Extracellular matrix in lung development, homeostasis and disease

Abstract

The lung's unique extracellular matrix (ECM), while providing structural support for cells, is critical in the regulation of developmental organogenesis, homeostasis and injury-repair responses. The ECM, via biochemical or biomechanical cues, regulates diverse cell functions, fate and phenotype. The composition and function of lung ECM become markedly deranged in pathological tissue remodeling. ECM-based therapeutics and bioengineering approaches represent promising novel strategies for regeneration/repair of the lung and treatment of chronic lung diseases. In this review, we assess the current state of lung ECM biology, including fundamental advances in ECM composition, dynamics, topography, and biomechanics; the role of the ECM in normal and aberrant lung development, adult lung diseases and autoimmunity; and ECM in the regulation of the stem cell niche. We identify opportunities to advance the field of lung ECM biology and provide a set recommendations for research priorities to advance knowledge that would inform novel approaches to the pathogenesis, diagnosis, and treatment of chronic lung diseases.

Figure 1. Role of the ECM in lung homeostasis and disease

Normal lung ECM is critical for embryonic lung development and the maintenance of lung homeostasis in adulthood. Aberrant alterations of the properties of lung ECM, including composition, biomechanics, dynamics and topography, are characteristic of a number of adult and child lung diseases, including IPF, COPD and BPD. IPF = idiopathic pulmonary fibrosis; COPD = chronic obstructive pulmonary disease; BPD = bronchopulmonary dysplasia.

Figure 2

A, An experimental pipeline to characterize the lung ECM using proteomics. B, Comparison of the lung ECM composition, defined by mass spectrometry-based proteomics from 3 independent studies (as denoted in the figure).

Figure 3. Matrix stiffness and topography guide IPF myofibroblast invasion into the ECM

Stiffened fibrotic matrix upregulates α₆ integrin expression by ROCK-dependent activation of c-Fos/c-Jun transcription factor complex. Interactions between α₆β1 integrin and the BM bring lung myofibroblasts into the close proximity to the BM. This facilitates MMP-2/9-mediated pericellular proteolysis of BM component collagen IV, leading to lung myofibroblast invasion (see ref. # for details). Matrix stiffness sensing by α₆ integrin and the highly organized, anisotropic matrix fibers, which could act as “highways” that aid IPF myofibroblast invasion through the BM and interstitial ECM to form a continuous fibrotic reticular network. MFB = myofibroblast; ROCK = Rho kinase; MMP = matrix metalloproteinase; BM = basement membrane; AEC = alveolar epithelial cell.

Figure 4. miR-29c-mediated positive feedback between the fibrotic ECM and the fibroblast amplifies the fibrotic phenotype

miR-29c targets ECM genes and limits ECM production in normal lungs. Downregulation of miR-29c activates the synthesis of ECM products by lung fibroblasts and persists in response to the fibrotic ECM (modified from ref. #196).

Figure 5. The central role of MMP-derived PGP in smoking-induced pulmonary inflammation

A, Neutrophil-derived MMP9 and prolyl endopeptidase (PE) degrade lung collagens to generate PGP. PGP serves as a chemoattractant to recruit neutrophils to lung interstitium. Cigarette smoke induces increases in MMP-9, PE and PGP production which promotes neutrophil influx. B, Leukotriene A4 hydrolase (LTA4H) is a pro-inflammatory enzyme that possesses aminopeptidase activity. LTA4H serves to degrade PGP and stop the PGP-mediated neutrophil chemotaxis in acute inflammation. Cigarette smoke selectively inactivates LTA4H’s aminopeptidase function, leading to accumulation of PGP and neutrophils (see ref. # for details). This contributes to the chronic inflammation that drives disease progression in COPD.