Effects of ranibizumab on growth factors and mediators of inflammation in the aqueous humor of patients with diabetic macular edema.
Angiogenesis Inhibitors
/ therapeutic use
Aqueous Humor
Cytokines
Diabetes Mellitus
Diabetic Retinopathy
/ diagnosis
Female
Humans
Intravitreal Injections
Macular Edema
/ diagnosis
Placenta Growth Factor
/ therapeutic use
Ranibizumab
/ therapeutic use
Tomography, Optical Coherence
Vascular Endothelial Growth Factor A
Visual Acuity
Cytokines
Diabetic macular edema
Ranibizumab
Journal
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie
ISSN: 1435-702X
Titre abrégé: Graefes Arch Clin Exp Ophthalmol
Pays: Germany
ID NLM: 8205248
Informations de publication
Date de publication:
Sep 2021
Sep 2021
Historique:
received:
01
11
2020
accepted:
09
03
2021
revised:
15
01
2021
pubmed:
28
3
2021
medline:
25
8
2021
entrez:
27
3
2021
Statut:
ppublish
Résumé
The study aims to investigate changes in the aqueous humor levels of 8 growth factors and inflammatory mediators after intravitreal ranibizumab injection (IRI) and the relationship between these substances and functional-morphological parameters in patients with diabetic macular edema (DME). We recruited 25 patients with DME who were scheduled to receive 2 doses of IRI at monthly intervals. At baseline and 1 month after IRI, we measured aqueous levels of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), monocyte chemoattractant protein 1 (MCP-1), soluble intercellular adhesion molecule-1 (sICAM-1), platelet-derived growth factor (PDGF)-AA, interleukin (IL)-6, IL-8, and interferon-gamma inducible protein 10 (IP-10) by the suspension array method. Central macular edema (CMT) or macular volume (MV) was examined by optical coherence tomography before and 1 month after IRI, and the improvement of macular edema was evaluated by calculating the percent change of CMT or MV. Aqueous humor levels of VEGF, PlGF, PDGF-AA, and IP-10 were significantly decreased 1 month after IRI (P < 0.001, P = 0.002, P = 0.002, and P = 0.005, respectively). In addition, the baseline aqueous humor levels of PlGF, MCP-1, and IL-6 were significantly correlated with the improvement in best corrected visual acuity (P = 0.036, P = 0.024, and P = 0.049, respectively). The baseline aqueous humor level of sICAM-1 was significantly negatively correlated with the change in CMT (P = 0.005), and the baseline aqueous humor levels of VEGF and PlGF were significantly correlated with the change in MV (P = 0.020 and P = 0.003, respectively). Furthermore, the percentage reduction in VEGF after IRI was significantly correlated with the change in MV (P = 0.037). Our findings suggest that the change in aqueous humor levels of VEGF, PlGF, and ICAM-1 in DME may not only be an anatomic response but also a potential therapeutic target. This study was registered in the University Hospital Medical Information Network (UMIN) clinical trial registry. The registration number is UMIN000030301.
Identifiants
pubmed: 33772356
doi: 10.1007/s00417-021-05154-8
pii: 10.1007/s00417-021-05154-8
doi:
Substances chimiques
Angiogenesis Inhibitors
0
Cytokines
0
Vascular Endothelial Growth Factor A
0
Placenta Growth Factor
144589-93-5
Ranibizumab
ZL1R02VT79
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2597-2603Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Références
Antcliff RJ, Marshall J (1999) The pathogenesis of edema in diabetic maculopathy. Semin Ophthalmol 14:223–232
doi: 10.3109/08820539909069541
Chun DW, Heier JS, Topping TM, Duker JS, Bankert JM (2006) A pilot study of multiple intravitreal injections of ranibizumab in patients with center-involving clinically significant diabetic macular edema. Ophthalmology 113:1706–1712
doi: 10.1016/j.ophtha.2006.04.033
Nguyen QD, Tatlipinar S, Shah SM, Haller JA, Quinlan E, Sung J, Zimmer-Galler I, Do DV, Campochiaro PA (2006) Vascular endothelial growth factor is a critical stimulus for diabetic macular edema. Am J Ophthalmol 142:961–969
doi: 10.1016/j.ajo.2006.06.068
Wells JA, Glassman AR, Ayala AR, Jampol LM, Aiello LP, Antoszyk AN, Arnold-Bush B, Baker CW, Bressler NM, Browning DJ et al (2015) Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med 372:1193–1203
doi: 10.1056/NEJMoa1414264
Noma H, Mimura T, Yasuda K, Shimura M (2014) Role of inflammation in diabetic macular edema. Ophthalmologica 232:127–135
doi: 10.1159/000364955
Elman MJ, Aiello LP, Beck RW, Bressler NM, Bressler SB, Edwards AR, Ferris FL 3rd, Friedman SM, Glassman AR, Miller KM et al (2010) Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 117:1064–1077 e1035
doi: 10.1016/j.ophtha.2010.02.031
Noma H, Mimura T, Yasuda K, Motohashi R, Kotake O, Shimura M (2017) Aqueous humor levels of soluble vascular endothelial growth factor receptor and inflammatory factors in diabetic macular edema. Ophthalmologica 238:81–88
doi: 10.1159/000475603
Hillier RJ, Ojaimi E, Wong DT, Mak MYK, Berger AR, Kohly RP, Kertes PJ, Forooghian F, Boyd SR, Eng K et al (2018) Aqueous humor cytokine levels and anatomic response to intravitreal ranibizumab in diabetic macular edema. JAMA Ophthalmol 136:382–388
doi: 10.1001/jamaophthalmol.2018.0179
DiSalvo J, Bayne ML, Conn G, Kwok PW, Trivedi PG, Soderman DD, Palisi TM, Sullivan KA, Thomas KA (1995) Purification and characterization of a naturally occurring vascular endothelial growth factor: placenta growth factor heterodimer. J Biol Chem 270:7717–7723
doi: 10.1074/jbc.270.13.7717
Yang X, Zhang Y, Yang Y, Lim S, Cao Z, Rak J, Cao Y (2013) Vascular endothelial growth factor-dependent spatiotemporal dual roles of placental growth factor in modulation of angiogenesis and tumor growth. Proc Natl Acad Sci U S A 110:13932–13937
doi: 10.1073/pnas.1309629110
Shibuya M (2011) Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: a crucial target for anti- and pro-angiogenic therapies. Genes Cancer 2:1097–1105
doi: 10.1177/1947601911423031
Funatsu H, Noma H, Mimura T, Eguchi S, Hori S (2009) Association of vitreous inflammatory factors with diabetic macular edema. Ophthalmology 116:73–79
doi: 10.1016/j.ophtha.2008.09.037
Shiraya T, Kato S, Araki F, Ueta T, Miyaji T, Yamaguchi T (2017) Aqueous cytokine levels are associated with reduced macular thickness after intravitreal ranibizumab for diabetic macular edema. PLoS One 12
Mastropasqua R, D’Aloisio R, Di Nicola M, Di Martino G, Lamolinara A, Di Antonio L, Tognetto D, Toto L (2018) Relationship between aqueous humor cytokine level changes and retinal vascular changes after intravitreal aflibercept for diabetic macular edema. Sci Rep 8:018–35036
doi: 10.1038/s41598-018-35036-9
Feldman ED, Weinreich DM, Carroll NM, Burness ML, Feldman AL, Turner E, Xu H, Alexander HR Jr (2006) Interferon gamma-inducible protein 10 selectively inhibits proliferation and induces apoptosis in endothelial cells. Ann Surg Oncol 13:125–133
doi: 10.1245/ASO.2006.03.038
Bodnar RJ, Yates CC, Wells A (2006) IP-10 blocks vascular endothelial growth factor-induced endothelial cell motility and tube formation via inhibition of calpain. Circ Res 98:617–625
doi: 10.1161/01.RES.0000209968.66606.10
Hossain MZ, Ao P, Boynton AL (1998) Rapid disruption of gap junctional communication and phosphorylation of connexin43 by platelet-derived growth factor in T51B rat liver epithelial cells expressing platelet-derived growth factor receptor. J Cell Physiol 174:66–77
doi: 10.1002/(SICI)1097-4652(199801)174:1<66::AID-JCP8>3.0.CO;2-E
Mamer SB, Chen S, Weddell JC, Palasz A, Wittenkeller A, Kumar M, Imoukhuede PI (2017) Discovery of high-affinity PDGF-VEGFR interactions: redefining RTK dynamics. Sci Rep 7:16439
doi: 10.1038/s41598-017-16610-z
Campochiaro PA (2013) Ocular neovascularization. J Mol Med 91:311–321
doi: 10.1007/s00109-013-0993-5
Shimura M, Yasuda K, Motohashi R, Kotake O, Noma H (2017) Aqueous cytokine and growth factor levels indicate response to ranibizumab for diabetic macular oedema. Br J Ophthalmol 101:1518–1523
doi: 10.1136/bjophthalmol-2016-309953
Miyamoto N, de Kozak Y, Normand N, Courtois Y, Jeanny JC, Benezra D, Behar-Cohen F (2008) PlGF-1 and VEGFR-1 pathway regulation of the external epithelial hemato-ocular barrier. A model for retinal edema. Ophthalmic Res 40:203–207
doi: 10.1159/000119877
Miyamoto N, de Kozak Y, Jeanny JC, Glotin A, Mascarelli F, Massin P, BenEzra D, Behar-Cohen F (2007) Placental growth factor-1 and epithelial haemato-retinal barrier breakdown: potential implication in the pathogenesis of diabetic retinopathy. Diabetologia 50:461–470
doi: 10.1007/s00125-006-0539-2
Roberts WG, Palade GE (1995) Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J Cell Sci 108:2369–2379
doi: 10.1242/jcs.108.6.2369
Miyamoto K, Khosrof S, Bursell SE, Rohan R, Murata T, Clermont AC, Aiello LP, Ogura Y, Adamis AP Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition. Proc Natl Acad Sci U S A 96:10836–10841
Inoue Y, Shimazawa M, Nakamura S, Imamura T, Sugitani S, Tsuruma K, Hara H (2014) Protective effects of placental growth factor on retinal neuronal cell damage. J Neurosci Res 92:329–337
doi: 10.1002/jnr.23316
Trettel F, Di Castro MA, Limatola C (2019) Chemokines: key molecules that orchestrate communication among neurons, microglia and astrocytes to preserve brain function. Neuroscience 31:30519–30516
Fischer AJ, Zelinka C, Milani-Nejad N Reactive retinal microglia, neuronal survival, and the formation of retinal folds and detachments. Glia 63:313–327
McLeod DS, Lefer DJ, Merges C, Lutty GA Enhanced expression of intracellular adhesion molecule-1 and P-selectin in the diabetic human retina and choroid. Am J Pathol 147:642–653
Miyamoto K, Khosrof S, Bursell SE, Moromizato Y, Aiello LP, Ogura Y, Adamis AP Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability is mediated by intercellular adhesion molecule-1 (ICAM-1). Am J Pathol 156:1733–1739
Joussen AM, Poulaki V, Qin W, Kirchhof B, Mitsiades N, Wiegand SJ, Rudge J, Yancopoulos GD, Adamis AP Retinal vascular endothelial growth factor induces intercellular adhesion molecule-1 and endothelial nitric oxide synthase expression and initiates early diabetic retinal leukocyte adhesion in vivo. Am J Pathol 160:501–509
Rao VR, Prescott E, Shelke NB, Trivedi R, Thomas P, Struble C, Gadek T, O’Neill CA, Kompella UB Delivery of SAR 1118 to the retina via ophthalmic drops and its effectiveness in a rat streptozotocin (STZ) model of diabetic retinopathy (DR). Invest Ophthalmol Vis Sci 51:5198–5204
Shimura M, Yasuda K, Nakazawa T, Abe T, Shiono T, Iida T, Sakamoto T, Nishida K Panretinal photocoagulation induces pro-inflammatory cytokines and macular thickening in high-risk proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 247:1617–1624