The extracellular matrix - the under-recognized element in lung disease?

Abstract

The lung is composed of airways and lung parenchyma, and the extracellular matrix (ECM) contains the main building blocks of both components. The ECM provides physical support and stability to the lung, and as such it has in the past been regarded as an inert structure. More recent research has provided novel insights revealing that the ECM is also a bioactive environment that orchestrates the cellular responses in its environs. Changes in the ECM in the airway or parenchymal tissues are now recognized in the pathological profiles of many respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). Only recently have we begun to investigate whether these ECM changes result from the disease process, or whether they constitute a driving factor that orchestrates the pathological outcomes. This review summarizes our current knowledge of the alterations in the ECM in asthma, COPD, and IPF, and the contributions of these alterations to the pathologies. Emerging data suggest that alterations in the composition, folding or rigidity of ECM proteins may alter the functional responses of cells within their environs, and in so doing change the pathological outcomes. These characteristics highlight potential avenues for targeting lung pathologies in the future. This may ultimately contribute to a better understanding of chronic lung diseases, and novel approaches for finding therapeutic solutions. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Keywords: asthma; chronic obstructive pulmonary disease; collagen; extracellular matrix; fibrosis; lung; myofibroblast; niche.

Figure 1

Histochemical staining of lung tissue sections. (1, 2) Large cartilaginous airway, small airway and surrounding alveolar parenchyma of a normal lung. Note the normal thickness of the mucosa, and the absence of inflammation. The alveoli have a normal size and architecture, and no fibrosis. (3, 4) Large airway and lung parenchyma of a patient with asthma. There is a thickened airway due to inflammation, and some matrix deposition, mainly at the submucosal level. The parenchyma shows an area of hyperinflation, but no fibrosis. (5, 6) Small airway and lung parenchyma in a patient with COPD. There is parenchymal destruction (emphysema) and some peribronchiolar fibrosis. (7, 8) Small airways and the lung parenchyma of a patient with IPF. There is architectural disorganization of the parenchyma around a dense fibrotic area, with cystic areas involving part of the parenchyma. The detail shows fibroblastic foci with areas of collagen deposition along alveolar walls. Verhoeff–Masson staining. Collagens are in blue, muscle is in red, and EFs are in black.

Figure 2

Representative SHG images of regions from the small airways mucosa or lung parenchyma from healthy donors or patients with asthma, COPD, or IPF. Yellow: backward immature/disorganized collagen. Cyan: mature/organized collagen.

Figure 3

Model of events contributing to fibrosis in lung disease. (A) The common view that persistent inflammatory responses contribute to fibrosis. (B) In response to injury and fibrotic events, fibroblasts migrate towards the site of injury, proliferate, and ultimately differentiate into myofibroblasts. These cells specialize in ECM production. (C) Several mesenchymal progenitor cells in the lung may be involved in fibrotic events and contribute to the fibroblast pool in lung fibrosis, including fibrocytes, MSCs, pericytes, and potentially other progenitors. Epithelial cells may contribute to the fibroblast pool through EMT. (D) Migration is influenced in a complex way by tissue stiffness.

Figure 4

A graphical representation of the complex cellular interactions with the ECM in the lung: potential impact on differentiation, migration, adhesion, proliferation, tissue stabilization, homeostasis, and fibrosis. Cellular interactions with the ECM provide a positive feedback loop to direct activities of the cells, alter tissue homeostasis, and drive fibrosis progression.

Figure 5

The remodelled ECM in the lungs is produced by multiple cell types, and in turn modulates the behaviour of the cells to impact on the perpetuation of disease pathology. Blue arrows indicate a positive/promoting effect, and red arrows indicate a negative/inhibitory effect. COLI, collagen I; COLIII, collagen III; COLIV, collagen IV; FN, Fibronectin.