19 The multi-faceted extracellular matrix: unlocking its secrets for understanding the perpetuation of lung fibrosis INTRODUCTION Lung fibrosis is a common characteristic of the heterogeneous group of interstitial lung diseases (ILDs). Of these the most common is idiopathic pulmonary fibrosis (IPF), which is a chronic, progressive lung disease, with a very poor survival rate (median: 3-5 years) [1]. Currently, there is no cure for IPF, other than lung transplantation, and while there are two therapeutic agents, pirfenidone and nintedanib, that can slow the disease progression, these therapies are not effective in all patients and have adverse, sometimes severe side effects [2]. Lung fibrosis is currently thought to result from an aberrant wound healing response following recurrent microinjuries to the alveolar epithelium, augmented by aberrant cross-talk between the fibroblasts and epithelial cells resulting in an excessive and abnormal deposition of extracellular matrix (ECM) proteins [3-5]. Under normal physiological conditions, ECM is composed of a multitude of different proteins, glycosaminoglycans (GAGs), and glycoproteins (collagen types I, III, IV and VI, fibronectin, laminin, periostin, and hyaluronic acid are a few examples), forming a dynamic network that provides support to the cells embedded within it [6, 7]. In addition to its structural support function, ECM is a bioactive component of the tissue and it provides cues to all cells to influence/instruct their behavior. In fibrosis, deposition of several different ECM proteins such as collagens and fibronectin is increased, while others are decreased, changing the biochemical composition of the tissue [8]. As a natural consequence of the changes in the protein composition and organization, the biomechanical properties of fibrotic lung tissues are also altered: fibrotic lungs are stiffer, have a greater degree of collagen crosslinking and altered topography [9-11]. This catalogue of changes was previously thought to only be the result of the fibrotic process within the tissue; however, a plethora of recent studies have illustrated the changes in the ECM are an emerging contributor to the disease progression process itself, influencing different cell types and cellular mechanisms [12-17]. Moreover, with the advances in the single-cell RNA sequencing methods, lung resident cell populations are shown to have great heterogeneity in lung fibrosis, compared to healthy lungs, which would also impact the diversity of ECM changes in fibrosis [18-21]. Interestingly, it has recently been suggested (in the context of embryonic development) that each cell type expresses its own unique ECM gene profile (indicative of the production of an individual ECM protein profile) that becomes more refined as the cells differentiate towards end-stage cells such as fibroblasts [22]. This finding implies the importance of the ECM microenvironment, which is disrupted in fibrosis, for the maintenance of a homeostatic status in tissue. However, the detailed mechanisms regarding how altered properties of ECM affect cellular responses or contribute to the cellular heterogeneity present in fibrosis and the consequent influence upon the disease outcome are yet to be investigated completely. 2
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