Louis Tong

Preeya. K. Gupta

Springer - Publisher Connector

COMMENTARY
Need for Animal Models of Meibomian Gland
Dysfunction
Louis Tong . Preeya. K. Gupta
Received: October 11, 2016 / Published online: November 11, 2016
 The Author(s) 2016. This article is published with open access at Springerlink.com
ABSTRACT
Evaporative dry eye has gained increasing
interest in recent years in academia,
pharmaceutical, and medical device industries.
The main cause of this type of dry eye is
attributed to meibomian gland dysfunction
(MGD). MGD is a diffuse abnormality of the
meibomian glands characterised by terminal
duct obstruction and eventually leading to signs
and symptoms of dry eye. There have been only
a few reported animal models of MGD, but
recent advances are likely to lead to new models
and better ways to assess the pathology in these
animals. Recent models reported include one
based on cautery of the meibomian glands in
mice and another based on aggravated allergy
in mice. These developments will enable better
pre-clinical assessment of novel therapies in the
future.
Keywords: Animal models; Dry eye;
Meibomian gland dysfunction; Mice; Ocular
disease; Pathology; Rat
COMMENTARY
Dry eye is a common problem worldwide, and
it has been reported that 70% of dry eye has an
evaporative component [1]. The major cause of
evaporative dry eye is meibomian gland
dysfunction (MGD). In MGD, the occlusion
of the terminal ducts leads to a cascade of
changes including retention of meibomian
lipids, abnormal tear lipid layer, signs of
evaporative dry eye, as well as atrophy and
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L. Tong
Ocular Surface Research Group, Singapore Eye
Research Institute, Singapore, Singapore
L. Tong
Corneal and External Eye Disease Service, Singapore
National Eye Center, Singapore, Singapore
L. Tong
Eye-Academic Clinical Program, Duke-NUS Medical
School, Singapore, Singapore
L. Tong (&)
Department of Ophthalmology, Yong Loo Lin
School of Medicine, National University of
Singapore, Singapore, Singapore
e-mail: Louis.tong.h.t@singhealth.com.sg
Preeya. K. Gupta
Duke Department of Ophthalmology, Duke
University School of Medicine, Durham, USA
Ophthalmol Ther (2016) 5:129–134
DOI 10.1007/s40123-016-0070-6
loss of meibomian glands. A recent
international workshop by international
experts mentioned that there is an unmet
medical need in MGD, research in MGD is a
priority, and one essential tool for translational
research is an appropriate animal model. With
increased clinical interest in MGD as it relates
to tear stability and tear lipid chemistry,
development of an animal model for MGD is
paramount. New therapeutic medical devices
for MGD are now available. There is increased
interest in the development of lipid-containing
eyedrops. It is advantageous to evaluate
efficacy and safety of these new treatments in
pre-clinical studies [2]. Currently available
animal models resemble only one or more of
these pathophysiological aspects, but are
dissimilar to human MGD in other ways,
either in the chronicity of the disease or the
requirement for glandular occlusion to be the
initiating event in the disease. It is important
to avoid excessive pain when inducing the
MGD features in animals.
An ideal animal model for MGD should
include anatomical features of human disease,
such as obstruction of the glands,
keratinisation of the ducts, and dilatation of
the ductules. As in human disease, the
observable characteristics should diffusely
affect the entire lids in a chronic or
progressive manner, with fibrosis or edema of
the eyelid margin. Even though the lipids of
murine meibum are quite different from
humans [3], there is likely biochemical
abnormality in the animal tear or meibum
that can be measured after induction of
disease, such as changes in saturation of wax
esters, decreases in O-acyl x-hydroxyl fatty
acids (OAHFAs), or increases in
lysophospholipids. Ideally, there should be a
high success rate for induction of the MGD,
and animals involved should have normal
lifespan and have little to no involvement of
other systemic organs.
Here we review the features of the reported
animal models (mouse and rat) that exhibit
abnormalities in meibomian glands (Table 1).
Animal models that report primarily blepharits
[4] or reflect an ocular surface dessication model
with secondary MGD [5] are not included in the
discussion. There are some pros and cons for
each of the models reported. Several animal
models are suitable for evaluation of
developmental abnormalities of meibomian
glands, for example, a mutation in the
EDARadd gene resulted in rats with abnormal
meibomian, sweat, mammary, and other
exocrine glands [6]. Such models may or may
not reflect acquired disease that obstruct the
meibomian glands. As MGD is more common in
older people, a model that used superoxide
dismutase deletion in mice reflects human
disease in that these mice also show
age-related MGD features. Furthermore, this
model also presents with evaporative dry eye
features that improved after treatment [7].
Superoxide dismutase is an important enzyme
that sequesters free radicals, and in the absence
of this enzyme, free radicals tend to increase,
which is a phenomenon observed in aging cells
and tissues. A mouse model that used cautery
was successful in the induction of MGD after 4
and 8 weeks due to induction of post-cautery
fibrosis, suggesting that glandular changes were
secondary to obstruction [8]. Another model in
rabbits using cautery of meibomian glands has
also been reported [9]. Two other interesting
novel models of MGD include one that is HR-1
mice fed with a lipid limiting diet [10], the
other an aggravated allergic model that
involved infiltration of eyelid neutrophils and
IL17-mediated inflammation [11].
There is much unknown in this exciting
research area. Some of the more recent studies
130 Ophthalmol Ther (2016) 5:129–134
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Ophthalmol Ther (2016) 5:129–134 131
evaluated here have only been reported in
conference proceedings, and there is no doubt
that the search is ongoing for a better and more
convenient animal model of MGD. Newer
imaging modalities and robust biochemical
techniques will be employed in the evaluation
of these future animal models. Novel image
analysis algorithms would be useful for in vivo
confocal microscopy, which is a
non-destructive process. In tissue sections
non-linear optical imaging and volumetric
analysis of meibomian glands is a promising
technique [12]. In cases where inflammation is
to be evaluated, observation of leukocytes in
two-photon live microscopy may be useful.
These novel techniques will likely further our
understanding of newer therapies of MGD such
as probing and intense pulse light, as to date
there are no suitable models to assess the effects
of these therapies at the microscopic level.
ACKNOWLEDGEMENTS
This work is supported by the Grant:
NMRC\CSA\045\2012 from the National
Medical Research Council, Singapore. All
named authors meet the International
Committee of Medical Journal Editors (ICMJE)
criteria for authorship for this manuscript, take
responsibility for the integrity of the work as a
whole, and have given final approval for the
version to be published.
Disclosures. L. Tong and P. Gupta have
nothing to disclose.
Compliance with Ethics Guidelines. This
article is based on previously conducted
studies and does not involve any new studies
of human or animal subjects performed by any
of the authors.
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132 Ophthalmol Ther (2016) 5:129–134
Open Access. This article is distributed
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License (http://creativecommons.org/licenses/
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Need for Animal Models of Meibomian Gland Dysfunction

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Need for Animal Models of Meibomian Gland Dysfunction

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