21 The multi-faceted extracellular matrix: unlocking its secrets for understanding the perpetuation of lung fibrosis Along with the changes in the biochemical distribution of the ECM proteins in fibrosis, post-translational modifications of these proteins are also altered. Collagen protein synthesis starts within the rough endoplasmic reticulum, with post-translational modifications adding hydroxyl groups to proline and lysine residues (Figure 1) [28]. Individual collagen molecules come together within the Golgi to form the triple helical structure, forming the procollagen molecule. This trimer then is secreted from the Golgi into the extracellular space, where its pro-collagen ends at both the C- and N-terminals are cleaved to generate the mature collagen molecule. The collagen molecules self-assemble to begin forming fibrils before lysyl oxidases (LOX), LOX-like enzymes (LOXLs) and transglutaminases (TGs) actively crosslink the triple helices to each other, forming the collagen fibers [28]. Increased expression and amount of LOXL1 and LOXL2 was reported in IPF lung tissue compared with non-disease control lung tissue [11]. In concert, fibrotic fibroblasts were found to have higher expression of TG2 compared with healthy fibroblasts in vitro [29]. Crosslinking of the collagen fibers by LOX/LOXL has also been shown to promote the TGF-β induced stiffening of the microenvironment [11]. ECM deposited by from IPF-lung derived fibroblasts increased the expression of LOXL3 and TG2; and in turn, the increased crosslinking of this ECM was demonstrated to boost fibroblast proliferation and adhesion [29]. These data together suggest that the increased collagen crosslinking, and dysregulation of the crosslinking enzyme amounts in pulmonary fibrosis could contribute to the positive feedback loop which Parker et al. first described [14]. Figure 1: Schematic illustration of synthesis, secretion and crosslinking of collagen fibrils. RER: Rough endoplasmic reticulum; LOX: lysyl oxidase; LOXL: LOX-like; TG: transglutaminase. 2
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