10 Chapter 1 Lung fibrosis encompasses several different pulmonary diseases, all of which result in fibrotic scar tissue accumulation in the lung interstitium, the region between the alveolar epithelium and blood vessels [1]. The most common type is idiopathic pulmonary fibrosis (IPF) which has an unknown etiology and is mainly characterized by progressive fibrosis and a poor prognosis [2]. The survival rate for patients with IPF is very low: a recent meta-analysis reported an overall median survival of 3.2 years [3]. Despite the fact that IPF is the most common type of lung fibrosis, it is still classified as a rare disease with a prevalence of 3-45 in 100,000 [4]. The current school of thought suggests that the IPF originates from repeating (micro)injuries in the alveolar epithelium of lung tissue, followed by an aberrant wound repair response involving the recruitment of the (myo)fibroblasts to the injured area [5]. Unfortunately, to date, there is no permanent cure for IPF except for lung transplantation [6]. The only two available therapeutics, Nintedanib and Pirfenidone, merely slow the progression of fibrosis, increase the median survival rate but cannot reverse or cure established disease [7, 8]. One of the main reasons for a lack of new treatment strategies is the lack of thorough knowledge of the mechanisms underlying disease progression, as the fibrotic process is already, usually, at a very late stage at the time of diagnosis. Another roadblock is the lack of adequate laboratory and animal models to investigate the complex disease mechanisms of IPF [9]. The formation of aberrant extracellular matrix (ECM), deposited as scar tissue, is a key disease mechanism not only for IPF but for all fibrotic lung diseases [10]. Forming the immediate environment around the cells, the ECM is composed of a plethora of proteins, proteoglycans and glycosaminoglycans [11]. ECM provides a mechanical scaffold for the resident cells to attach; moreover, it provides bioactive cues through its own composition, as well as the growth factors that are stored in it [12]. Lung ECM is of vital importance for lung function through providing structural support and elasticity [13]. In fibrotic lung diseases, including IPF, the native ECM is disrupted with respect to its composition, mechanics and organization [14]. These collective changes during fibrosis result in a stiff and rigid scaffold instead of a soft and elastic network [15, 16]. In the last decade, our thoughts on how ECM plays a role in biological processes, has evolved drastically from an inert scaffold towards a bioactive and instructive network. Parallel to these revelations, our understanding on the realms of how ECM might be involved in the progression of a fibrotic response in lung diseases has also improved. We now know that the presence of fibrotic ECM alone, in vitro, guides cells towards a more pro-fibrotic state in a positive feedback loop, possibly resulting in generation of more fibrotic ECM [17-19]. Together with aberrant composition, disorganized fibers and altered mechanics, abnormal cells
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