3. Pathophysiological changes in the asthmatic airway
epithelium:
Asthmatic patients have different degrees of chronic persistent
inflammation of the airway epithelium with airway epithelial damage
occurring even in mild, early and nonfatal asthma [39]. The degree
of inflammation is variable but airway edema, inflammatory cell
infiltration, goblet cell hyperplasia, mucus plug formation, epithelial
tissue damage and epithelial cell shedding are observed in the airways
of asthma patients [40]. Airway epithelial cell damage and shedding
are important pathological features of asthma with the abnormal
epithelium being more susceptible to injury and apoptosis than that of
healthy control subjects [41]. AECs from asthmatic subjects obtained
by bronchial brushing appear to be less viable and more hyperreactive as
compared to healthy subjects [42]. This decrease in viability may be
the result of inflammatory damage. In asthma, basal AECs can
preferentially differentiate into goblet cells that secrete mucus, and
the number and volume of mucous glands is increased. Recent genetic
evidence also emphasizes the role of goblet cells and mucus production
in asthma [43, 44].
AECs have diverse and complex functions rather than the initial concept
of a passive barrier and these are key to maintaining a dynamic defense
against the external environment. The airways of asthmatic patients
display characteristic signs of dysregulation of airway epithelial
repair, leading to a chronic cycle of wound repair and subsequent lung
remodeling. A new paradigm for asthma epithelial injury and aberrant
repair is that it is involved in the origins of the disease and not
merely as a consequence of longstanding inflammation [2]. Thus, the
inherent abnormality of the ability to repair and restore an effective
barrier to the external environment after epithelial injury seems to be
indispensable for the occurrence and development of asthma.
There is widespread airway epithelial damage in asthma patients. The
abnormal morphology and function of AECs is seen very early on in
disease and this abnormal state of injury and repair is sustained
throughout the patient’s life. These changes result in impaired airway
epithelial barrier function, which is also the cause of airway
remodeling and airway hyperresponsiveness, and the associated decline in
lung function. Analysis of samples from patients who died from asthma
obtained at autopsy revealed extensive airway remodeling including
airway smooth muscle hypertrophy, epithelial goblet cell hyperplasia and
sub-epithelial tissue collagen deposition [41]. There is a
thickening of the basal lamina in both adults and children with asthma
that is usually associated with subepithelial myofibroblast recruitment
and fibrosis prior to the establishment of airway inflammation [45,
46].
The repair of airway epithelial cells in asthmatic patients is
dysregulated although the AEC of asthmatic patients have a higher
proliferative capacity than those from normal subjects [47].
Monolayers of AEC from asthmatic children fail to repair post wounding
and these cells produce less fibronectin (FN) than AECs from normal
children. Supplementation with exogenous FN does not completely repair
these paediatric asthmatic AECs [47]. In addition, the
transcriptomic map of epithelial cells in asthma patients also provides
clues to the importance of chronic epithelial damage and repair in the
pathogenesis of asthma. The expression of at least 60 genes in AEC is
reduced and many are related to wound healing and inflammation including
the chemokine ligands (CCL)-3, CCL-5 and CCL-18; TLR2, TLR8; CD14; IL-1α
and IL-1β and the receptors IL-1R and IL-8RA; galectin-1 and galectin-3,
and the binding proteins for galectin-3 and galectin-9 [47].
Airway epithelial damage triggers the induction of inflammation and
repair mechanisms that involve cell-to-cell communication and
intracellular signal transmission [48]. Thus, airway remodeling in
asthma is a consequence of dysfunctional epithelial repair post
wounding, where dysregulated inflammation and an imbalance in the
epithelial-mesenchymal trophic unit leads to a vicious cycle of
dysfunctional wound repair and attempted resolution [14, 49]. In
asthma, epidermal growth factor receptor (EGFR) immunoreactivity is
significantly higher in biopsies of patients with mild and severe asthma
compared to that of normal people suggesting the potential for altered
EGFR signaling and epithelial repair [50]. Extrinsic factors induce
AECs to release recruitment factors such as IL-5 and EGF thereby
recruiting and stimulating inflammatory cells such as eosinophils,
resulting in an imbalance of epithelial mesenchymal units [51, 52].
In addition, heightened secretion of fibroblast growth
factor-transforming growth factor-β (TGF-β) and EGF is an important
mechanism leading to airway remodeling in refractory asthma. Abnormal
expression of ECM proteins and integrins is likely to further drive the
pathological defects seen in the functional responses of the airway
epithelium in asthma [48].