Abstract
In addition to providing a macromolecular scaffold, the extracellular matrix (ECM) is a critical regulator of cell function by virtue of specific physical, biochemical, and mechanical properties. Collagen is the main ECM component and hence plays an essential role in the pathogenesis and progression of chronic lung disease. It is well-established that many chronic lung diseases, e.g., chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) primarily manifest in the elderly, suggesting increased susceptibility of the aged lung or accumulated alterations in lung structure over time that favour disease. Here, we review the main steps of collagen biosynthesis, processing, and turnover and summarise what is currently known about alterations upon lung ageing, including changes in collagen composition, modification, and crosslinking. Recent proteomic data on mouse lung ageing indicates that, while the ER-resident machinery of collagen biosynthesis, modification and triple helix formation appears largely unchanged, there are specific changes in levels of type IV and type VI as well as the two fibril-associated collagens with interrupted triple helices (FACIT), namely type XIV and type XVI collagens. In addition, levels of the extracellular collagen crosslinking enzyme lysyl oxidase are decreased, indicating less enzymatically mediated collagen crosslinking upon ageing. The latter contrasts with the ageing-associated increase in collagen crosslinking by advanced glycation endproducts (AGEs), a result of spontaneous reactions of protein amino groups with reactive carbonyls, e.g., from monosaccharides or reactive dicarbonyls like methylglyoxal. Given the slow turnover of extracellular collagen such modifications accumulate even more in ageing tissues. In summary, the collective evidence points mainly toward age-induced alterations in collagen composition and drastic changes in the molecular nature of collagen crosslinks. Future work addressing the consequences of these changes may provide important clues for prevention of lung disease and for lung bioengineering and ultimately pave the way to novel targeted approaches in lung regenerative medicine.
Highlights
The extracellular matrix (ECM) is a highly dynamic noncellular component of tissues that provides a complex structural network which serves as a scaffold for adherent and migrating cells
We summarise what is known about collagen alterations in the ageing lung and what can be tentatively inferred from studies in other organs
There can be no doubt that collagen plays an important role in lung physiology and pathology
Summary
The extracellular matrix (ECM) is a highly dynamic noncellular component of tissues that provides a complex structural network which serves as a scaffold for adherent and migrating cells. By virtue of sequestered growth factors and ECM binding receptors at the surface of adherent cells, the ECM affects a plethora of cellular processes including cell proliferation, differentiation and migration and acts as a critical regulator of cell function [1, 2]. It is well-established that the ECM plays an important role in the pathogenesis and progression of chronic lung disease [3, 4]. How the ECM changes during ageing, has not been comprehensively assessed or discussed
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