Epithelial-mesenchymal crosstalk in COPD: An update from in vitro model studies

Abstract

Chronic Obstructive Pulmonary disease (COPD) involves airway inflammation and remodeling leading to small airways disease and emphysema, which results in irreversible airflow obstruction. During lung development, reciprocal interactions between the endoderm and mesoderm (epithelial-mesenchymal trophic unit (EMTU)) are essential for morphogenetic cues that direct cell proliferation, differentiation, and extracellular (ECM) production. In COPD, a significant number of the inflammation and remodeling mediators resemble those released during lung development, which has led to the hypothesis that aberrant activation of the EMTU may occur in the disease. Studies assessing lung epithelial and fibroblast function in COPD, have been primarily focused on monoculture studies. To capture the in vivo environment of the human lung and aid in the understanding of mechanisms and mediators involved in abnormal epithelial-fibroblast communication in COPD, complex co-culture models are required. In this review, we describe the studies that have used co-culture models to assess epithelial-fibroblast interactions and their role in the pathogenesis of COPD.

Introduction

Chronic obstructive pulmonary disease (COPD) imposes an enormous world-wide public health burden, with 10 % of the population over 40 years having moderate COPD (Vogelmeier et al., 2017). The Global Initiative for Obstructive lung disease (GOLD) defines COPD as “a common, preventable, and treatable disease, characterized by airflow limitation and persistent respiratory symptoms resulting from abnormalities in the airway and alveoli, caused by exposure to noxious particles and gases” (Vogelmeier et al., 2017). It has been known since 1968 that the major site of airflow obstruction in COPD lungs occurs below the small conducting airways <2 mm in internal diameter due to structural alterations within the lung that result in small airways disease and emphysema (Hogg et al., 1968).

Small airways disease results from chronic airway remodeling that involves chronic mucus hypersecretion and activation of fibroblasts with the production of excess extracellular matrix (ECM) proteins, leading to thickening of the airway wall (Hogg et al., 2017). Using micro-CT, it has now been shown that in COPD the smallest conducting airways, terminal bronchioles, within the lung are already lost by 40 % in mild (GOLD1) COPD, 43 % in moderate (GOLD2) COPD and between 70– 90 % in very-severe COPD (Koo et al., 2018; McDonough et al., 2011). Emphysema is defined pathologically as the presence of permanent enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of their walls and capillary networks without obvious fibrosis, resulting in non-functional airspaces (Snider, 1985).

In COPD, the significant inflammation and remodeling of the airways and parenchyma has been proposed to occur due to aberrant activation of the “epithelial-mesenchymal trophic unit” (EMTU)–a structural and functional element in the lung (Evans et al., 1999; Ward and Walters, 2005). The role of epithelial-fibroblast crosstalk within the COPD EMTU, has been difficult to study as 2-dimensional (2D) in vitro models cannot capture the complex cellular environment of the human lung. Further, animal models are limited by the lack of comparison in human lung structure, immune and tissue responses. In this review, we summarize the use of 3D in vitro co-culture systems to understand epithelial-fibroblast communication and aid in the understanding of disease pathobiology in COPD.