부산대학교 도서관

Matrix stiffening with downstream activation of mechanosensitive pathways is strongly implicated in progressive fibrosis; however, pathologic changes in extracellular matrix (ECM) that initiate mechano-homeostasis dysregulation are not defined in human disease. By integrated multiscale biomechanical and biological analyses of idiopathic pulmonary fibrosis lung tissue, we identify that increased tissue stiffness is a function of dysregulated post-translational collagen cross-linking rather than any collagen concentration increase whilst at the nanometre-scale collagen fibrils are structurally and functionally abnormal with increased stiffness, reduced swelling ratio, and reduced diameter. In ex vivo and animal models of lung fibrosis, dual inhibition of lysyl oxidase-like (LOXL) 2 and LOXL3 was sufficient to normalise collagen fibrillogenesis, reduce tissue stiffness, and improve lung function in vivo. Thus, in human fibrosis, altered collagen architecture is a key determinant of abnormal ECM structure-function, and inhibition of pyridinoline cross-linking can maintain mechano-homeostasis to limit the self-sustaining effects of ECM on progressive fibrosis. eLife digest Idiopathic pulmonary fibrosis (IPF) is a devastating disease of the lung, which scars the tissue and gradually destroys the organ, ultimately leading to death. It is still unclear what exactly causes this scarring, but it is thought that increasing amounts of proteins in the space surrounding the cells of the lungs, the extracellular matrix, could play a role. These proteins, including collagen, normally form a 'scaffold' to stabilize cells, but if they accumulate uncontrollably, they can render tissues rigid. It has been assumed that these changes are a consequence of the disease. However, recent evidence suggests that the increased stiffness itself could stimulate cells to produce even more extracellular matrix, driving the progression of the disease. A better understanding of what exactly causes the tissue to become gradually stiffer may identify new ways to block the progression of IPF. Now, Jones et al. compared measurements of the tissue stiffness and the collagen structure taken from samples of patients with IPF. The results showed that the collagen fibres were faulty and had an abnormal shape. This suggests that these problems, rather than an increased amount of collagen, alter the flexibility of the lung tissue. Jones et al. also found that a specific family of proteins, which helps to connect the collagen fibres, was increased in the tissue of patients with IPF. When these proteins were blocked with a newly developed drug, the collagen structure returned to normal and the stiffness of the tissue decreased. As a consequence, the lung capacity improved. This suggests that treatment approaches that help to maintain a normal collagen structure, may in future prevent the stiffening of the lung tissue and so limit feed-forward mechanisms that drive progressive IPF. Moreover, it indicates that measurements of the structure of collagen rather than the its total concentration could serve as a more suitable indicator for the disease.
Byline: Mark G Jones, Orestis G Andriotis, James JW Roberts, Kerry Lunn, Victoria J Tear, Lucy Cao, Kjetil Ask, David E Smart, Alessandra Bonfanti, Peter Johnson, Aiman Alzetani, Franco Conforti, [...]