20 Chapter 2 In this review, we summarize the varied aspects of the contribution of ECM in lung fibrosis and how ECM influences cellular responses. First, we focus on updates for understanding how changes in ECM composition, coupled with altered mechanical properties, impact cellular responses. Then, we look beyond the ECM scaffold to illustrate how ECM degradation and the released bioactive ECM fragments play a role in lung fibrosis. Finally, we reflect on how targeting (changes in) ECM can be leveraged to provide new avenues for managing lung fibrosis. ECM CHANGES IN FIBROSIS AND THEIR FUNCTIONAL CONSEQUENCES Composition and Crosslinking In pulmonary fibrosis, changes in the quantities of ECM proteins have been extensively described [6, 9, 23] : including, but not limited to, increased collagen types I and III, fibronectin, periostin, and hyaluronic acid. One of the most important pieces of evidence illustrating how fibrotic ECM induces fibrotic responses in fibroblasts, as a result of the feedback in two dimensional (2D) cell culture models, was described by Parker et al [14]. In concert, primary lung fibroblasts cultured on scaffolds made with stacked sections of decellularized IPF lung were shown to produce a protein output that mirrored the fibrotic matrix composition compared to the fibroblasts cultured on scaffolds made with control lung tissue [24]. By comparing the decellularized fibrotic and alveolar tissue-derived sections of mouse ex vivo lung tissue scaffolds, the fibrotic microenvironment was found to decrease the spontaneous movement speed of immortalized mouse fibroblasts, compared to healthy mouse tissue [13]. The effect of the microenvironment was shown to also influence responses in other cells: Monocyte-derived macrophages in the fibroblastic-foci were found to perpetuate the fibrotic response, suggesting the fibrotic microenvironmental cues were guiding these cellular responses [25]. Similarly, pericytes were also shown to have higher gene and protein expression of α smooth muscle actin (α-SMA) when cultured on decellularized IPF lung samples compared to decellularized control lung samples [26]. Interestingly, culturing alveolar epithelial cells on IPF lung derived decellularized matrices was found to protect alveolar epithelial cells from transforming growth factor β (TGF-β) induced apoptosis, while additionally strengthening the profibrotic response of IPF lung-derived decellularized matrix-seeded fibroblasts to TGF-β via engagement of integrin α2β1, compared with cells seeded on non-disease control lung derived decellularized matrices [27]. These studies collectively show the influence of the fibrotic ECM on different cells, illustrating the different responses of the cells to the changing microenvironment in lung fibrosis.
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