290 Chapter 10 Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with poor prognosis, high mortality rate and no cure available [1]. In IPF, the extracellular matrix (ECM), a dynamic and biologically active network of molecules that provides structural support to organs and tissues, is replaced with a disorganized and abnormal ECM structure. The deposition of this aberrant ECM in alveolar septa in the form of scar tissue is hypothesized to originate from abnormal wound repair responses to (micro) injuries in lung epithelium and resulting in recruitment of activated fibroblasts, the main producers of ECM, in a positive feedback cycle that results in generation of more fibrotic ECM for fibroblasts to respond [2]. How we look at the disease processes is changing: modifications in ECM are not just a silent byproduct of disease progression but an active contributor to this process [3]. We now know that (fibrotic) lung ECM does not only hold the tissue together but can provide cues to both resident and transmigrating cells [4, 5]. The details of these cell-ECM interactions in the context of IPF have not been thoroughly explored previously. This thesis aimed to investigate fibrotic ECM-cell interactions and how the fibrotic ECM stimulates profibrotic response in cells within this microenvironment. Lung ECM in IPF is drastically altered compared to control (non-IPF) lung ECM. Increased amounts of ECM components, higher amounts of crosslinking of collagens, altered topography and biomechanics in IPF lung ECM have been well-described (as reviewed in Chapter 2). Among these changes, collagen production, organization and crosslinking have been the main focuses: collagen synthesis biomarkers have been shown to predict disease progression in IPF [6, 7], increased levels of collagen maturity have been described in IPF lungs compared with control lungs [8], and collagen crosslinking has been shown to enhance fibroblast proliferation in IPF [9]. One of the important aspects in collagen organization is the presence of FACIT (Fibril Associated Collagens with Interrupted Triple helices) [10]. Collagen types IX, XII and XIV belong to this category of collagens, which provide support in the organization of collagen fibrils during fibril assembly in tissue [11]. However, their involvement in IPF, which is now known to include altered collagen organization, has not been described in detail. In Chapter 3, I describe the occurrence and distribution of collagen type XIV (COL14) in the lungs of patients with IPF, compared with control donor lungs. I found proportionally lower amounts of collagen type XIV in IPF lungs. These proportionally lower amounts point at possible mechanisms of decreased synthesis or increased degradation of collagen type XIV compared to other ECM components, which paves the way to a potential biomarker for IPF. Currently, it is not possible to discern whether rate of production of collagen type XIV does not match the production rate of other ECM components in IPF or whether this particular collagen is degraded more in IPF lungs. However, the consistently lower proportion of collagen type XIV in IPF
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