ULASAN JURNAL

TENTANG PERANAN REGULASI ADHESI SEL

Oleh :

Angelina Natalia Ricardo

BKU Farmakologi

04112682327003

Dosen Pembimbing :
Septi P. S.St, M.Biomed

PROGRAM STUDI MAGISTER ILMU BIOMEDIK

FAKULTAS KEDOKTERAN
UNIVERSITAS SRIWIJAYA
PALEMBANG
2023
 DISINTEGRITAS EPITEL ALVEOLAR PADA FIBROSIS PARU

Fibrosis paru idiopatik merupakan salah satu penyakit paru yang ditandai dengan
pneumonia interstitial pada biopsi paru. Kondisi ini diduga berkaitan disfungsi sel epitel
alveolar yang ditandai dengan hilangnya bentuk normal alveolar secara progresif, selain itu
juga diduga akibat cedera yang terjadi secara berulang pada sel epitel alveolar yang diikuti oleh
perbaikan atau regenerasi barrier epitel, persistensi fibroblas yang teraktivasi, dan perubahan
pada matriks ekstraseluler sehingga menyebabkan terjadinya fibrosis paru secara progresif.
Selain itu, penelitian terbaru menunjukkan bahwa adanya peranan variasi genetika yang
berkaitan dengan kerusakan pada sel inang dan adhesi sel ke sel.

Adhesi sel sangat penting dalam menjaga integritas epitel alveolar di mana adhesi sel
mempertahankan fungsi barrier pelindung terhadap patogen dan memungkinkan terjadinya
pertukaran molekul dan sinyal antarepitel. Molekul adhesi sel merupakan sekelompok protein
khusus yang ditemukan di permukaan sel epitel dan memediasi interaksi sel-sel adhesif antar
sel epitel yang berdekatan. Molekul adhesi sel terdiri dari integrin, cadherin, selectin, dan
immunoglobulin yang masing-masing memiliki fungsi dan struktur yang khas. Molekul adhesi
sel berperan penting dalam memfasilitasi interaksi antara sel-sel dan matriks sel. Mereka
diekspresikan pada permukaan sel dan berkontribusi dalam meregulasi cell junction. Cell
junction terdiri dari tight junction, adherens junction, gap junction, dan desmosome yang
merupakan struktur khusus dalam menghubungkan sel dan memberikan kekuatan mekanis
pada jaringan.

Adheren junction terdiri dari cadherin dan nectin yang dihubungkan oleh sitoskeleton
aktin melalui protein pengikat catenin dan afadin. Adheren junction berfungsi untuk
menstabilkan adhesi sel dan mengatur organisasi sitoskeletal aktin, sinyal intraseluler, dan
transkripsi gen. Epithelial cadherin (E-cadherin) merupakan molekul adhesi sel yang
bergentung pada kalsium yang berperan penting dalam menentukan perilaku sel epitel dan
seringkali digunakan sebagai marker sel epitel.

Paparann asap rokok yang terus menerus menyebabkan terjadinya cedera pada sel epitel
alveolar disertai kerusakan membran basal, hal ini dapat menyebabkan disregulasi perbaikan
atau regenerasi sel dan perubahan pada penghubung antara epitel dan mesenkim yang diikuti
dengan fibrosis progresif. Asap rokok dapat merusak protein, ZO-1, ZO-2, dan E-cadherin pada
sel epitel bronkus manusia sehingga menyebabkan perubahan permeabilitas barrier epitel dan
berpotensi menyebabkan diferensiasi mesenkim sel epitel.

Kesimpulannya, terdapat semakin banyak bukti yang menunjukkan bahwa cacat

perkembangan dan yang didapat pada adhesi sel-sel epitel yang berperan dalam patogenesis
fibrosis paru. Disfungsi perkembangan atau didapat dari kompleks epithelial intercellular
junctional diduga memiliki peran penting dalam patogenesis fibrosis paru. Apakah perubahan
dalam ekspresi protein fungsional antar sel tertentu terlibat secara kausal dalam perkembangan
fibrosis paru masih belum dapat dijelaskan. Cedera sel epitel alveolar yang persisten akibat
paparan kronis terhadap asap rokok atau racun lingkungan dapat mengubah ekspresi protein
yang penting dalam pemeliharaan adhesi sel dan integritas epitel alveolar. Meskipun data yang
mengeksplorasi mekanisme molekuler yang terkait dengan perubahan dan perkembangan
Fibrosis paru idiopatik masih terbatas, bukti yang muncul menunjukkan bahwa kegagalan
respon perbaikan cedera alveolar yang normal berujung pada melanggengkan siklus aktivasi
myofibroblast dan deposisi matriks ekstraseluler. Kemajuan terkini dalam mengidentifikasi
varian genetik, khususnya gen yang terkait dengan perubahan adhesi sel, dapat mengubah
pemahaman kita saat ini tentang patogenesis fibrosis paru idiopatik
Am J Physiol Lung Cell Mol Physiol 311: L185–L191, 2016.
First published May 27, 2016; doi:10.1152/ajplung.00115.2016.
CALL FOR PAPERS Translational Research in Acute Lung Injury and Pulmonary
Fibrosis
Alveolar epithelial disintegrity in pulmonary fibrosis
X Tejaswini Kulkarni, Joao de Andrade, Yong Zhou, Tracy Luckhardt, and Victor J. Thannickal
Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham,
Birmingham, Alabama
Submitted 18 March 2016; accepted in final form 18 May 2016
Kulkarni T, de Andrade J, Zhou Y, Luckhardt T, Thannickal
VJ. Alveolar epithelial disintegrity in pulmonary fibrosis. Am J
Physiol Lung Cell Mol Physiol 311: L185–L191, 2016. First pub-
lished May 27, 2016; doi:10.1152/ajplung.00115.2016.—Idiopathic
pulmonary fibrosis (IPF) is a chronic lung disease characterized by
progressive decline in lung function, resulting in significant morbidity
and mortality. Current concepts of the pathogenesis of IPF primarily
center on dysregulated epithelial cell repair and altered epithelial-
mesenchymal communication and extracellular matrix deposition fol-
lowing chronic exposure to cigarette smoke or environmental toxins.
In recent years, increasing attention has been directed toward the role
of the intercellular junctional complex in determining the specific
properties of epithelia in pulmonary diseases. Additionally, recent
genomewide association studies suggest that specific genetic variants
predictive of epithelial cell dysfunction may confer susceptibility to
the development of sporadic idiopathic pulmonary fibrosis. A number
of genetic disorders linked to pulmonary fibrosis and familial inter-
stitial pneumonias are associated with loss of epithelial integrity.
However, the potential links between extrapulmonary clinical syn-
dromes associated with defects in epithelial cells and the development
of pulmonary fibrosis are not well understood. Here, we report a case
of hereditary mucoepithelial dysplasia that presented with pulmonary
fibrosis and emphysema on high-resolution computed tomography.
This case illustrates a more generalizable concept of epithelial disin-
tegrity in the development of fibrotic lung diseases, which is explored
in greater detail in this review article.
pulmonary fibrosis; epithelial barrier dysfunction; cell-cell adhesion;
epithelial junctional complex
INTERSTITIAL LUNG DISEASES represent a heterogeneous group of
diffuse lung diseases characterized by chronic, progressive
dyspnea that occurs primarily in older adults. Idiopathic pul-
monary fibrosis (IPF) is the most common among the idio-
pathic interstitial pneumonias (IIPs) and is characterized by
usual interstitial pneumonia on high-resolution computed to-
mography (HRCT) and lung biopsy (45). Two drugs, pirfeni-
done and nintedanib, were approved by the United States Food
and Drug Administration for IPF based on reduction in the rate
of lung function decline (24, 46); however, these drugs do not
appear to arrest (or reverse) fibrosis. The mechanisms of their
antifibrotic actions remain unclear, and treatment efficacy may
be influenced by effects on the epithelium and/or mesenchymal
cells.
Address for reprint requests and other correspondence: V. J. Thannickal,
1900 University Blvd., 422 THT, Birmingham, AL 35294-0006 (e-mail:
vjthan@uab.edu).
http://www.ajplung.org 1040-0605/16 Copyright © 2016 the American Physiological Society
Perspectives
The fibrosing varieties of IIPs are thought to be associated
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with alveolar epithelial cell (AEC) dysfunction, characterized
by progressive loss of the normal alveolar architecture. The
current paradigm is that recurrent injury to AECs followed by
aberrant repair/regeneration of epithelial barrier, persistence of
activated fibroblasts, and alterations in extracellular matrix
(ECM) result in progressive pulmonary fibrosis (52, 71). In
recent years, increasing attention has been directed toward the
role of the intercellular junctional complex in determining the
specific properties of epithelia in pulmonary diseases (19, 23,
26, 29, 50, 54). Identification of familial cases of interstitial
pneumonias with gene mutations in surfactant protein C (40) or
telomerase (3), and clinical syndromes such as Hermansky-
Pudlak syndrome (11, 67), further support a critical role for
AEC injury in disease pathogenesis. Additionally, recent pop-
ulation studies in patients with IIP demonstrate multiple sus-
ceptibility loci that indicate an increasingly important role of
specific genetic variants associated with defects in host defense
and cell-to-cell adhesion (8, 17, 41).
A broad spectrum of inherited and acquired conditions,
including infections or autoimmune diseases, in which essen-
tial components of intercellular junctional complexes are miss-
ing or structurally altered, can lead to epithelial barrier disin-
tegrity. In this report, we describe a case characterized by
epithelial cell defects: hereditary mucoepithelial dysplasia
(HMD), presenting with features of pulmonary fibrosis. Trans-
lating this finding “bedside to bench,” we explore the role of
dysfunction of components of the intercellular junctional com-
plex in the alveolar epithelium in the development of fibrotic
lung diseases, in general. Furthermore, we discuss emerging
concepts in the involvement of epithelial cell defects and
polymorphisms of genes associated with lung epithelium in the
pathogenesis of IPF.
Case Report
A 39-yr-old Caucasian male was evaluated for progressively
worsening dyspnea on exertion and persistent nonproductive
cough for over 5 years. He has had alopecia, skin scaling, and
visual disturbances since childhood. He denied any other
rashes, joint pains, or mucosal lesions. He was a lifelong
nonsmoker without identifiable environmental exposures. He
has a family history of HMD confirmed by pathology reports in
a sibling (sister) who died at age 12 of pulmonary complica-
tions. His father also died at an early age (24 yr) of an unknown
lung disease. With this family history and characteristic clini-
cal presentation during childhood, he was given the diagnosis
of HMD prior to his presentation to our institution. Physical
L185
Perspectives
L186 CELL-CELL ADHESION DEFECTS IN PULMONARY FIBROSIS
exam at presentation to our clinic was remarkable for fine
crackles and scant expiratory wheezes bilaterally, digital
clubbing, and skin scaling of the arms. Pulmonary function
tests (PFTs) revealed severe obstruction [forced expiratory
volume in 1 s (FEV1) ⫽ 1.57 liters (37%); forced vital
capacity (FVC) ⫽ 3.36 liters (59%); FEV1/FVC ratio ⫽
47%], air trapping [total lung capacity (TLC) ⫽ 6.45 liters
(81%); residual volume (RV) ⫽ 3.10 (135%)] and moder-
ately reduced diffusion [carbon monoxide diffusion capacity
(DLCO) ⫽ 13 (43%)]. During the 6-min walk test, he was able
to walk 351 m without oxygen desaturation. HRCT scans
showed predominantly reticulations with honeycombing and
traction bronchiectasis in a peripheral and basilar distribution
with coexistent paraseptal emphysema (Fig. 1). Complete
blood count and routine chemistry panels were normal. Tests
for specific antibodies including antinuclear factor (ANA),
anti-SS-A and SS-B antibodies, antineutrophilic cytoplasmic
antibodies (ANCA), anti-DNA antibodies, anti-Jo-1, anti-Scl-
70, and anticyclic citrullinated peptide (CCP) antibodies were
all negative. Over the course of 4 years of follow-up in our
clinic, his PFTs showed a decline in FVC to 2.40 liters (43%),
TLC 4.82 liters (61%), and DLCO 9.5 (35%). He has been
treated with inhaled corticosteroids and bronchodilators.
Pathogenesis of Hereditary Mucoepithelial Dysplasia
HMD is a dyshesive, dyskeratotic epithelial syndrome
caused by an abnormality in desmosomes and gap junctions
(GJs) with autosomal dominant inheritance (64). It can present
with phenotypic variants involving mucosae, skin, hair, lungs,
and eyes. Patients have severe airflow obstruction with com-
bined interstitial fibrosis and emphysema; lung involvement
commonly presents with spontaneous pneumothorax from rup-
ture of giant bullae (4, 32, 63, 64). There are fewer reports of
an association with pulmonary fibrosis, perhaps related to
availability of HRCT until more recently. A 1979 report
indicated the presence of fibrosis with thickened septa and
small cysts throughout the lung parenchyma on postmortem
examination of lung tissue section in a patient with HMD (63);
in this report, histopathology of oral and vaginal mucosa
demonstrated dyshesive epithelium with lack of maturation and
atrophy, dyskeratosis, and unusual cytoplasmic inclusions. Ul-
trastructural studies showed a paucity of desmosomes and the
presence of perinuclear filamentous inclusions resembling in-
ternalized GJ and desmosome material in dyskeratotic cells
(63). A more recent report of mucosal biopsies of eight patients
with HMD indicated the presence of numerous cytoplasmic
Fig. 1. High-resolution computed tomogra-
phy sections of a patient with hereditary
mucoepithelial dysplasia demonstrating sub-
pleural reticulation with honeycombing and
traction bronchiectasis in a peripheral and
basilar distribution with coexistent parasep-
tal emphysema.
R R
AJP-Lung Cell Mol Physiol • doi:10.1152/ajplung.00115.2016 • www.ajplung.org
vacuoles and the filament bundles interspersed between these
vacuoles expressing keratin; however, the expression of junc-
tional and cytoskeletal proteins was normal (4). These findings
suggest that this disease likely represents a defect in the
development of cytoskeletal components and/or assembly of
intercellular GJs. The desmosomal cadherin gene cluster in
chromosome 18q12.1 including desmoglein and desmocollin
was excluded as possible candidate genes in the haplotype
analysis of one family (4). However, the specific genetic
mutation(s) involved in HMD is yet to be identified.
Epithelial Barrier Composition and Dynamics in Pulmonary
Fibrosis
Persistent exposure to cigarette smoke or environmental
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toxins results in AEC injury with associated basement mem-
brane damage. This may lead to dysregulated repair/regenera-
tion and altered epithelial-mesenchymal communication with
subsequent progressive fibrosis (13, 25). Cell-cell adhesion is
critical for maintaining the integrity of alveolar epithelium,
thus maintaining its protective barrier function against toxic
agents or pathogens and allowing interepithelial transfer of
molecules and signals. Cell adhesion molecules (CAMs), a
group of specialized proteins, are found on epithelial cell
surfaces and mediate the adhesive cell-cell interactions be-
tween adjacent epithelial cells. The intercellular junction com-
plexes at cell-cell contact sites of epithelial cells are comprised
of the tight junction (TJ), adherens junction (AJ), GJ, and
desmosomes (Fig. 2).
Epithelial barrier dysfunction due to repetitive tissue injury
leads to host responses involving a myriad of interactions
among various cells and soluble factors that are orchestrated to
restore normal lung structure and function. Few studies have
examined the potential role of intercellular junctional complex
proteins in maintenance of the epithelial barrier integrity and
development of pulmonary fibrosis following loss of this bar-
rier function. In this section, we will briefly review the role of
each component of the alveolar epithelial intercellular junc-
tional complex.
Tight junctions. TJs form the apical component of the
junction complex and are essential for innate immunity, as well
as cellular differentiation and proliferation. They comprise the
membrane proteins (claudins and occludins) in addition to
scaffold proteins known as zona occludens (ZO-1, ZO-2, and
ZO-3) (48). Claudins, particularly claudin 18, are the major
proteins contributing to the epithelial barrier function of TJs in
the lungs and maintain alveolar fluid homeostasis (33, 47).

CELL-CELL ADHESION DEFECTS IN PULMONARY FIBROSIS
Occludin
ZO-1, ZO-2,
Tight Junction
ZO-3
Claudin
E-cadherin
P120/ Catenin Adherens
Junction
IFs
Desmosome
Desmoplakin
Desmoglein
Desmocolin
HMD
Gap
Junction
Hemidesmosomes
BASEMENT MEMBRANE
Fig. 2. Cell-cell junctions: Tight junctions, adherens junctions, and desmo-
somes are the three main junctional complexes connecting adjacent epithelial
cells. Tight junctions are the most apical protein complexes and regulate
epithelial barrier paracellular permeability. Adherens junctions and desmo-
somes stabilize cell-to-cell adhesion and maintain lung homeostasis. They also
regulate the actin-cytoskeletal organization and confer mechanical strength to
the alveolar epithelial barrier. Gap junctions are essential for intercellular
communication and secretion of surfactant. Hemidesmosomes bind basal
epithelial cells to the basement membrane. Hereditary mucoepithelial dysplasia
(HMD) affects desmosomal structures. ZO, zona occludens; IFs, intermediate
filaments.
Disruption of TJs can result in increased paracellular permea-
bility, thus permitting entry of antigens, toxins, and protein-
rich fluid into alveolar spaces. Reduced expression of claudins,
particularly claudin-18, along with lower levels of mRNA
encoding TJ proteins was reported in an experimental bleomy-
cin-induced lung injury model (42). Differential claudin and
cadherin expression in hyperplastic AECs compared with nor-
mal AECs during an aberrant repair process suggests focal
changes in permeability of this barrier (19, 29). Although the
lower expression of claudins could simply be due to epithelial
cell death from bleomycin exposure, the structural disruption
of TJs in fibrotic lesions suggests that bleomycin injury causes
alveolar barrier dysfunction by other possible mechanisms.
Transforming growth factor-␤1 (TGF-␤1), a well-established
profibrotic cytokine, has been shown to cause disruption of TJs
in human alveolar epithelial cells and induce epithelial-to-
mesenchymal transition (EMT) (42). Additionally, TGF-␤1-
induced TJ disruption was augmented in a bleomycin injury
model of phosphatase and tensin homolog (pten)-null mice
(38). In this study, pten-null mice demonstrated disassembly of
TJs of AECs and exacerbated lung fibrosis following injury.
Furthermore, this study also demonstrated decreased PTEN
expression in AECs of human IPF lungs. Taken together, these
studies suggest that structural disruption of TJs with subse-
quent loss of alveolar epithelial integrity play an important role
in the development of pulmonary fibrosis.
AJP-Lung Cell Mol Physiol • doi:10.1152/ajplung.00115.2016 • www.ajplung.org
Perspectives
L187
In addition to preservation of barrier function, adequate
expression of claudins may be essential to restore alveolar
epithelial barrier during normal injury-repair responses. In-
creased expression of both TJ and AJ proteins was demon-
strated in regenerative alveolar epithelium (29). However,
expression of claudin-1, claudin-3, and claudin-4 in fibrotic
lung was shown to be similar to or even lower than that
measured in the healthy controls (29). Interestingly, claudin
knockout mice demonstrated impaired alveologenesis and al-
veolar barrier dysfunction (28). It is possible that the dimin-
ished capacity of epithelial cells to produce claudin could lead
to incomplete repair and differentiation of epithelial cells, thus
resulting in hyperplastic type II AECs seen in pulmonary
fibrosis.
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Adherens junctions. Located more basal to TJs, AJs consist
of cadherin and the nectin family CAMs; they are linked to the
actin cytoskeleton through the binding proteins catenins and
afadin, respectively. AJs function to stabilize cell-cell adhesion
and regulate actin cytoskeletal organization, intracellular sig-
naling, and gene transcription. Epithelial cadherin (E-cadherin)
is a calcium-dependent CAM with pivotal roles in epithelial
cell behavior (20), and it is often used as a marker of epithelial
cells. Expression of E-cadherin is reduced in lung sections of
patients with IPF; cytoplasmic localization of this protein
during EMT is associated with disruption of epithelial barrier
function and increased cell migration (20, 61). Cigarette smoke
impairs the proteins, ZO-1, ZO-2, and E-cadherin in human
bronchial epithelial cells, thus resulting in altered permeability
of the epithelial barrier and, potentially, mesenchymal differ-
entiation of epithelial cells (49, 69). Thoracic radiation and
bleomycin-induced lung injury can also decrease E-cadherin
and aquaporin-5 expression in AECs, increasing plasma/water
permeability into alveolar spaces (2, 9). Immunohistochemistry
of lung tissue in aquaporin-5 knockout mice demonstrated
fibrosis with increased deposition of type I collagen in alveolar
walls (9). Although these changes in permeability and in-
creased alveolar fluid accumulation are typically associated
with acute lung injury, persistent injury to the epithelial barrier
may lead to a cascade of reactions with release of soluble
factors that promote myofibroblast differentiation and ECM
deposition.
␣3␤1 Integrin is a laminin receptor that promotes cell-cell
communications through its interactions with the E-cadherin/
␤-catenin complex (34, 59). It was recently reported that ␣3␤1
integrin interacts with E-cadherin and the TGF-␤ receptor to
form a trimolecular complex that triggers phosphorylation of
␤-catenin at Y654 in AECs (23). Phosphorylated ␤-catenin
subsequently interacts with phosphorylated Smad2, a TGF-␤
receptor-regulated effector protein, to induce fibrotic gene
expression. This study suggests a role for interactions between
␣3␤1, E-cadherin, and ␤-catenin signaling in the development
of lung fibrosis. Additionally, increased expression of cad-
herin-11 (CDH11) in IPF patients and animal models of lung
fibrosis have been reported (50); treatment with CDH11-block-
ing antibody or genetic deletion of Cdh11 protects mice against
bleomycin injury-induced lung fibrosis. These data support a
pivotal role of CDH11 in pulmonary fibrosis. Given the fact
that multiple cell populations including AECs, fibroblasts, and
macrophages express CDH11 in pulmonary fibrosis, it is likely
that CDH11 regulates multiple steps in the fibrotic process.
Perspectives
L188 CELL-CELL ADHESION DEFECTS IN PULMONARY FIBROSIS
Gap junctions. GJs are essential for intercellular communi-
cation and secretion of surfactant necessary for barrier func-
tion. They consist of an array of transmembrane channels
composed of connexins (Cx) that connect to similar structures
in the adjacent cells. Differential expression of various con-
nexins in the lung, especially Cx43 and Cx46, has an important
role in the regulation of normal lung homeostasis and remod-
eling in response to epithelial cell injury (1, 31). Fibroblasts
from patients with IPF demonstrate significant reduction in
Cx43 mRNA with alteration to GJ intercellular communication
compared with fibroblasts from normal subjects (53). Addi-
tionally, mice deficient in vascular endothelial cell-specific
Cx43 and Cx40 develop spontaneous fibrosis with fibroblast
accumulation and aberrant alveolar remodeling (26). Further
studies are required to determine whether abnormalities in
alveolar epithelial cell-specific connexins and epithelial cell
GJs predispose to lung fibrosis.
Hemidesmosomes. Hemidesmosomes are specialized multi-
protein transmembrane complexes that facilitate the binding of
keratin intermediate filament (IF) in epithelial cells to the
underlying basement membrane and ECM. This binding is
essential in maintenance of integrity and mechanical stability
of the lung. The hemidesmosomes are formed by integrin
␣6␤4, laminin 5, and tetraspanin CD151 (37, 56). Tetraspanins
belong to a family of proteins that form multimolecular com-
plexes with a variety of other proteins including integrins.
Tetraspanin CD151 is predominantly expressed in the baso-
lateral surface of epithelial cells and is crucial for the mainte-
nance of epithelial integrity via adhesion of the basal surface of
AECs to basement membrane. Deletion of CD151 in AECs
results in alterations to the cell structure and degradation of the
epithelial integrity due to impaired adhesion to basement mem-
brane (54). In this study, CD151 knockout mice were shown to
spontaneously develop age-related pulmonary fibrosis; AECs
from these mice exhibit fibroblast-like changes through up-
regulation of TGF-␤1 signaling and augmented phosphory-
lated Smad2. Furthermore, decreased CD151 expression was
observed in AECs from patients with IPF (54), supporting a
role for loss of CD151 and epithelial integrity in at least a
subset of IPF patients. Interestingly, tetraspanin CD151-integ-
rin ␣3␤1 association has been shown to be functionally im-
portant for ␣3␤1-integrin-mediated cell migration and matrix
remodeling (21). Further studies to understand the role of
tetraspanin CD151-integrin interactions and their effects on
TGF-␤1 in the development of pulmonary fibrosis are war-
ranted.
Genetic Variants Affecting Epithelial Cell Integrity
Over the past decade, there has been remarkable progress in
the understanding of IPF pathogenesis. In addition to acquired
defects in epithelial barrier integrity, there have been recent
advances in identifying polymorphisms of genes associated
with lung epithelium and their association with higher risk of
IPF. Population studies initially implicated the role of specific
genetic variants including MUC5B, TERT, TERC, SFTPC,
and SFTPA2 in the development of IPF and other fibrosing
IIPs (8, 17, 41). Additional genetic variants including desmo-
plakin (DSP) and dipeptidyl peptidase 9 (DPP9) genes associ-
ated with cell-to-cell adhesion were recently identified in
patients with fibrotic IIP (8).
AJP-Lung Cell Mol Physiol • doi:10.1152/ajplung.00115.2016 • www.ajplung.org
Desmosomes are intercellular junctions located in the baso-
lateral membranes of epithelial cells. There is calcium-depen-
dent transmembrane interaction between the extracellular do-
mains of the desmosomal cadherins between adjacent cells.
The cadherin cytoplasmic tails then associate with the linker
proteins plakoglobin and plakophilins. Linkage of this desmo-
somal assembly to the cytoskeleton is mediated through a
series of interactions between binding proteins, desmoplakin,
and linker proteins (7). Thus desmosomes primarily provide
mechanical support for maintenance of tissue architecture by
tethering the keratin IF network to the plasma membrane (10).
This is particularly important in maintaining the integrity of
tissues that experience mechanical stress such as peripheral
portions of the lungs, myocardium, skin, bladder, and gastro-
intestinal mucosa.
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Mutations in expression of DSP gene that encodes for
desmoplakin have been associated with several skin diseases
including keratoderma, alopecia, and severe acantholytic epi-
dermolysis bullosa (18, 60). More importantly, DSP mutations
that affect exon 24 encoding the COOH-terminal domain have
been associated with cardiac interstitial fibrosis and arrhyth-
mogenic right ventricular dysplasia/cardiomyopathy (35, 66).
This was shown to be due to disruption of mechanical linkage
between cells and modifications to cell-cell adhesion proteins.
The minor allele of variant rs2076295 in intron 5 has been
associated with decreased whole lung DSP expression and
higher risk of IPF (8, 36). The differential expression of DSP
in association with this variant suggests that disruption of
desmosomal integrity with resultant impairment of cell-cell
adhesion and aberrant epithelial barrier injury-repair response
may participate in the development of IPF.
DSP has been shown to inhibit Wnt/␤-catenin signaling
pathway through regulation of plakoglobin, ␤-catenin, and
matrix metalloproteinase 14 in a lung cancer model (65).
Ineffective re-epithelialization
Loss of cell-cell adhesion
Impaired AEC migration
Basement membrane
AEC Apoptosis/Senescence
damage
Integrin-mediated Secretion of proteases,
TGF-β1 activation; H2O2 Fas ligand
TGF-β1
cytokines and soluble
Biomechanical AT-II growth factors
signaling
Myofibroblast differentiation
Fibroblast senescence
Apoptosis resistance
ECM accumulation
ECM crosslinking
Protease resistance
Fig. 3. Epithelial-mesenchymal cross talk in pulmonary fibrosis: Cellular
homeostasis of the alveolar structure is dependent on bidirectional signaling
between alveolar epithelial cells (AECs) and mesenchymal cells. Loss of
homeostasis and ineffective reepithelialization may occur with loss of cell-cell
adhesion, impaired AEC migration, senescence, and/or apoptosis. The resul-
tant epithelial disintegrity leads to integrin-mediated activation of transforming
growth factor-␤1 (TGF-␤1), altered biomechanics, and release of proteases,
cytokines, and growth factors from the epithelium that activate the underlying
mesenchyme. In turn, activated fibroblasts and myofibroblasts that acquire an
apoptosis-resistant phenotype secrete a number of soluble factors that can
induce apoptosis/senescence of AECs; these soluble factors include TGF-␤1,
hydrogen peroxide (H2O2), angiotensin-II (AT-II), and Fas ligand, thus per-
petuating the injury-repair cycle leading to extracellular matrix (ECM) mod-
ification and accumulation.

CELL-CELL ADHESION DEFECTS IN PULMONARY FIBROSIS
Aberrant activation of Wnt/␤-catenin signaling pathway has
been implicated in the development of pulmonary fibrosis (6)
and is, thus, one potential mechanism for a profibrotic role of
DSP in IPF. Interestingly, increased DSP gene expression was
demonstrated in lung tissue of IPF patients without the DSP
gene variant rs2076295 (36). This increase could be the con-
sequence of epithelial cell injury-repair response to maintain
epithelial barrier integrity in response to persistent epithelial
injury. Desmosomes have intra- and extracellular components,
and changes to any part of this structure could lead to altera-
tions in yet-undetermined cell signaling pathways.
DPP9 is an enzyme ubiquitously expressed by epithelial
cells and fibroblasts and is necessary for intracellular signaling,
cell adhesion, and migration (68). DPP9 gene silencing or
enzyme inhibition has been shown to suppress the adhesion-
signaling pathway through decreased phosphorylation of focal
adhesion kinase and paxillin (68). Thus alterations in this gene
may result in impaired cell movement during repair and lead to
aberrant healing. Taken together, these findings suggest that
genetic variations in the expression of DSP and DPP9 contrib-
ute to biochemical and biomechanical modifications that alter
cell-cell adhesion in the lung. The presence of these genetic
variations may increase epithelial cell susceptibility to barrier
disintegrity in response to persistent injury, thus resulting in
pulmonary fibrosis.
Epithelial-Mesenchymal Cross Talk
Epithelial and mesenchymal cell interactions are critical in
the process of lung development, homeostasis during adult-
hood, and injury-repair responses (5). Loss of epithelial barrier
integrity and the altered alveolar microenvironment disrupts
the tightly orchestrated temporal and spatial regulation of
epithelial-mesenchymal cross talk (52). Injured alveolar epi-
thelial cells and macrophages release/activate profibrotic me-
diators, in particular TGF-␤1 (22, 30). TGF-␤1, activated by
AEC-integrin-mediated process (39) or by biomechanical sig-
nals (62), induces myofibroblast differentiation and activation.
Recent studies indicate that myofibroblasts in IPF acquire a
senescent and apoptosis-resistant phenotype (15). These mes-
enchymal cells secrete additional paracrine factors, such as
hydrogen peroxide (16, 55), angiotensin-II (43, 57), Fas-ligand
(12, 58), and TGF-␤1 (14, 51), that may potentiate or perpet-
uate injury/apoptosis of AECs. In turn, the accumulation of a
highly cross-linked and stiff matrix may perpetuate mesenchy-
mal activation and progressive fibrosis (27, 70) (Fig. 3).
Future Directions
In summary, there is increasing evidence indicating a role
for developmental and acquired defects in epithelial cell-cell
adhesion in the pathogenesis of fibrotic lung diseases. In this
review, we highlight a unique case of a young man with a
known genetic defect that results in loss of cell-cell adhesion
that resulted in early and severe fibrosis of the lungs. We posit
that developmental or acquired dysfunction of epithelial inter-
cellular junctional complexes may have pivotal role in the
pathogenesis of pulmonary fibrosis. Whether changes in the
expression of specific intercellular junctional proteins are caus-
ally involved in the development of pulmonary fibrosis is yet to
be elucidated. Persistent alveolar epithelial cell injury from
chronic exposure to cigarette smoke or environmental toxins
AJP-Lung Cell Mol Physiol • doi:10.1152/ajplung.00115.2016 • www.ajplung.org
Perspectives
L189
could alter the expression of proteins critical in maintenance of
cell-cell adhesion and alveolar epithelial integrity. Although
data exploring the molecular mechanisms associated with these
alterations and development of IPF are limited, emerging
evidence suggests that failure of normal alveolar injury-repair
responses culminate in perpetuating cycles of myofibroblast
activation and ECM deposition. Recent progress in identifying
genetic variants, specifically the genes associated with altera-
tions in cell-cell adhesion, could transform our current under-
standing of the pathogenesis of IPF.
An integrated approach including genotyping, environmen-
tal risk factor assessment, and proteomic analyses of epithelial
cell junctional proteins is needed to develop personalized
approaches to diagnosis and treatment of patients with IPF. It
is not known whether defects in cell-cell adhesion in distal
Downloaded from http://ajplung.physiology.org/ by 10.220.33.4 on January 2, 2017
airway/bronchiolar epithelia contribute to disease pathogene-
sis; for example, the previously reported association between a
MUC5B promoter polymorphism and development of IPF
with improved survival (44) suggests loss of epithelial
homeostasis in the distal airway. Further investigation of
specific mechanisms involved in epithelial disintegrity
would be invaluable in providing genetic and molecular
targets for the development of interventions that prevent/
ameliorate disease progression in IPF.
GRANTS
This research was supported by National Heart, Lung, and Blood Institute
Grants P01 HL114470, R01 AG046210, and R01 HL124076.
DISCLOSURES
T. Kulkarni has no conflicts of interest to disclose. V. J. Thannickal and Y.
Zhou have received research grants from NIH. J. de Andrade has received
research grants from the NIH, Genentech, Boehringer Ingelheim, and Fibrogen
and consulting fees from Genentech, Boehringer Ingelheim, and Immune-
works, outside the submitted work. T. Luckhardt has received research grants
from the NIH, the Pulmonary Fibrosis Foundation, Gilead, Celgene, and
Boehringer Ingelheim, outside the submitted work.
AUTHOR CONTRIBUTIONS
T.K., J.A.d.A., Y.Z., T.R.L., and V.J.T. conception and design of research;
T.K. prepared figures; T.K. drafted manuscript; T.K., J.A.d.A., Y.Z., T.R.L.,
and V.J.T. edited and revised manuscript; T.K., J.A.d.A., Y.Z., T.R.L., and
V.J.T. approved final version of manuscript.
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