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Intravitreal Triamcinolone Acetonide Inhibits Choroidal Neovascularization in a Laser-Treated Rat Model
Thomas A. Ciulla, MD;
Mark H. Criswell, PhD;
Ronald P. Danis, MD;
Tiffany E. Hill, BS
Arch Ophthalmol. 2001;119:399-404.
ABSTRACT
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Objective To determine if intravitreal triamcinolone acetonide (TAAC) inhibits
experimental choroidal neovascular membranes induced by laser trauma in a
rat model.
Methods Nineteen anesthetized male Brown Norway rats received a series of 8
krypton red laser lesions per eye (647 nm, 0.05 seconds, 50 µm, and
150 mW in 17 rats, and 200 mW in 2 rats). One eye received an intravitreal
injection of triamcinolone acetonide (20 µL, 0.8 mg) and the other eye
received an injection of isotonic sodium chloride solution. Fundus and fluorescein
angiography examinations occurred just before euthanasia and tissue processing
for histopathology on day(s) 0, 1, 3, 7, 14, 21, 28, and 35.
Results From the control eyes that underwent photocoagulation at 150 mW, 57
discrete lesions with definitive fibrovascular proliferations were observed
at 21, 28, and 35 days, arising from a total of 72 spots placed (79% yield).
From the control eyes that underwent photocoagulation at 200 mW, 11 discrete
lesions with definitive fibrovascular proliferations were observed at 28 days,
arising from a total of 16 spots placed (69% yield). In the TAAC-treated group,
no fibrovascular proliferations were observed in the 72 lesions and in the
16 lesions created with 150 mW and 200 mW, respectively.
Conclusion Intravitreal TAAC is a potent inhibitor of fibrovascular proliferations
in a rat model of choroidal neovascular membranes induced by laser trauma.
Clinical Relevance This study corroborates previous investigations that propose TAAC as
a potential treatment for choroidal neovascular membranes in humans.
INTRODUCTION
AGE-RELATED nacular degeneration (AMD), the leading cause of irreversible
visual loss in the United States, has many treatment limitations. Steroid
compounds are well-known antiangiogenic agents, which have been suggested
as treatment for the choroidal neovascular membranes (CNVMs) that cause visual
loss in exudative AMD.1-6
Although there are no direct animal models of AMD-related CNVMs, there are
several animal models of CNVMs secondary to laser trauma. In the current study,
we sought to characterize the effect of intravitreal triamcinolone acetonide
(TAAC) on CNVM formation in a previously described and validated rat model
of CNVM due to laser trauma.
MATERIALS AND METHODS
ANIMALS
Nineteen male adult (250-g) Brown Norway rats (Harlan Sprague-Dawley
Inc, Indianapolis, Ind) were used to evaluate the effect of intravitreal TAAC
vs a control injection on CNVMs. All procedures were performed with strict
adherence to guidelines for animal care and experimentation prepared by the
Association for Research in Vision and Ophthalmology (Bethesda, Md), and by
the Indiana University Animal Care Committee. For all procedures, including
examination and photography, animals received intramuscular ketamine hydrochloride
at 75 mg/kg and acepromazine maleate at 2.5 mg/kg, along with atropine sulfate
at 0.05 mg/kg intramuscularly to minimize bronchial secretions. Maintenance
amounts (10%-15%) were administered at 45-minute intervals, when necessary.
For all procedures, 1% topical cyclopentolate hydrochloride, 2.5% phenylephrine
hydrochloride, and 1% atropine sulfate, were administered for pupillary dilation.
All animals underwent ocular examination, color fundus photography, and fluorescein
angiography using 25% sodium fluorescein (0.1 mL/kg) administered intravenously.
A Zeiss FK 30 fundus camera (Zeiss Instruments, Jena, Germany) was used.
LASER PHOTOCOAGULATION
After receiving anesthesia and undergoing pupillary dilation, the animals
were positioned on a Mayo stand before slitlamp laser delivery. The fundus
was visualized using a microscope slide coverslip and 2.5% hydroxypropyl methylcellulose
solution as a contact lens. A krypton red (647-nm) laser at 0.05 seconds and
150 mW or 200 mW was used. Laser power was verified with a power meter. In
all experiments, a series of 8 lesions was concentrically placed at equal
distances around the optic discs of both eyes. The 50-µm spot at 150-mW
power was the most reliable at producing acute vapor bubbles, which suggested
Bruch membrane rupture, Fibrovascular proliferations (FVP) emanated from disrupted
Bruch membrane and infiltrated the outer retina. To evaluate the effect of
intravitreal TAAC vs the control injection, 17 rats underwent laser photocoagulation
using the 50-µm spot size at 150-mW power and 0.05 seconds, and 2 rats
underwent laser photocoagulation using the same parameters, except at a power
of 200 mW. This latter group of rats was killed at 28 days. In the entire
group of 19 rats, a total of 304 spots were placed. Histopathological findings
of the experimental groups are presented in Table 1.
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Histopathologic Findings*
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ADMINISTRATION OF ANTIANGIOGENIC AGENT AND CONTROL SOLUTION
A TAAC suspension (Kenalog, 40 mg/mL; Bristol-Myers Squibb, Conn) was
administered intravitreally using a 30-gauge needle inserted 1 mm and angled
towards the optic nerve immediately after laser photocoagulation. One eye
received an intravitreal injection of TAAC (20 µL, 0.8 mg) through the
sclera into the vitreous cavity. A higher dose of TAAC was chosen (approximately
9 times the empiric dose used in prior human pilot studies2, 6-7)
because the pharmacokinetics of the drug in the rat vitreous cavity were unknown,
because insufficient dosing was to be avoided, and because this volume could
be reproducibly administered. Proparacaine hydrochloride (0.5%) was used for
topical anesthesia (in addition to general anesthesia) during this procedure.
Prior to injection, 5% povidone was applied to the ocular surface. The posterior
segment was evaluated immediately after injection to confirm placement of
the drug into the vitreous cavity. The fellow (control) eye received an injection
of isotonic sodium chloride solution at the same volume (20 µL) to comparatively
evaluate any changes that might have resulted from the physical insertion
of the needle tip or from changes in intraocular pressure subsequent to fluid
injection. The entire group of 19 rats was treated in this fashion.
ASSESSMENT
Follow-up examination, fundus photography, and fluorescein angiography
occurred just before euthanasia on day(s) 0, 1, 3, 7, 14, 21, 28, and 35.
The angiograms were subjected to masked analysis by 2 investigators (T.A.C.
and M.H.C.) for the presence of staining or leakage at each lesion. Differences
in the evaluations were resolved though joint discussions of the data.
Eyes were enucleated immediately after euthanasia and eyecup preparations
were fixed in 4% phosphate-buffered paraformaldehyde solution (overnight at
room temperature). For each eye, a single square-shaped tissue block (approximately
1.5 mm per side), containing the optic disc and the 8-lesion sites, was hand
sectioned from the eyecup preparation. Tissue sections were dehydrated, embedded
in paraffin, serially sectioned (6 µm), and stained for light microscopy
with hematoxylin-eosin. Each laser lesion site was individually evaluated
and photographed. The histologic findings were correlated with those from
fundus photography and fluorescein angiography. Specifically, histologic specimens
were methodically assessed in a masked fashion by 1 reader (M.H.C.) for the
presence or absence of neovascularization; the level of neovascularization
with respect to the choroid, Bruch membrane, or the retina; the response of
the retinal pigment epithelium (RPE) to the original injury and subsequent
FVP; and the inflammatory response to the original injury and subsequent FVP.
Lesions that showed FVP with thickening greater than 10 µm between the
choroid and retina overlying the laser lesion were deemed to show the presence
of neovascularization.
RESULTS
In the controls treated with isotonic sodium chloride solution, gray-white
lesion sites were apparent by day 3. By day 14, the lesions had faded on examination
(Figure 1). On fluorescein angiography,
all lesions showed early hyperfluorescence with late staining and leakage
at the border of the lesion (Figure 2). At day 0, there was disruption of the RPE and Bruch membrane, mild hemorrhage
in the outer retina, and vascular dilation in the choroid. On day 1, the presence
of macrophages was noted. On day 3, there was clearing of red blood cells
and resolution of choroidal vascular dilation. Also on day 3, and more prominently
on day 7, there was discrete thickening of the choriocapillaris with early
FVP, consisting of collagenous tissue and proliferating vessels with erythrocytes
in the luminal spaces. At 21, 28, and 35 days, the lesions showed distinct
FVP arising from the disrupted RPE and Bruch membrane and infiltrating the
retina. In the rats that were laser treated at 150 mW power, 57 discrete lesions
with definitive FVP were observed at 21, 28, and 35 days, arising from a total
of 72 spots placed (79% yield). Representative histopathologic findings are
shown in Figure 3. In the rats laser
treated at 200-mW power, 11 discrete lesions with definitive FVP were observed
at 28 days, arising from a total of 16 spots placed (69% yield).
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Figure 1. Color fundus photographs of laser
lesions (150 mW) at 28 days. A series of 8 lesions was placed at equal distances
around the optic discs of both eyes. There is a photographic reflex present
centrally overlying the optic nerve head. A, Control eye treated with isotonic
sodium chloride solution. Note the obscuring of the lesion boundaries due
to fibrovascular proliferations. B, Triamcinolone acetonide–treated
eye. Note the discrete white lesions representing visible sclera through the
defect in the Bruch membrane and retinal pigment epithelium.
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Figure 2. Fluorescein angiography (late
phase, 10 minutes postinjection) of the identical region at 28 days. A, Control
eye treated with isotonic sodium chloride solution. There is late leakage
at the borders of the lesions. B, Triamcinolone acetonide–treated eye.
There is intense late staining of the lesions due to the absolute defect in
the Bruch membrane and retinal pigment epithelium. Mild leakage cannot be
reliably ruled out owing to the very intense staining.
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Figure 3. Histopathologic analysis of the
identical region at 28 days (hematoxylin-eosin; retinal thickness adjacent
to the lesion measures 100 ± 10 µm). A, Control eye treated with
isotonic sodium chloride solution. Note the fibrovascular proliferations (FVP)
arising through the disrupted retinal pigment epithelium (RPE) and the Bruch
membrane and infiltrating the retina. There are red blood cells seen within
lumenal structures. B, Triamcinolone acetonide–treated eye. Note the
prominent defects in the RPE and the Bruch membrane with a striking absence
of FVP. The retina is drawn into the defect.
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In some eyes from the TAAC-treated group, the opaque white drug partially
obscured the posterior segment from days 0 to 7 when the drug began to settle
inferiorly and clear. At all later time points, when clinical examination
was possible, the clinical and angiographic appearance of these lesions was
distinct from the lesions seen in untreated eyes. In particular, the lesions
showed absolute RPE and Bruch membrane defects with prominent white sclera
evident in the defect (Figure 1).
On fluorescein angiography, the absolute atrophy associated with each lesion
caused very intense staining, and mild leakage could not be reliably ruled
out (Figure 2). It became apparent
that histopathologic analysis more reliably determined the presence or absence
of FVP. The early findings (days 0 and 1) were similar to the findings in
the control eyes treated with isotonic sodium chloride solution. These included
disruption of the RPE and Bruch membrane, mild hemorrhage in the outer retina,
and vascular dilation in the choroid on days 0 and 1, followed by some clearing
of red blood cells and resolution of choroidal vascular dilation on day 3.
On day 7, there appeared to be fewer macrophages infiltrating the lesions
relative to the controls injected with isotonic sodium chloride solution,
but the macrophages were not quantitatively compared with the control eyes
by cell-specific staining. At all later time points, the TAAC-treated eyes
showed prominent defects in the RPE and Bruch membrane with a striking absence
of FVP at each laser lesion. In the rats laser treated at 150-mW power, no
FVP were observed in the 72 lesions at 21, 28, and 35 days, arising from the
original 72 lesions placed (0%). Representative histopathologic findings are
shown in Figure 3. From the TAAC-injected
rats that were laser treated at 200-mW power, no FVP were observable in the
16 lesions at 28 days, arising from the original 16 lesions placed (0%). Triamcinolone
acetonide exerted an inhibitory effect on the development of FVP in every
recovered laser lesion (P<.001, Fisher exact test).
COMMENT
This study demonstrates that intravitreal TAAC is a potent inhibitor
of FVP in a laser-treated rat model. The best-known model for CNVMs, however,
is the laser-treated primate model, developed by Ryan.4, 8-16
In this model, high-intensity laser burns are used to create ruptures in Bruch
membrane/RPE complex to initiate a repair process in the fundus that results
in the development of subretinal neovascularization.14
To avoid the use of primates, several groups have validated the laser-treated
rat model using intense diode17 or kypton18-24
laser photocoagulation to acutely rupture Bruch membrane, which leads to rapid
reproducible CNVM. This model does not show rapid spontaneous regression of
the neovascular process,19, 25
as in the laser-treated primate model, which is a useful feature when evaluating
antiangiogenic treatments. Other investigators have developed rat models using
lower-intensity krypton laser photocoagulation, which did not result in acutely
rupturing the Bruch membrane. This led to slower development of CNVM, presumably
through focal digestion of Bruch membrane by enzymes elaborated by proliferating
choroidal endothelial cells.26-27
The stimulus for neovascularization in the laser models obviously differs
from that in AMD, because the laser models invoke a traumatic repair process,
which may better mimic traumatic CNVMs and not AMD-related CNVMs. This point
may be especially relevant for the high-intensity laser photocoagulation models
that cause acute rupture of Bruch membrane, as in our study. Nevertheless,
the laser trauma in both the high-intensity and low-intensity laser models
may initiate a cascade of angiogenic growth factors, which may be relevant
to AMD-related CNVM. For example, one group of investigators has demonstrated
the expression of basic fibroblast growth factor in their rat model using
lower-intensity krypton red photocoagulation.28-29
An Australian group has found evidence of expression of cell adhesion molecules
and vascular endothelial growth factor in their model using intense krypton
laser photocoagulation.19 A Japanese group,
who has had the most published experience with the intense krypton laser-treated
rat model, has demonstrated expression of basic fibroblast growth factor,
vascular endothelial growth factor, and transforming growth factor  ).20-24
Several of these growth factors have been implicated in human CNVM formation.
For example, surgically excised and postmortem CNVM tissue, as well RPE cells,
have been shown to be immunoreactive for vascular endothelial growth factor,
transforming growth factor , platelet-derived growth factor, and basic
fibroblast growth factor.30-35
Our study establishes the potent inhibition of FVP by intravitreal TAAC
in the laser-treated rat model, corroborating and amplifying some of the findings
from prior studies. Unlike some recent studies using a diode laser in the
rat,36-37 however, fluorescein
angiography seemed to be of limited value in determining the presence or absence
of CNVMs. This could be due to the absolute atrophy associated with the TAAC-treated
lesions, which caused very intense staining, limiting the ability to rule
out superimposed mild leakage in these eyes. Alternatively, the diode laser
could induce lesions with different angiographic characteristics compared
with the krypton red laser used in this study. Nevertheless, the differences
seen on histopathologic analysis were striking.
Steroid compounds have long been known to possess angiostatic properties
via alteration of extracellular matrix degradation1
and possibly through inhibition of leukocytes that release angiogenic growth
factors.2, 6-7,38
Oral prednisone or sub-Tenon injections of depot forms of steroids have been
advocated for treatment of CNVMs due to the presumed ocular histoplasmosis
syndrome,3 although no controlled studies have
been performed. Intravitreal steroid injections potently inhibit experimental
subretinal4 and preretinal5
neovascularization in primates and pigs, respectively. Intravitreal TAAC produced
an apparent beneficial effect in an uncontrolled pilot study of CNVM treatment
in AMD,2 which was followed (in a study by
Challa et al7) by a favorable effect on the
course of the disease during an 18-month period. More recently, a prospective
pilot study involving 27 patients randomized to intravitreal TAAC vs observation
demonstrated a statistically significant beneficial effect of TAAC on best-corrected
visual acuity at 3 months.6 These authors speculate
that intravitreal TAAC has a beneficial effect on AMD-related CNVM development
through the inhibition of leukocytes, including macrophages, which release
angiogenic factors.2, 6-7
Investigators using the Ryan primate CNVM model have also postulated that
macrophages involved in the initial response to Bruch membrane injury secrete
angiogenic growth factors.38 In this study,
there appeared to be relatively fewer leukocytes observed at the TAAC-treated
laser lesions at day 7, although macrophages were not quantitatively assessed
and their role in CNVM development in this model remains speculative.
Obviously, the TAAC dosage level used in this study probably accounts
for the absolute inhibition of FVP. It should also be noted that this study,
by its design, demonstrated inhibition or prevention of FVP, but not regression
of preexisting FVP, which would be more relevant to human CNVM. Nevertheless,
this study corroborates and amplifies previous investigations that propose
TAAC as a promising potential treatment modality for CNVM in humans. Further
studies of the mechanism by which TAAC exerts its antiangiogenic effect to
inhibit the action of growth factors, as well as the determination of optimal
TAAC dose-response levels for both inhibition of FVP formation and regression
or stabilization of preexisting FVP are warranted.
AUTHOR INFORMATION
Accepted for publication August 22, 2000.
Supported by an unrestricted grant from Research to Prevent Blindness
Inc, New York, NY; a Career Development Award from Research to Prevent Blindness
Inc (Dr Ciulla); an Indiana University Purdue University Indianapolis Faculty
Development Grant, Grant-in-Aid for Research (Dr Criswell); and the Project
Development Program, Research and Sponsored Program, Indiana University Purdue
University Indianapolis (Dr Ciulla).
We wish to thank Lisa Bird, BA, for her technical expertise and assistance
with histopathologic analysis.
Corresponding author and reprints: Thomas A. Ciulla, MD, Retina Service,
Department of Ophthalmology, Indiana University School of Medicine, 702 Rotary
Cir, Indianapolis, IN 46260 (e-mail: tciulla{at}iupui.edu).
From the Retina Service, Department of Ophthalmology, Indiana University
School of Medicine, Indianapolis. The authors have no financial or proprietary
interest in the information presented.
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Intravitreal triamcinolone in recurrence of choroidal neovascularisation
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