Nanoscale dysregulation of collagen structure-function disrupts mechano-homeostasis and mediates pulmonary fibrosis.
Mark G JonesOrestis G AndriotisJames Jw RobertsKerry LunnVictoria J TearLucy CaoKjetil AskDavid E SmartAlessandra BonfantiPeter JohnsonAiman AlzetaniFranco ConfortiRegan DohertyChester Y LaiBenjamin JohnsonKonstantinos N BourdakosSophie V FletcherBen G MarshallSanjay JogaiChristopher J BreretonSerena J CheeChristian Hermann OttensmeierPatricia SimeJack GauldieMartin KolbSumeet MahajanAurelie FabreAtul BhaskarWolfgang JarolimekLuca RicheldiKatherine Ma O'ReillyPhillip D MonkPhilipp J ThurnerDonna E DaviesPublished in: eLife (2018)
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.