Fibrosis dysregulation in repair mechanisms and the

Fibrosis is the
permanent scarring, thickening and hardening of tissue caused by a
dysregulation in repair mechanisms and the deposition of proteins of the extracellular
matrix (ECM). Classically, it occurs after a continuous chronic inflammation,
usually in a person with a genetic predisposition. Fibrotic diseases in the
lung, which is known collectively as interstitial lung disorders, manifest in
many ways and are associated with environmental exposure such as antigens and
viruses. They are also associated with chronic inflammatory diseases such as rheumatoid
arthritis, though they are more commonly idiopathic (Rowley and Johnson, 2014).

Asthma is a
heterogenic disease that currently affects 300 million people worldwide (Johnson
et al., 2015). Allergic asthma
is defined as a respiratory disease that is driven by exposure to an
aeroallergen resulting in a subsequent allergen-driven immune response. The
pathology of allergic asthma is characterized by airway remodelling which encompasses
changes to the airway epithelium and sub-epithelial regions (Rowley and
Johnson, 2014). Changes to the epithelium include excess mucus production, goblet cell
hyperplasia and epithelial shedding, and changes to the sub-epithelial regions
include angiogenesis, fibrosis and airway smooth muscle thickening. These
structural changes to the airway wall and the pulmonary microvasculature
ultimately lead to impaired lung function (Al-Muhsen, Johnson and Hamid, 2011).
 However little
is known about the mechanism of airway remodelling although a number of
mechanisms have be proposed. Numerous research has shown that pericytes are
involved in this process and contribute to fibrotic disease.

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Pericytes are
mesenchymal cells found embedded within the abluminal surface of the
endothelium of microvessels such as capillaries, pre-capillary arterioles,
post-capillary and collecting venules. They maintain microvascular homeostasis
and participate in angiogenesis. Studies in models of lung fibrotic
inflammatory disease have demonstrated an important role of pericytes in
myofibroblast activation, collagen deposition and microvascular remodelling.
All of which are characteristic features of chronic lung diseases such as
asthma. Pericytes have
been shown to contribute to fibrotic disease in various organs; Lin et al. (2008) concluded that the majority
of myofibroblasts present in renal fibrosis are derived from pericytes. Comparable
results have been observed in mouse models of hepatic fibrosis. Liver-resident
pericytes, also known as hepatic stellate cells (HSCs), have been shown to be the
primary source of collagen in the liver following injury and the initiation of
fibrosis. Further evidence using lineage tracing strategy has provided support
a role for pericytes in liver fibrosis. Lineage tracing of HSCs based on Cre
expression driven by lecithin-retinol acyltransferase, was found to reliably
label 99% of HSCs in the healthy liver. Following injury to the liver, HSCs
were found to be the dominant source of myofibroblasts, which supports the
results generated from the investigations into the role of pericytes in kidney fibrosis
(Rowley and Johnson, 2014). Regardless of this however,
little is known about the role of pericytes in airway remodelling in

Studies undertaken by Johnson et
al. (2015) have shown that, in the mouse model of house dust mite (HDN) induced
allergic airway disease, pericytes detach from the airway microvasculature and
contribute to airway remodelling in chronic allergic inflammation. The
mechanisms driving this process are not fully understood, though they proposed that
that the pericytes are incorporated into the airway smooth muscle (ASM) and
thus contribute to the airway hypersensitivity (AHR) through an unknown
mechanism. During this study CP-673451, a selective PDGFR? inhibitor, was used to
investigate the role of PDGFR? signaling in airway remodelling and lung
dysfunction. The result showed that pharmacological inhibition of PDGFR?
signaling led to aggravated lung dysfunction and airway smooth muscle
thickening. Further studies revealed that the in?ammatory response to challenge
of the HDN allergen in mice was associated with a decrease in PDGF-BB expression
and the loss of pericytes from the airway microvasculature. Cells positive for
pericyte markers NG2 and ?-SMA were found amassed in the sub-epithelial region
of the chronically in?amed airways. This process was aggravated in animals
treated with CP-67345he r1 and results indicated that disturbed PDGF-BB/PDGFR?
signaling and pericyte accumulation in the airway wall may contribute to airway
remodeling in chronic allergic asthma.


have been some investigations into fibrosis treatment targeting pericyte,
including the study by Zhang et al.
(2014) in which curcumin, a major component of the turmeric spice, was
investigated with the aim of impairing pathological tissue remodelling in a hepatic
fibrosis rat model induced by carbon tetrachloride. Results showed that oral delivery
of curcumin was able to dose-dependently inhibit organ fibrosis and
vascularisation. The mechanism of this action was hypothesised to be related to
PDGFR? transrepression through the activation of peroxisome proliferator-activated
receptor gamma (PPAR-?). Pericytes have also been targeted in a number of mouse
models of kidney fibrosis, in which the pericyte-to-myofibroblast transition
has been shown by several groups to contribute to tissue fibrosis (Lin et al.,
2008; Scharpfenecker et al., 2013). Another recent study, investigated by Scharpfenecker
et al. (2014) used thalidomide with
the aim of normalising kidney microvasculature and inhibiting fibrosis
development in a model modelof radiation-induced kidney fibrosis. Thalidomide
has anti-inflammatory and angiogenesis-modulating properties. The results of
this investigation were poor as whilst vessel perfusion was improved, possiblely
due to increased PDGFR? expression promoting pericyte retention in the
vasculature, there was significant tubular damage and thalidomide was unable to
inhibit tissue fibrosis. According to Wong et
al. (2015), in 2011 Lin et al.,
produced some promising results which suggested that pericytes can be targeted
in organ fibrosis using a unilateral ureter obstruction (UUO) mouse model of
kidney fibrosis. These invetsigations focused on inhibiting growth factor receptor
signalling in pericytes using adenoviral vectors to overexpress the soluble
ectodomains of PDGFR? and VEGFR. Results showed that blocking either PDGFR?
signalling in pericytes or VEGFR2 signalling in ECs diminished tissue fibrosis
and capillary rarefaction following kidney. Despite these promising results no
treatment has been discovered yet.