Asthma affects an estimated 262 million people and caused over 461,000 deaths in 2019
[24]. Asthma is characterized by chronic airway inflammation, bronchial hyperresponsiveness and airway remodeling. Airway remodeling was first described in cases of fatal asthma by Huber and Koessler
[25]. Since then, features of airway remodeling have been documented for all stages of asthma severity and have been linked to reduced lung function, airways hyperresponsiveness, and greater use of asthma medications
[26][27][28]. The deposition of ECM is a prominent feature of lung remodelling in patients with asthma irrespective of age, disease severity or steroid use
[28][29][30]. ECM remodelling in asthma involves the airway epithelial basement membrane, laminar propria, bronchial and pulmonary vasculature
[28][31][32]. The compositions of the airway smooth muscle (ASM) ECM, epithelial basement membrane and interstitial ECM have also been shown to be altered in asthma, with a predominant deposition of fibronectin, collagen I and III
[33]. Most recently, the topography of fibrillar collagen fibers has also been assessed and shown to be more disorganized and fragmented in the airway laminar propria and pulmonary vasculature
[28][34]. However, recent emerging studies using various samples including serum, ASM, bronchial fibroblasts and airway epithelial cells have shown miRNAs that are differentially expressed in asthma pathology and contribute to ECM remodelling.
3.2. Chronic Obstructive Pulmonary Disease
COPD is one of the most common lung diseases worldwide, and the third leading cause of death
[35] due to exposure of tobacco smoke and/or environmental pollutants
[36]. COPD is characterized by chronic lung inflammation and irreversible airflow limitation. COPD is caused by the chronic inhalation of cigarette smoke or other harmful particles, which cause pulmonary injury, leading to chronic airway inflammation and tissue remodelling. The major histopathological changes observed within the lung include chronic bronchitis, small airway disease and emphysema. Recent studies have shown that small airway disease precedes emphysematous tissue destruction, suggesting a temporal pattern of ECM deposition and destruction in the disease progression
[37]. Using a large cross-sectional study, Hogg and colleagues showed that the progression of COPD from GOLD (Global Initiative for Obstructive Lung Disease) stage 0 to GOLD stage 4 is strongly associated with thickening of the airway wall and each of its compartments by remodelling of the ECM, which affects airway wall elasticity, thickness and resistance
[38][39]. In addition, loss of elastic recoil from the destruction of the ECM within the parenchyma (emphysematous tissue destruction) is a well-described feature of COPD
[40], with several studies showing decreased protein expression and volume fraction of elastin in both the conducting airways and the parenchyma of patients with mild, moderate or severe COPD
[41][42].
3.3. Idiopathic Pulmonary Fibrosis
IPF is the most common and progressive type of idiopathic interstitial pneumonia that is unresponsive to treatment, leading to a median survival of 3–5 years
[43][44][45][46]. The pathology of IPF is characterized by heterogeneous interstitial fibrosis, honeycomb cysts and fibrotic foci associated with excessive deposition of ECM proteins resulting in aberrant matrix metalloproteinases, connective tissues, morphogens and impaired signalling of growth factors
[47][48][49][50][51]. More recently the early pathology of IPF has been shown to involve the loss of small airways
[52].The current hypothesis for tissue destruction in IPF involves continuous damage and senescence of the alveolar epithelium, leading to the destruction of the basement membrane and activation of myofibroblasts
[53]. As the disease progresses, the composition of the ECM has been shown to vary, with an accumulation of versican in the onset of IPF, whereas collagen I and collagen III accumulation is observed in both the early and late stages of IPF
[54]. The severity of fibrosis in IPF has also been shown to correlate with the number of elastic fibers, with a higher elastic fiber score being related to worse disease outcomes
[55]. The diseased ECM is a critical linchpin in IPF, and it serves as a causal link for alteration in cell gene expression patterns at the translational level
[3].
4. Conclusions
The initiation and progression of chronic lung diseases are modulated by complex environmental and epigenetic factors. In the initiation and progression of these diseases, there is an intricate interaction between cells and the ECM through various molecules and signalling pathways. Alterations in the lung ECM are driven by synthesis, degradation, and changes in topography by multiple cell types in the lung, but more importantly, dysregulation of the ECM seems to provide a positive feedback loop to drive fibrosis progression. The development of complex models and screening of human tissues is essential to understand how ECM regulation is abnormal in lung disease and how it could be targeted therapeutically.