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Chapter 02
Pterygium: A Complex and Multifactorial
Ocular Surface Disease. A Review on its
Pathogenic Aspects
Horacio M Serra1#*, Maria F Suarez1#, Juan P Maccio2, Evangelina
Esposito2 and Julio A Urrets-Zavalia2
1
CIBICI, Department of Clinical Biochemistry, Faculty of Chemical Sci-
ences, Universidad Nacional de Córdoba, Argentina
2
Department of Ophthalmology, University Clinic Reina Fabiola, Universi-
dad Católica de Córdoba, Argentina
*
Corresponding Author: Horacio Marcelo Serra, CIBICI, Faculty of
Chemical Sciences, Universidad Nacional de Córdoba, Haya de la Torre
esquina Medina Allende, 5000 Córdoba, Argentina, Tel: 54 351 4344973;
Fax: 54 351 4333048; Email: hserra@fcq.unc.edu.ar
This article is distributed under the terms of the Creative Commons Attribu-
tion 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted
use, distribution, and reproduction in any medium, provided you give ap-
propriate credit to the original author(s) and the source.
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Summary
Pterygium is an abnormal overgrowth of epithelial and fibrovas-
cular tissue of the bulbar conjunctiva onto the corneoscleral limbus
that may progress invading the superficial corneal layers. Usually, it
develops horizontally on the nasal area of the interpalpebral fissure,
but it may also affect the temporal side, and rarely both areas in a
same eye. Its prevalence rate varies from 0.7 to 31% in different geo-
graphical regions around the world, being especially common in the
tropics. Although many factors, such as ultraviolet radiation expo-
sure, may contribute to the development and progression of pterygia,
its pathogenesis remains elusive.
In this chapter, we review the anatomy and histology of the
normal conjunctiva, the molecular characterization of conjunctival
epithelial cells and the expression of different types of cytokeratins,
clinical aspects, presentation and treatment of pterygium, and possi-
ble pathogenetic factors influencing its development, such as expres-
sion of cytokeratins and matrix metalloproteinases, dysregulation of
the elastin metabolism, inflammatory mediators and growth factors,
alterations in gene expression, and lipid metabolism and peroxidation
in pterygium.
Keywords
Pterygium; Conjunctiva; Cytokeratins; Collagenases; Pax6 Gene;
Actinic Elastosis; Ultraviolet Radiation; Ophthalmoeliosis
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[5]. Although Donisi et al. proposed initially that K19 was a specific
marker of conjunctival epithelial cells [6], other groups found that
this cytokeratin is not specific to conjunctival epithelial cells because
it is also expressed in corneal epithelial cells as well [7,8].
More recently, Barbaro et al. compared expression of K3, K12,
K19 and mucin 1 in both sclerocorneal tissues and impression cytol-
ogy specimens by immunofluorescence and their results confirmed
the previous finding that K19 is not specific to conjunctival epithelial
cells [9].
In 2007 Turner et al. and later on in 2011 Ramirez-Miranda et al.
searched for a more specific marker of limbal and conjunctival epithe-
lia. They performed preferential gene profiling in the conjunctiva in
direct comparison to that in the cornea using microarray technique,
qRT–PCR, and immunohistochemistry. K13 at both the mRNA and
protein levels was expressed only in the posterior limbal and conjunc-
tival epithelia and completely absent on the cornea, and it expression
pattern was mutually exclusive of the K12 [10,11].
Paired box homeotic gene 6 (Pax6) functions as an early ecto-
dermal gene expressed during optic vesicle formation for eye develop-
ment. Since this DNA-binding transcription factor PAX6 was cloned
25 years ago numerous genetic, cellular, molecular and evolutionary
studies have been made and it is currently considered the universal
master control gene for eye morphogenesis. It has been shown that
Pax6 is expressed by different types of retina cells, iris, ciliary body
and in the epithelially-derived lens and cornea cells from early gesta-
tion until the postnatal stage. Postnatally, Pax6 expression is restricted
to corneal, conjunctival, lens and iris epithelia and amacrine cells of
the retina. Pax6 expression is linked with the control of EGF-induced
cultured corneal epithelial cell proliferation, and K12 gene expres-
sion; it also regulates cell differentiation, and mediates apoptosis [12].
As have been reviewed by Li et al., cumulative evidence indicates
that limbal epithelial stem cells (LSC) are regulated by their surround-
ing micro-environment, the so-called limbal stem cell niche where
cornea epithelial cells undergo continuous renewal from LSC [13].
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Pterygium
The term “pterygium” is a Latinized version of the Greek term
“pterygion” meaning “small wing” [15]. Pterygium is an abnormal
growth of epithelial and fibrovascular tissue from the corneoscleral
limbus that centripetally invades the cornea, causing ocular surface
inflammation and potential vision impairment. It is characterized by
an altered basal epithelial cell proliferation, vascularization, and inva-
sion of the adjacent corneal epithelium. Its usually develops nasally,
rarely temporally, and very infrequently both sectors simultaneously.
Clinically, initial signs of disease progression are represented by the
presence of circumscribed superficial gray dots in the prelimbal cor-
nea, taut conjunctiva opposite to the area of corneal affection, and
displacement of the plica. Later, a wing-shaped extension of the fleshy
growth of the bulbar conjunctiva onto the cornea takes place. A fully
developed pterygium presents a well formed “apex” or “head” (apical
aspect present on the cornea), a “body” (conjunctival aspect extend-
ing between the limbus and the canthus), and a “neck” (limbal aspect)
[16,17].
The pathogenesis of pterygia remains partly understood [18].
Histologically, pterygia show basophilic degeneration (actinic or
senile elastosis) of the subepithelial substantia propria. The epithe-
lium overlying a pterygium may show a variety of secondary changes
such as orthokeratosis, acanthosis, and dyskeratosis, and mast cells
can be found in several pterygia [19]. Deep corneal changes at the
level of Descemet’s membrane and the endothelium, such as reduced
endothelial cell density, may be seen in association with long-stand-
ing nasal pterygia in elderly individuals [20].
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Classifications of Pterygium
Pterygium was firstly classified histologically and divided into
three morphological types: angiomatous, fibrous and mixed [19]. In
the angiomatous pterygium, the stroma contains a significant num-
ber of vascular vessels with edema in the intervascular space; in the
fibrous form the stroma is predominantly fibrous with a few scattered
vascular elements; in the mixed pterygium the stroma contains both
vascular vessels and thin bundles of collagenous tissue (Figure 1).
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Figure 2: Pterygium morphological classification. (A) Pterygium grade T1. (B) Pteryg-
ium grade T2 and (C) temporal pterygium grade T3 (*).
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Pterygium Etiopathogenesis
Although pterygium has been studied for many years, its patho-
genesis still remains uncertain. It is thought to be an ophthalmohe-
liosis because of its possible relationship with high exposure to ul-
traviolet radiation (UVR). A wide range of other pathogenic factors
have been proposed, including epithelial-mesenchymal transition,
deregulation of extracellular matrix (ECM) modulators and growth
factors, viral infections, epigenetic aberrations, immunologic and
anti-apoptotic mechanisms, angiogenic and lymphangiogenic stimu-
lation, inflammation cascades, recruitment of bone-marrow-derived
stem- and progenitor cells, and modifications in the cholesterol me-
tabolism. Most of these factors are thought to be more related to the
development and maintenance of the disease than to its origin [40].
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The authors also demonstrated that the head epithelial cells grew and
migrated faster than body cells and the efficiency was influenced by
expression of active MMP-2 and 9 proteins. Results from this study
clearly showed a spatial expression pattern of markers for stem cells,
cell growth, and matrix metalloproteinases in the primary pterygium
tissue [43].
Josifovska et al. have very recently developed an ex vivo model
of tissue engineered pterygium in which cells were adherently cul-
tivated and grown out of the abnormal conjunctival tissue explants
using gravitational force from viscoelastic material for more than
three months. After that the authors used multiple antibodies specific
for hematopoietic- and mesenchymal stem cell markers, for pluri-
potency and stemness, oxidative stress, migration and proliferation,
cytokeratin, and secretory markers to determine the phenotype and
possible origin of these cells. Cells showed high expression of mi-
gration- (CXCR4), secretory- (MUC1, MUC4) and oxidative dam-
age- (8-OHdG) markers, and low expression of proliferation- (Ki-67)
marker. Moderate and low expression of the pluripotency markers
(Vimentin and ΔNp63) was present, respectively, while the putative
markers of stemness (Sox2, Oct4, ABCG-2) and epithelial cell mark-
ers- (CK19, CK8-18) were weak. The surface marker profile of the
outgrowing cells revealed high expression of the hematopoietic mark-
er CD47, mesenchymal markers CD90 and CD73, and minor or less
positivity for the hematopoietic marker CD34, mesenchymal marker
CD105, progenitor marker CD117. The authors concluded that hu-
man pterygium explants can give rise to 3-dimensional outgrowing
cells which could proliferate and migrate out of the grafts and form
a stratified structure very much like the one in vivo. The expanding
cells carried markers related to an undifferentiated state, but also a
commitment towards epithelial lineage. Stemness markers suggest a
flexible cell phenotype in the long-term cultures [44].
Pterygium is also characterized by highly vascularized mass of
hypertrophic and elastotic degenerated connective tissue. The sub-
epithelial tissue of the pterygium shows elastodysplasia (immature
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Role of Viruses
Many studies have been conducted to investigate the involve-
ment of a variety of oncogenic viruses, including human papillomavi-
rus (HPV), cytomegalovirus (CMV), and herpes simplex virus (HSV)
or Epstein barr virus (EBV), in the development and recurrence of
pterygium, and as it has been reviewed by Chalkia et al. [49] the re-
sults are not irrefutable. Such a disparity in the prevalence of onco-
genic virus detection in pterygium may partly be explained by ethnic
or geographical factors or by laboratory techniques. However, it may
also reflect the heterogeneous nature of pterygium pathogenesis and
the possibility that oncogenic viruses affect only a sub-group of oph-
thalmic pterygia.
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Di Girolamo et al. have also demonstrated that ERK1/2, JNK, and p38
mitogen-activated protein kinases are involved in pterygium patho-
genesis and using inhibitors for these pathways significantly abolished
the UVR-B-mediated increase in IL-6, IL-8, and vascular endothelial
growth factor (VEGF) [65].
It has been postulated that increased proliferation and angiogen-
esis in pterygium resembles tumor characteristics [40,66]. The expres-
sion of VEGF, TGF-β and PGE2 using inmmunohistochemical assays
was studied by Bianchi et al. [67], comparing primary pterygium sam-
ples with normal conjuctiva. The first one was significantly increased
in the epithelium, vascular endothelium and stromal cells, TGF-β
showed a moderate expression in the epihelium and stroma, while
PGE2 was markedly expressed in the epithelial cells from primary
pterygium in comparison with healthy conjunctiva. The authors have
suggested that these growth factors may contribute to the progres-
sion of pterygium by means of angiogenesis, leading to the formation
of new vessels, thus these factors could be potential therapeutic tar-
gets for the treatment of this pathology. Pterygium tissue also shows
elevated levels of cell signaling and adhesion molecules, including
VCAM-1 and ICAM-1 [68]. Lee et al. have studied the effect of chon-
drocyte-derived extracellular matrix (CDECM) on human primary
pterygium epithelial cells (hPECs), showing that CDECM signifi-
cantly downregulated MMP-9 and fibronectin and upregulated tissue
inhibitor of metalloproteinase 1 (TIMP-1) and -2. Angiogenic factors
such as VEGF, VCAM-1, CD31, pro-inflammatory factors such as
TNF-α, COX-2, IL-6 and PGE2 were significantly reduced in hPECs.
CDECM also inhibited expression of NADPH oxidase subunits Nox2
and p47phox, with the subsequently inhibition of the generation of
intracellular reactive oxygen species (ROS). CDECM also suppressed
NF-κB activation and the phosphorylation of p38 MAPK, protein ki-
nase C alpha (PKCα), and PKCθ [69].
Kim et al. have studied the effect of stromal cell-derived factor 1
(SDF-1) and the interaction with its chemokine receptor 4 (CXCR4),
since SDF-1-CXCR4 increased signaling contributes to hypertrophic
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Epigenetic Factors
Epigenetics refers to the study of the heritable alterations in gene
expression that do not involve the underlying DNA sequence. Epige-
netic mechanisms include DNA methylation, histone modifications,
and micro RNAs [78]. There is only one publication about epigenetic
changes in pterygium. In this article, authors described altered meth-
ylation patterns at CpG loci near the genes encoding transglutami-
nase 2 (TGM2), MMP-2, and CD24 [79]. Hyper methylation at the
promoter region of TGM2 led to decreased transcript and protein
levels, and hypo methylation of intergenic regions of MMP2 and the
promoter region of CD24 led to increased transcript and protein lev-
els. These changes could have implication in pterygium development
since they play key roles in extracellular matrix remodeling and cell
adhesion [80,81].
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Conclusions
Although the pathogenesis of pterygium has been studied for
many years, its still remains uncertain. A wide range of pathogenic
factors have been proposed, including high exposure to ultraviolet
radiation (UVR), viral infections, epigenetic aberrations, epithelial-
mesenchymal transition, deregulation of extracellular matrix (ECM)
modulators and growth factors, immunologic and anti-apoptotic
mechanisms, angiogenic and lymphangiogenic stimulation, inflam-
mation cascades, recruitment of bone-marrow-derived stem- and
progenitor cells, and modifications in the cholesterol metabolism.
Since there are some discrepancies among the involvement of diverse
factors it is possible that there could be different pterigia with various
geneses.
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