23 The multi-faceted extracellular matrix: unlocking its secrets for understanding the perpetuation of lung fibrosis could improve our understanding and help identify novel therapeutic approaches for targeting the progression of lung fibrosis. Another emerging parameter among the biomechanical properties of ECM is the viscoelasticity, which is the ability to dissipate an applied stress through time [35]. The importance of the viscoelasticity of ECM both in healthy and diseased conditions has been recently reviewed elsewhere [36]. Similar to many other tissues and organs, lung ECM has viscoelastic properties and the loss of viscoelastic relaxation in fibrotic tissues has recently been established by our group [10]. The implications of (the loss of) viscoelasticity on cellular function in vivo is yet to be clarified; however, it is known that changes in the viscoelasticity of the microenvironment can affect cell migration, proliferation and ECM deposition by the cells [36]. All of these cellular functions are recognized as being altered in lung fibrosis, so now the challenge lies in separating the individual contributions of these different mechanical stimuli to the perpetuation of the fibrotic response. Promisingly, a recent study revealed the possibility of modifying stiffness and viscoelasticity independently of each other [37]. Developing advanced in vitro culture systems will further our understanding of viscoelasticity and its contribution to the progression of the lung fibrosis. Topography Topography of the ECM influences many cellular responses including migration and proliferation, as recently reviewed by Ouellette et al. [38]. While the altered composition alone could influence the topography of the ECM in lung fibrosis, the increased crosslinking and abnormal alignment of the fibers in the ECM are two other important factors changing the topography. In lung fibrosis, the topography of the ECM is drastically altered (Figure 2), due to the increased mature and organized collagen content, compared to the healthy lungs [11]. 2
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