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ARCH SOC ESP OFTALMOL. 2011;86(3):77–80
ARCHIVOS
DE LA SOCIEDAD
ESPAÑOLA
DE OFTALMOLOGÍA
ARCHIVOS DE LA SOCIEDAD
ESPAÑOLA DE OFTALMOLOGÍA
Vol. 85
Mayo 2010
Núm. 5
Contenido
Editorial
La retina como marcador biológico de daño neuronal
Artículos originales
Comparación de tres instrumentos de tomografía de
coherencia óptica, un time-domain y dos Fourierdomain, en la estimación del grosor de la capa de
fibras nerviosas de la retina
Idoneidad de tratamiento en sospechosos de glaucoma. Estudio de concordancia con el grupo de estudio RAND
Atrofia de la capa de fibras nerviosas de la retina en
pacientes con esclerosis múltiple. Estudio prospectivo con dos años de seguimiento
Comunicaciones cortas
Hipercorrección secundaria a transposición muscular
aumentada
Crítica de libros, medios audiovisuales y páginas
web oftalmológicos
Clinical Neuro-Ophthalmology: The Essentials
Sección histórica
Del mal de la rosa y la queratoconjuntivitis pelagrosa
Sección iconográfica
El estrabismo de Rembrandt
Sociedades y Reuniones Científicas
Ofertas de trabajo
www.elsevier.es/oftalmologia
Indexada en:
PubMed/MEDLINE, Scopus, EMBASE/
Excerpta Medica, IBECS, IME, SCIELO,
BIOSIS, SENIOR y COMPLUDOC
www.oftalmo.com/seo
www.elsevier.es/oftalmologia
Original article
Intraocular levels of pigment epithelium-derived factor
in patients with active uveitis
C. Marín-Lambíes,* D. Salom, S. García-Delpech, M. Díaz-Llopis
Departamento de Oftalmología, Hospital Universitario La Fe, Valencia, Spain
A RT I C L E I N F O R M AT I O N
A B S T R A C T
Article history:
Objective: Pigment epithelium-derived factor (PEDF) is an antiangiogenic/neurotrophic
Received on July 12, 2010
dual functional factor, and recently it was also shown to mediate antioxidative and anti-
Accepted on Dec. 22, 2010
inflammatory action. The purpose of this study was to evaluate the levels of PEDF in the
aqueous humor in eyes with idiopathic acute anterior uveitis (IAAU).
Keywords:
Methods: A comparative control study. Aqueous humor was collected from 20 eyes of
Uveitis
20 patients with IAAU. The control group included 20 aqueous humor samples from
Pigment epithelium-derived factor
20 patients who underwent a cataract surgery and without any other ocular or systemic
Inflammation
diseases. Levels of PEDF were determined with the ELISA test.
Cytokines
Results: Concentration of PEDF in aqueous humor was remarkably higher in patients
Aqueous humor
with IAAU than in control subjects (Mann-Whitney U test, P<.001). Levels of PEDF
were 6,291,637.70±8,564,836.48 pg/ml (mean±SD) in eyes with IAAU and 449,178.10±
158,670.19 pg/ml in the eyes of the control group.
Conclusion: The aqueous humor PEDF levels are increased in eyes with IAAU and may be
increased as self-protection against inflammation.
© 2010 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.
All rights reserved.
Niveles intraoculares del factor derivado del epitelio pigmentario
en pacientes con uveítis activa
R E S U M E N
Palabras clave:
Uveítis
Factor derivado del epitelio
pigmentario
Inflamación
Citocinas
Humor acuoso
Objetivo: El factor derivado del epitelio pigmentario (PEDF) es un factor antiangiogénico y neurotrófico que recientemente también ha demostrado tener poder antioxidante y antiinflamatorio. El objetivo de nuestro estudio fue determinar los niveles de
PEDF en humor acuoso de ojos con uveítis anterior aguda idiopática (UAAI).
Métodos: Se realizó un estudio comparativo con grupo control. El humor acuoso fue
estudiado en 20 ojos de 20 pacientes con UAAI. El grupo control comprendía 20 muestras de humor acuoso de 20 pacientes intervenidos de cataratas, sin ninguna otra
*Corresponding author.
E-mail: [email protected] (C. Marín-Lambíes).
0365-6691/$ - see front matter © 2010 Sociedad Española de Oftalmología. Published by Elsevier España, S.L. All rights reserved.
78
ARCH SOC ESP OFTALMOL. 2011;86(3):77–80
enfermedad ocular ni sistémica. Los niveles de PEDF se determinaron mediante el
test de ELISA.
Resultados: La concentración de PEDF en humor acuoso fue marcadamente superior
en los pacientes con UAAI que en los sujetos control (test U Mann-Whitney, p < 0,001).
Los niveles de PEDF fueron 6.291.637,70 ± 8.564.836,48 pg/ml (media ± DS) en los ojos
con UAAI y 449.178,10 ± 158.670,19 pg/ml en los ojos del grupo control.
Conclusiones: Los niveles de PEDF en humor acuoso están aumentados en ojos con
UAAI lo cual podría considerarse como un mecanismo de autoprotección frente a la
inflamación.
© 2010 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.
Todos los derechos reservados.
Introduction
The pigment epithelium-derived factor (PEDF) is a glucoprotein
that belongs to the superfamily of protease serine inhibitors,
with a high neuronal differentiation activity which has proved
to be the most potent angiogenesis inhibitor.1 It inhibits
the growth and migration of retina endothelial cells and
suppresses ischemia-induced retinal neovascularization.2 In
addition, PEDF reduces oxidative stress and the production of
inflammatory cytokines in the retina, acting as an endogenous
anti-inflammatory factor.3 Recently it was demonstrated that
the levels of PEDF in the aqueous humor of uveitis patients
correlate with inflammatory markers such as the alpha tumor
necrosis factor (TNF-a) and the monocyte 1 chemoattractant
protein (MCP-1) and could be raised as a reaction system
against inflammation in uveitis.4,5 However, the role of PEDF
in ocular inflammatory diseases such as uveitis is not yet
sufficiently defined. This study assessed the levels of PEDF in
the aqueous humor of patients with idiopathic acute anterior
uveitis (IAAU) and its possible involvement as a self-protection
mechanism against inflammation in acute uveitis episodes.
Subjects, material and methods
A comparative study with control group. The PEDF levels
were determined in the aqueous humor of patients with
IAAU. The protocol of the study fulfilled the rules of the
Helsinki Declaration and was reviewed and approved by the
Ethical Committee of our tertiary hospital. Each patient was
requested to sign an informed consent.
The study included patients of the uveitis unit of the La Fe
University Hospital of Valencia. The aqueous humor samples
were collected from 20 eyes of 20 patients with anterior uveitis
in acute episodes. All these patients underwent a complete
ophthalmological assessment as well as a range of lab tests
in order to discard any other possible associated ocular or
systemic diseases. The control samples were obtained from
20 eyes of 20 patients at the time of undergoing cataract
surgery.
The aqueous humor samples of the patients with IAAU
were collected under steroid conditions utilizing slit lamp
and applying iodinated povidone and after anterior chamber
punction with a 30-gauge needle. The aqueous humor of
control was obtained with 30 gauge needles before undergoing
cataract surgery. In both groups antibiotic prophylaxis was
applied with ciprofloxacine eyedrops, Oftacilox, Alcon (1 drop
every 8 hours) during 5 days following the extraction. Samples
were collected in a volume of at least 0.05 ml for each patient
and maintained in sterilized tubes stored immediately at
–80°C up to their assessment.
The levels of PEDF were quantified utilizing commercial
kits of ELISA (immunoabsorption essay linked to enzymes) of
the aqueous humor (Searchlight Array; Pierce Biotechnology,
Inc., Woburn, MA). The demographic characteristics of the
patients were studied with the statistical program SPSS 13.0
for Windows (SPSS for Windows, SPSS Inc, Chicago, USA). In
order to compare the PEDF levels in the study groups, the U
Mann-Whitney test was applied for independent samples,
accepting p<0.05 as a statistically significant value.
Results
Overall, 20 aqueous humor samples of 20 patients with IAAU
were analyzed. The mean age ±SD of this group was of 47±
3.2 years and 30% were female. Similarly, 20 samples from
20 patients who were going to be operated for cataracts
were obtained as control group, with a mean age ± SD of 55±
2.7 years. 40% were female.
The levels of PEDF observed in the eyes with IAAU were
of 6.291.637.70 ± 8,564,836.48 pg/ml (mean±SD) and 449,178.10
± 158,670.19 pg/ml in the control group eyes (table 1). These
results illustrate that the PEDF levels differ significantly in
both groups, with considerably higher levels in patients with
IAAU compared to the control patients (fig. 1), with these
results being statistically significant (U Mann-Whitney test,
p<0.001). Table 2 shows the detailed levels of PEDF in each
patient.
Discussion
PEDF, which initially demonstrated to be a powerful
angiogenesis inhibitor,1,2 has also demonstrated a potent
anti-inflammatory3 and antioxidant action.6,7 However, these
actions are not sufficiently clarified. It has been pointed out
that the PEDF levels in plasma are drastically diminished in
experimental uveitis induced in rats, which would indicate
that PEDF could operate as a negative acute phase protein and
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ARCH SOC ESP OFTALMOL. 2011;86(3):77–80
Table 1 – Levels of PEDF in aqueous humor and group characteristics.
Study groups
PEDF levels in aqueous humor (pg/ml) mean ± SD
IAAU (n=20)
Control (n=20) 6.291.637.70±8.564.836.48
p<0.001a to
449.178.10±158.670.197
PEDF: pigment epithelium derived factor; IAAU: idiopathic acute anterior uveitis.
to control group (U Mann-Whitney Test).
aCompared
Table 2 – Detailed PEDF levels in aqueous humor.
10.000.000
10,000,000
PEDF (pg/ml)
8.000.000
8,000,000
6,000,000
6.000.000
4,000,000
4.000.000
2,000,000
2.000.000
0
Control
Uveitis
GRUPOS
GROUPS
Figure 1 – Pigment epithelium derived factor (PEDF) levels
in the aqueous humor of 20 eyes with idiopathic acute
anterior uveitis (IAAU) and 20 control eyes. The levels of
PEDF were different in both groups but significantly higher
in patients with IAAU than in controls (U Mann-Whitney
Test p<0.001).
also that the diminishment of PEDF per se could be enough
to induce inflammatory responses. Accordingly, PEDF would
constitute an endogenous anti-inflammatory factor, and
diminished levels at the ocular level would contribute to
vascular inflammation and hyperpermeability.
On the other hand, intravitreal PEDF injections and the
ensuing increase at the intraocular level leads to a reduction
of vascular hyper permeability and inflammation as a
consequence of diminished inflammatory factor levels such
as the vascular endothelial growth factor (VEGF), monocyte 1
chemoattractant protein (MCP-1), alpha tumor necrosis factor
(TNF-a) and the intercellular adhesion molecule 1 (ICAM-1),
as well as in experimental uveitis.3
Feher et al. demonstrated that the retrobulbar
administration of PEDF in rats with capsaicine-induced
keratouveitis reduced inflammation both in the anterior
and posterior chamber. It was also observed that the antiinflammatory effect of PEDF is dosage dependent.8
Patient IAAU: levels of PEDF (pg/ml)
Control: levels
of PEDF
(pg/ml)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
641,290
2,941,700
1,850,000
22,833,900
1,174,114
3,543,100
3,608,200
1,194,840
1,089,740
1,064,980
727,640
1,575,685
3,581,000
4,016,700
4,284,100
21,427,000
31,354,700
4,231,421
8,462,721
6,229,923
343,215
545,145
382,080
265,070
376,785
281,685
510,420
683,900
651,100
644,882
494,800
748,500
549,100
148,500
249,200
345,050
420,500
448,815
399,600
495,215
PEDF: pigment epithelium derived factor; IAAU: idiopathic acute
anterior uveitis.
Even though there is an abundance of studies about the
anti-inflammatory action of PEDF with animal models, studies
in humans are scarce. In 2007 Yoshida et al.4 described for the
first time high PEDF levels in the aqueous humor of a group
of patients with infectious and noninfectious uveitis when
compared to a control group. In addition, they pointed out
that infectious uveitis exhibited significantly higher levels of
PEDF than noninfectious uveitis, and that PEDF increases in
proportion to the activity of the disease. For these orphans,
the PEDF levels in the aqueous humor are correlated to
inflammatory markers such as TNF-a and MCP-1. and they
consider that PEDF could be high as a reaction system against
inflammation.5 Likewise, PEDF will correlate with endogenous
antioxidant factors such as asymmetric dimethyl argynine
(ADMA), the levels of which are also high in the aqueous
humor of patients with uveitis.6,7
In this study, notwithstanding the limitations thereof
such as the small number of percent and the high confidence
interval obtained in the group of patients with IAAU, the
determination of PEDF levels has allowed us to observe
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ARCH SOC ESP OFTALMOL. 2011;86(3):77–80
significantly high levels in a homogeneous group of patients
with IAAU when compared with healthy patients. In addition,
our results match those of previous studies of uveitis of
different etiologies. Therefore, we consider that the elevation
of PEDF would constitute a response against inflammation by
acting as a self-protection mechanism against it independently
of the etiology of the uveitis under study.
Conflict of interests
None of the authors have declared any conflict of interests.
R e f e r e n c e s
1. Tombran-Tink J, Chader CG, Johnson LV. PEDF: pigment
epithelium-derived factor with potent neuronal differentiative
activity. Exp Eye Res. 1991;53:411-4.
2. Duh EJ, Yang HS, Suzuma I, Miyagi M, Youngman E, Mori K, et al.
Pigment epithelium-derived factor suppresses ischemiainduced retinal neovascularization and VEGF-induced migration
and growth. Invest Ophthalmol Vis Sci. 2002;43:821-9.
3. Zhang SX, Wang JJ, Gao G, Shao C, Mott R, Ma JX. Pigment
epithelium-derived factor (PEDF) is an endogenous antiinflammatory factor. FASEB J. 2006;20:323-5.
4. Yoshida Y, Yamagishi S, Matsui T, Nakamura K, Imaizumi T,
Yoshimura K, et al. Increased levels of pigment epitheliumderived factor in aqueous humor of patients with uveitis.
Br J Ophthalmol. 2007;91:149-50.
5. Yoshida Y, Yamagishi S, Matsui T, Nakamura K, Imaizumi T,
Yoshimura K, et al. Positive correlation between pigment
epithelium-derived factor and monocyte chemoattractant
protein-1 levels in the aqueous humour of patients with
uveitis. Br J Ophthalmol. 2007;91:737-8.
6. Yoshida Y, Yamagishi S, Ueda S, Yoshimura K, Okuda S,
Yamakawa R. Aqueous humour levels of asimetric
dimethylarginine (ADMA) are correlated with pigment
epithelium-derived factor (PEDF) in patients with uveitis.
J Intern Med Res. 2007;35:892-5.
7. Yoshida Y, Yamagishi S, Matsui T, Nakamura K, Imaizumi T,
Yoshimura K, et al. Positive correlation of pigment epitheliumderived factor and total antioxidant capacity in aqueous
humour of patients with uveitis and proliferative diabetic
retinopathy. Br J Ophthalmol. 2007;91:1133-4.
8. Feher J, Kovacs I, Pacella E, Keresz S, Spagnardi N, Balacco
Gabrieli C. Pigment epithelium-derived factor (PEDF)
attenuated capsaicin induced neurotrophic keratouveitis.
Invest Ophthalmol Vis Sci. 2009;50:5173-80.