130 Chapter 6 factor activity and tissue modeling and remodeling [14, 15]. Four subfamilies of GAGs can be distinguished in the lung including heparan sulfate, hyaluronic acid, chondroitin sulfate/dermatan sulfate and keratan sulfate [16]. With the exception of hyaluronic acid, which is not synthesized as a PG, the other GAGs are synthesized as PGs, which consist of a protein backbone (referred to as the core protein) to which GAGs bind covalently [17]. Thus, major proteoglycan families can be classified based on their GAG composition, molecular weight and function [14]. Extracellular PGs can be classified in two groups, aggregating and small leucine-rich repeat PGs [16]. Known for their role in matrix-cell interactions, glycoproteins including fibronectin, laminins, vitronectin, thrombospondin, tenascin and nidogens play a crucial role in regulating cellular responses [18]. To investigate the role of the ECM in the development of lung pathologies, different in vitro experimental models such as traditional two-dimensional (2D) and more recently innovative three-dimensional (3D) cell culture systems have been developed. The 2D culture system is a wellestablished and broadly used system which (as discussed in Chapter 2), while having facilitated the generation of valuable data as the main workhouse of the in vitro lab for many years, has now been recognized to be limited in respect to its ability to mirror the physiological microenvironment from which cells are derived. Therefore, the importance of model systems that further mimic the natural physiological microenvironment of cells is necessary for a better understanding of cellular responses during homeostasis and disease. In this chapter, we discuss the 3D in vitro models for representing lung disease, repair and regeneration. First, we outline the changes in the ECM during chronic lung diseases and summarize the major differences between 2D and 3D culture systems. Next, we describe the single ECM protein-based models used for advanced 3D lung modeling. Then, we illustrate state-of-the-art research that is performed using the complete lung ECM as a basis for the model. In conclusion, we discuss the limitations of actual conceptualized and available 3D culture systems, the encountered challenges and the novel approaches to improve the quality and robustness of 3D culture systems.
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