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Intravitreal Neurodegenerative and Inflammatory Mediators In A RQUIVOS B RASILEIROS DE ORIGINAL ARTICLE Intravitreal neurodegenerative and inflammatory mediators in proliferative diabetic retinopathy Mediadores intravítreos da neurodegeneração e inflamação na retinopatia diabética proliferativa Felipe Mallmann1,2, Luis Henrique Canani 2 1. Ophthalmology Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil. 2. Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. ABSTRACT | Purpose: To compare the intravitreal concen- levels of tumor necrosis factor-alpha and tumor necrosis factor- trations of cellular mediators involved in neurodegeneration, beta were undetectable. Serum Amyloid P, C-reactive protein, inflammation, and angiogenesis in patients with proliferative platelet-derived growth factor A, platelet-derived growth factor diabetic retinopathy and other vitreoretinal diseases. Methods: B, interleukin-6, and interleukin-8 were correlated positively A multiplex bead immunoassay was used to measure vitreous with vascular endothelial growth factor. Conclusions: Cellular levels of pigment epithelium-derived factor, serum amyloid mediators involved in neurodegeneration and inflammation P, C-reactive protein, complement C4, alpha-1 antitrypsin, demonstrated increased levels in the vitreous humor of patients vascular endothelial growth factor, platelet-derived growth with proliferative diabetic retinopathy and may be part of the factor-AA, platelet-derived growth factor-BB, interleukin-6, pathogenesis of diabetic retinopathy. interleukin-8, interleukin-10, tumor necrosis factor alpha and beta in patients undergoing 23-gauge vitrectomy for Keywords: Diabetic retinopathy; Retinal degeneration; Cytoki- proliferative diabetic retinopathy and other diagnoses (control nes; Acute phase proteins; Vitreous humor group). Results: We evaluated 55 patients, of whom 24 had proliferative diabetic retinopathy and 31 had other diagnoses RESUMO | Objetivo: Comparar as concentrações intravítreas including vitreous hemorrhage, retinal detachment, macular de mediadores celulares envolvidos na neurodegeneração, in- hole, and epiretinal membrane. Patients with proliferative flamação e angiogênese em pacientes com retinopatia diabética diabetic retinopathy demonstrated increased levels of serum proliferativa e outras doenças vítreo-retinianas. Métodos: amyloid P (85.49 vs. 31.38 ng/mL); C-reactive protein (59.89 vs. Um ensaio imunomagnético foi utilizado para medir os níveis 41.75 ng/mL), vascular endothelial growth factor (2,330.11 vs. vítreos do fator derivado do epitélio pigmentar, amilóide P 554.25 pg/mL; p<0.001), platelet-derived growth factor A (127.32 sérico, proteína-C-reativa, complemento C4, e alfa-1-antitripsina, vs. 39.11 pg/mL), platelet-derived growth factor B (29.37 vs. fator de crescimento do endotélio vascular, fator de crescimento 7.12 pg/mL), interleukin-6 (69.37 vs. 33.58 pg/mL), interleukin-8 derivado das plaquetas AA, fator de crescimento derivado das (175.25 vs. 59.71 pg/mL), and interleukin-10 (3.70 vs. 1.88 pg/mL); plaquetas BB, interleucina-6, interleucina-8, interleucina-10, all p<0.004 when compared with the control group. Levels fator de necrose tumoral alfa e beta em pacientes submetidos of pigment epithelium-derived factor (30.06 vs. 27.48 ng/mL; à vitrectomia 23-gauge para retinopatia diabética proliferativa p=0.295), complement C4 (570.78 vs. 366.24 ng/mL; p=0.069), ou outros diagnósticos (grupo controle). Resultados: Foram and alpha-1-antitrypsin (359.27 vs. 522.44 ng/mL; p=0.264) avaliados 55 pacientes, dos quais 24 tinham retinopatia dia- were not significantly different between the groups. Intravitreal bética proliferativa e 31 tinham outros diagnósticos, incluindo hemorragia vítrea, descolamento de retina, buraco macular e membrana epirretiniana. Pacientes com retinopatia diabética proliferativa demonstraram níveis aumentados de amilóide Submitted for publication: May 25, 2018 P sérico (85,49 vs 31,38 ng/mL), proteína-C-reativa (59,89 Accepted for publication: October 23, 2018 vs 41,75 ng/mL), fator de crescimento do endotélio vascular Funding: This study was supported by Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS) and Conselho Nacional de Desenvolvimento (2.330,11 vs 554,25 pg/mL, p<0.001), fator de crescimento Científico e Tecnológico (CNPq). derivado das plaquetas-A: (127,32 vs 39,11 pg/mL), fator de Disclosure of potential conflicts of interest: None of the authors have any potential conflicts of interest to disclose. crescimento derivado das plaquetas-B (29,37 vs 7,12 pg/mL), Corresponding author: Felipe Mallmann interleucina-6 (69,37 vs 33,58 pg/mL), interleucina-8 (175,25 Rua Anita Garibaldi, 1076/401 - E-mail: [email protected] vs 59,71 pg/mL) e interleucina-10 (3,70 vs 1,88 pg/mL), todos Approval by the following research ethics committee: Hospital de Clínicas de Porto Alegre (CAAE: 143734.13.8.0000.5327). com p<0,004 quando comparados ao grupo controle. Níveis This content is licensed under a Creative Commons Attributions 4.0 International License. ■ http://dx.doi.org/10.5935/0004-2749.20190055 Arq Bras Oftalmol. 2019;82(4):275-82 275 Intravitreal neurodegenerative and inflammatory mediators in proliferative diabetic retinopathy de fator derivado do epitélio pigmentar (30,06 vs 27,48 ng/mL; is the most distinct of the 3 factors involved in neuro- p=0,295), complemento C4 (570,78 vs 366,24 ng/mL; p=0,069), protection, antipermeability, and antiangiogenesis(2). alfa-1 antitripsina (359,27 vs 522,44 ng/mL; p=0,264) não foram Other factors in neurodegenerative diseases, such as significativamente diferente entre os grupos. Níveis intravítreos Alzheimer’s and Parkinson’s diseases, have not been de fator de necrose tumoral alfa e fator de necrose tumoral beta (3) foram indetectáveis. O amilóide P sérico, a proteína C-reativa, well studied in DR . Alpha-1 antitrypsin (A1AT), serum o fator de crescimento derivado das plaquetas A e B, a inter- amyloid P (SAP), C-reactive protein (CRP), and com- leucina-6 e a interleucina-8 correlacionaram-se positivamente plement C4 (CC4) are associated with cell imbalance com o fator de crescimento do endotélio vascular. Conclusões: in these diseases, contributing to a neuroinflammatory Os medidores celulares envolvidos na neurodegeneração e process(6-8). Similar to what happens in these diseases, inflamação demonstraram níveis aumentados no humor vítreo there appears to be a loss of neural homeostasis in DR, de pacientes com retinopatia diabética proliferativa e podem thus changing the neurovascular unit(1,2). ser parte da patogênese da retinopatia diabética. Therefore, a better understanding of the neurodege- Descritores: Retinopatia diabética; Degeneração retiniana; Ci­­ nerative pathogenesis of DR and the development of a tocinas; Proteínas da fase aguda; Humor vítreo therapy focusing on this pathogenesis could hinder its progression to more advanced stages of the disease(1,2). INTRODUCTION Nevertheless, few studies have evaluated the presence Diabetic retinopathy is considered a microvascular of neurodegenerative/neuroprotective factors in DR in complication of diabetes mellitus (DM), with diagnosis humans(1,2,9). The objective of the present study was to and classification based on visible vascular alterations measure the intravitreal levels of different inflammatory detected on clinical examination. The current clinical and neurodegenerative mediators in patients with proli- treatment aims to stabilize the vascular system, disre- ferative diabetic retinopathy (PDR). garding changes in the neurosensory retina(1,2). Much evidence from experimental models and hu- METHODS mans shows that DM involves a neurodegenerative pro- We conducted a cross-sectional study of patients un- cess related to retinal vascular changes(1,2). Barber et al.(3) dergoing 23-gauge posterior pars plana vitrectomy (PPV) demonstrated that DM increases the rate of apoptosis of at the Retina Division of the Department of Ophthalmo- neural cells, with this rate remaining constant over time, logy of the Hospital de Clínicas de Porto Alegre (HCPA) resulting in a cumulative loss with subsequent chronic between January 2011 and August 2012. neurodegeneration. Human studies using optical cohe- rence tomography and electrophysiology have confir- Inclusion and exclusion criteria med this hypothesis, exhibiting significant anatomical changes and dysfunctions in the upper retinal layers The present study included all patients undergoing even before vascular changes can be seen(1,2). Neuro- 23-gauge PPV at the Retina Division of the HCPA over degeneration involves several mechanisms. Changes in the study period. Cases consisted of patients with DM neurotrophic factors and neuroinflammation appear and PDR who underwent 23-gauge PPV for vitreous to play a key role in the onset and perpetuation of this hemorrhage (VH) and/or tractional retinal detachment process(1,2). Growing evidence suggests that inflamma- (RD). Patients without DM undergoing 23-gauge PPV for tory mediators increase endothelial dysfunction and other reasons were included in the control group. The neurodegeneration in patients with diabetic retinopathy control group (without DM) comprised patients with (DR), regardless of vascular endothelial growth factor VH due to a different etiology (n=12), RD (n=10), and (VEGF) levels(1,3,4). maculopathy (macular hole [MH] and epiretinal mem- In the normal retina, neural tissue is in close contact brane [ERM], n=9). We excluded patients meeting the with the vascular endothelium, forming a neurovascular
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