:10.1007/s11154-008-9090-4]
13 Barber AJ,Lieth E,Khin SA,Antonetti DA,Buchanan AG,Gardner TW.Neural apoptosis in the retina during experimental and human diabetes.Early onset and effect of insulin.J Clin Invest1998;102:783-791[PMID:9710447 DOI:10.1172/JCI2425]
14 Roy S,Kern TS,Song B,Stuebe C.Mechanistic Insights into Pathological Changes in the Diabetic Retina:Implications for Targeting Diabetic Retinopathy.Am J Pathol 2017;187:9-19[PMID:27846381 DOI:10.1016/j.ajpath.2016.08.022]
15 Barber AJ,Gardner TW,Abcouwer SF.The significance of vascular and neural apoptosis to the pathology of diabetic retinopathy.Invest Ophthalmol Vis Sci 2011;52:1156-1163[PMID:21357409 DOI:10.1167/iovs.10-6293]
16 Barber AJ.A new view of diabetic retinopathy:a neurode-generative disease of the eye.Prog Neuropsychopharmacol Biol Psychiatry 2003;27:283-290[PMID:12657367 DOI:10.1016/S0278-5846(03)00023-X]
17énzs?ly A,SzabóA,Kántor O,Dávid C,Szalay P,SzabóK,Szélá,Németh J,Lukátsá.Pathologic alterations of the outer retina in streptozotocin-induced diabetes.Invest Ophthalmol Vis Sci 2014;55:3686-3699[PMID:24845643 DOI:10.1167/iovs.13-13562]
18 Zampetaki A,Willeit P,Burr S,Yin X,Langley SR,Kiechl S,Klein R,Rossing P,Chaturvedi N,Mayr M.Angiogenic microRNAs Linked to Incidence and Progression of Diabetic Retinopathy in Type 1 Diabetes.Diabetes 2016;65:216-227[PMID:26395742 DOI:10.2337/db15-0389]
19 Schorr SG,Hammes HP,Müller UA,Abholz HH,Landgraf R,Bertram B.The Prevention and Treatment of Retinal Complica-tions in Diabetes.Dtsch Arztebl Int 2016;113:816-823[PMID:28073426 DOI:10.3238/arztebl.2016.0816]
20 Ford JA,Lois N,Royle P,Clar C,Shyangdan D,Waugh N.Current treatments in diabetic macular oedema:systematic review and meta-analysis.BMJ Open 2013;3:pii:e002269[PMID:23457327 DOI:10.1136/bmjopen-2012-002269]
21 El Rami H,Barham R,Sun JK,Silva PS.Evidence-Based Treatment of Diabetic Retinopathy.Semin Ophthalmol 2017;32:67-74[PMID:27700224 DOI:10.1080/08820538.2016.1228397]
22 Lechner J,O’Leary OE,Stitt AW.The pathology associated with diabetic retinopathy.Vision Res 2017;139:7-14[PMID:28412095DOI:10.1016/j.visres.2017.04.003]
23 Rajalakshmi R,Prathiba V,Mohan V.Does tight control of systemic factors help in the management of diabetic retinopathy?Indian J Ophthalmol 2016;64:62-68[PMID:26953026 DOI:10.4103/0301-4738.178146]
24 Danilova IG,Sarapultsev PA,Medvedeva SU,Gette IF,Bulavintceva TS,Sarapultsev AP.Morphological restructuring of myocardium during the early phase of experimental diabetes mellitus.Anat Rec(Hoboken)2015;298:396-407[PMID:25251897 DOI:10.1002/ar.23052]
25 Radenkovi?M,Stojanovi?M,Prostran M.Experimental diabetes induced by alloxan and streptozotocin:The current state of the art.J Pharmacol Toxicol Methods 2016;78:13-31[PMID:26596652DOI:10.1016/j.vascn.2015.11.004]
26 Lenzen S.The mechanisms of alloxan-and streptozotocin-induced diabetes.Diabetologia 2008;51:216-226[PMID:18087688 DOI:10.1007/s00125-007-0886-7]
27 Szkudelski T.The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas.Physiol Res 2001;50:537-546[PMID:11829314]
28 Gelashvily OA.Variant of periodization of biologically similar stages of human and rat`s ontogenesis(in Russian).Saratov J Med Sci Res 2008;4:125-126
29 Karpischev AI.Medical laboratory technology(in Russian).St.Petersburg:Intermedika,2002
30 Yakovleva GE.The enzymes in clinical biochemistry(in Russian).Novosibirsk:Vector-Best,2005
31 Jeppsson JO,Kobold U,Barr J,Finke A,Hoelzel W,Hoshino T,Miedema K,Mosca A,Mauri P,Paroni R,Thienpont L,Umemoto M,Weykamp C;International Federation of Clinical Chemistry and Laboratory Medicine(IFCC).Approved IFCC reference method for the measurement of HbA1c in human blood.Clin Chem Lab Med 2002;40:78-89[PMID:11916276 DOI:10.1515/CCLM.2002.016]
32 Kumar GL,Rudbeck L.Education guide.Immunohistoche-mical(IHC)staining methods.California:Dako North America,Carpinteria,2009:224.Available from:URL:http://www.kanidis.gr/common/files/ANOSOISTOCHIMIA/DETECTION/ihc_staining_methods_5ed.pdf
33 Taylor PR,Martinez-Pomares L,Stacey M,Lin HH,Brown GD,Gordon S.Macrophage receptors and immune recognition.Annu Rev Immunol 2005;23:901-944[PMID:15771589 DOI:10.1146/annurev.immunol.23.021704.115816]
34 Brochhausen C,Schmitt VH,Mamilos A,Schmitt C,Planck CN,Rajab TK,Hierlemann H,Kirkpatrick CJ.Expression of CD68positive macrophages in the use of different barrier materials to prevent peritoneal adhesions-an animal study.J Mater Sci Mater Med 2017;28:15[PMID:27995493 DOI:10.1007/s10856-016-5821-3]
35 Weakley BS.A beginner’s handbook in biological transmission electron microscopy.Edinburg:Churchill Livingstone,1981:264
36 Robinson R,Barathi VA,Chaurasia SS,Wong TY,Kern TS.Update on animal models of diabetic retinopathy:from molecular approaches to mice and higher mammals.Dis Model Mech 2012;5:444-456[PMID:22730475 DOI:10.1242/dmm.009597]
37 Capit?o M,Soares R.Angiogenesis and Inflammation Crosstalk in Diabetic Retinopathy.J Cell Biochem 2016;117:2443-2453[PMID:27128219 DOI:10.1002/jcb.25575]
38 Park SH,Park JW,Park SJ,Kim KY,Chung JW,Chun MH,Oh SJ.Apoptotic death of photoreceptors in the streptozotocin-induced diabetic rat retina.Diabetologia 2003;46:1260-1268[PMID:12898017 DOI:10.1007/s00125-003-1177-6]
39 Nickla DL,Wallman J.The multifunctional choroid.Prog Retin Eye Res 2010;29:144-168[PMID:20044062 DOI:10.1016/j.pret eyeres.2009.12.002]
40 Hua R,Li Q,Wong IY,Ning H,Wang H.Choroidal microvascular proliferation secondary to diabetes mellitus.Oncotarget 2017;8:2034-2036[PMID:28008140 DOI:10.18632/oncotarget.14020]
41 Melancia D,Vicente A,Cunha JP,Abeg?o Pinto L,Ferreira J.Diabetic choroidopathy:a review of the current literature.Graefes Arch Clin Exp Ophthalmol 2016;254:1453-1461[PMID:27109344 DOI:10.1007/s00417-016-3360-8]
42 Adini I,Ghosh K,Adini A,Chi ZL,Yoshimura T,Benny O,Connor KM,Rogers MS,Bazinet L,Birsner AE,Bielenberg DR,D’Amato RJ.Melanocyte-secreted fibromodulin promotes an angiogenic microenvironment.J Clin Invest 2014;124:425-436[PMID:24355922 DOI:10.1172/JCI69404]
43 Cherepanoff S,McMenamin P,Gillies MC,Kettle E,Sarks SH.Bruch’s membrane and choroidal macrophages in early and advanced age-related macular degeneration.Br J Ophthalmol 2010;94:918-925[PMID:19965817 DOI:10.1136/bjo.2009.165563]
44 Aveleira CA,Lin CM,Abcouwer SF,Ambrósio AF,Antonetti DA.TNF-αsignals through PKCζ/NF-κB to alter the tight junction complex and increase retinal endothelial cell permeability.Diabetes2010;59:2872-2882[PMID:20693346 DOI:10.2337/db09-1606]
45 Nita M,Grzybowski A,Ascaso FJ,Huerva V.Age-related macular degeneration in the aspect of chronic low-grade inflammation(pathophysiological parainflammation).Mediators Inflamm 2014;2014:930671[PMID:25214719 DOI:10.1155/2014/930671]
46 Aizu Y,Oyanagi K,Hu J,Nakagawa H.Degeneration of retinal neuronal processes and pigment epithelium in the early stage of the streptozotocin-diabetic rats.Neuropathology 2002;22:161-170[PMID:12416555 DOI:10.1046/j.1440-1789.2002.00439.x]
47 Rizzolo LJ.Barrier properties of cultured retinal pigment epi-thelium.Exp Eye Res 2014;126:16-26[PMID:24731966 DOI:10.1016/j.exer.2013.12.018]
48 Grant WM,Schuman JS.Toxicology of the Eye:Effects on the Eyes and Visual System from Chemicals,Drugs,Metals and Minerals,Plants,Toxins,and Venoms;Also,Systemic Side Effects from Eye med(4th edition).Springfield,Ill.,USA:Charles CThomas Pub Ltd.,1993:1608
49 Koskenoja M.Alloxan diabetes in the pregnant mouse.Its effect on the offspring and particularly on their eyes.Acta Ophthalmol Suppl 1961;Suppl 68:1-92[PMID:14458651]
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