The Diseased Extracellular Matrix in Chronic Obstructive Pulmonary Disease Modeling

Chronic obstructive pulmonary disease (COPD) is currently the fourth leading cause of death in the world, with an increasing prevalence as the world’s population ages. In the distal regions of the lungs, COPD is characterized by progressive emphysema due to an imbalance of proteases that continuously degrade essential extracellular matrix (ECM) proteins within the alveolar walls, causing fatal tissue impairment. This dissertation examines the unique properties of this diseased lung ECM in two parts: (1) As a key constituent in inflammatory signaling that leads to increased inflammation and progression of COPD, and (2) as a tool in three-dimensional (3D) in vitro lung disease modeling. The lung ECM is elastin-rich, providing the lung with the elastic recoil necessary to expel air. The degradation of this ECM in the alveolae leads to an abnormal accumulation of elastin-derived peptides (EDPs). While many ECM proteins and their byproducts are known to impact cell behavior through binding to cell surface molecules, the mechanism by which EDPs interact with cells in not well defined and has yet to be investigated in relation to COPD. Here, we consider how EDPs influence inflammation through the activation of calpain-1, leading to downstream protein regulation and subsequent inflammation. The findings reported herein suggest that EDPs perpetuate an inflammatory feedback loop by interacting with elastin binding protein (EBP) and activating calcium channels in human lung cells, which influence calpain-1 activity, resulting in the production and/or activation of COPD-related proteins IL-6, MMP-2, and MMP-12. This work indicates that the diseased ECM is involved in the inflammatory progression of COPD and must be considered in regard to ongoing investigations. However, studies continue on tissue culture plastic and in animal models that are not translatable to the COPD microenvironment. This dissertation continues by examining how decellularized ECM, derived from human COPD lung, can be utilized to create a 3D in vitro lung model that captures key COPD microenvironment characteristics. This work describes a novel human lung ECM hybridgel that supports encapsulated cell culture, retains pathologic characteristics of its source tissue, and mimics the elasticity of intact human lung tissue. This report concludes by defining a COPD human lung ECM hybridgel with native composition, disease-specific elastin/collagen ratios, depletion of sulfated GAGs, increased insoluble collagen, and reduced elastic properties. Collectively, this evidence furthers our understanding of how COPD ECM plays a significant role in disease progression and how it can be manipulated to engineer more physiologically relevant in vitro disease models for future investigation into the mechanisms of COPD.