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].