Nanoscale dysregulation of collagen structure-function disrupts mechano-homeostasis and mediates pulmonary fibrosis
Nanoscale dysregulation of collagen structure-function disrupts mechano-homeostasis and mediates pulmonary fibrosis
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.
Jones, Mark
a6fd492e-058e-4e84-a486-34c6035429c1
Andriotis, Orestis
a32519c3-d1db-4183-9189-f3419cf32b06
Roberts, James
ab020b43-ace7-4032-aefe-6b6bf7fec5b9
Lunn, Kerry
6f21772b-2978-4cbd-93d8-3de66fce5a23
Tear, Victoria
5ee86839-b950-4aaa-8dd0-2bae9abb2f52
Cao, Lucy
2e195b93-783b-49b9-962f-546b1ce77666
Ask, Kjetil
0b88ffad-3bd2-41ce-a1c3-2b0ff6743698
Smart, D.E.
3fc82f4e-727a-4f79-96ee-8c80765cad59
Bonfanti, Alessandra
61f52944-226a-4078-8e50-88036bf85dc8
Johnson, Peter
862b092d-ac8b-4c9b-804f-10d42d8b0d21
Alzetani, Aiman
04d65796-5c8e-4c5b-aeeb-ea093c118f03
Conforti, Franco
28bf123c-e42a-4fb5-8b26-f79e1095c586
Doherty, R.
beb5503d-2436-4f6b-8505-27a0acad9bcd
Lai, Chester
29ba48ea-2d38-497f-8cf9-400237f6a3a0
Johnson, Benjamin
dce3d588-86b3-4647-a871-1b0408b456bb
Bourdakos, Konstantinos
83f6fc3a-db12-476b-9a78-4aad8756f82f
Fletcher, Sophie
71599088-9df7-4d4a-8570-aef773ead0fe
Marshall, Benjamin
9abf382c-977f-459c-9b91-5ed8cbf2284f
Jogai, Sanjay
18c2f36b-4572-46d5-b17d-a6d2cdaa916c
Brereton, Christopher, J
948ca4ea-b04c-4b7a-bfe4-f79f184d7e43
Chee, Serena, Jamie Tzu Wen
51a261fc-2b72-43cc-98dd-79617de7573b
Ottensmeier, Christian
42b8a398-baac-4843-a3d6-056225675797
Sime, Patricia J.
d96733e9-a51c-4dc0-90c0-203e550827d1
Gauldie, Jack
7ec6f101-1eff-45d7-85be-ced183526ea2
Kolb, Martin
f7169cba-735d-4c03-b348-55f170d1b5dd
Mahajan, Sumeet
b131f40a-479e-4432-b662-19d60d4069e9
Fabre, A.
45c70593-8020-40a8-9cf1-2d2128062219
Bhaskar, Atul
d4122e7c-5bf3-415f-9846-5b0fed645f3e
Jarolimek, Wolfgang
fc072a1f-e47e-412e-831b-4537b8e07125
Richeldi, Luca
89f3b3b9-2dc9-4803-a190-3d4facabd8c2
O'Reilly, Katherine M.A.
6c323cd0-0c68-4913-9666-7e4f655b816f
Monk, Phillip
f0b35062-133d-4d96-8347-742d27a46fa6
Thurner, Philipp
8d4204ab-f003-4668-9fa2-39cf54bdd99a
Davies, Donna
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
3 July 2018
Jones, Mark
a6fd492e-058e-4e84-a486-34c6035429c1
Andriotis, Orestis
a32519c3-d1db-4183-9189-f3419cf32b06
Roberts, James
ab020b43-ace7-4032-aefe-6b6bf7fec5b9
Lunn, Kerry
6f21772b-2978-4cbd-93d8-3de66fce5a23
Tear, Victoria
5ee86839-b950-4aaa-8dd0-2bae9abb2f52
Cao, Lucy
2e195b93-783b-49b9-962f-546b1ce77666
Ask, Kjetil
0b88ffad-3bd2-41ce-a1c3-2b0ff6743698
Smart, D.E.
3fc82f4e-727a-4f79-96ee-8c80765cad59
Bonfanti, Alessandra
61f52944-226a-4078-8e50-88036bf85dc8
Johnson, Peter
862b092d-ac8b-4c9b-804f-10d42d8b0d21
Alzetani, Aiman
04d65796-5c8e-4c5b-aeeb-ea093c118f03
Conforti, Franco
28bf123c-e42a-4fb5-8b26-f79e1095c586
Doherty, R.
beb5503d-2436-4f6b-8505-27a0acad9bcd
Lai, Chester
29ba48ea-2d38-497f-8cf9-400237f6a3a0
Johnson, Benjamin
dce3d588-86b3-4647-a871-1b0408b456bb
Bourdakos, Konstantinos
83f6fc3a-db12-476b-9a78-4aad8756f82f
Fletcher, Sophie
71599088-9df7-4d4a-8570-aef773ead0fe
Marshall, Benjamin
9abf382c-977f-459c-9b91-5ed8cbf2284f
Jogai, Sanjay
18c2f36b-4572-46d5-b17d-a6d2cdaa916c
Brereton, Christopher, J
948ca4ea-b04c-4b7a-bfe4-f79f184d7e43
Chee, Serena, Jamie Tzu Wen
51a261fc-2b72-43cc-98dd-79617de7573b
Ottensmeier, Christian
42b8a398-baac-4843-a3d6-056225675797
Sime, Patricia J.
d96733e9-a51c-4dc0-90c0-203e550827d1
Gauldie, Jack
7ec6f101-1eff-45d7-85be-ced183526ea2
Kolb, Martin
f7169cba-735d-4c03-b348-55f170d1b5dd
Mahajan, Sumeet
b131f40a-479e-4432-b662-19d60d4069e9
Fabre, A.
45c70593-8020-40a8-9cf1-2d2128062219
Bhaskar, Atul
d4122e7c-5bf3-415f-9846-5b0fed645f3e
Jarolimek, Wolfgang
fc072a1f-e47e-412e-831b-4537b8e07125
Richeldi, Luca
89f3b3b9-2dc9-4803-a190-3d4facabd8c2
O'Reilly, Katherine M.A.
6c323cd0-0c68-4913-9666-7e4f655b816f
Monk, Phillip
f0b35062-133d-4d96-8347-742d27a46fa6
Thurner, Philipp
8d4204ab-f003-4668-9fa2-39cf54bdd99a
Davies, Donna
7de8fdc7-3640-4e3a-aa91-d0e03f990c38