Control of lung vascular permeability and endotoxin-induced pulmonary oedema by changes in extracellular matrix mechanics.

Abstract:

:Increased vascular permeability contributes to many diseases, including acute respiratory distress syndrome, cancer and inflammation. Most past work on vascular barrier function has focused on soluble regulators, such as tumour-necrosis factor-α. Here we show that lung vascular permeability is controlled mechanically by changes in extracellular matrix structure. Our studies reveal that pulmonary vascular leakage can be increased by altering extracellular matrix compliance in vitro and by manipulating lysyl oxidase-mediated collagen crosslinking in vivo. Either decreasing or increasing extracellular matrix stiffness relative to normal levels disrupts junctional integrity and increases vascular leakage. Importantly, endotoxin-induced increases of vascular permeability are accompanied by concomitant increases in extracellular matrix rigidity and lysyl oxidase activity, which can be prevented by inhibiting lysyl oxidase activity. The identification of lysyl oxidase and the extracellular matrix as critical regulators of lung vascular leakage might lead to the development of new therapeutic approaches for the treatment of pulmonary oedema and other diseases caused by abnormal vascular permeability.

journal_name

Nat Commun

journal_title

Nature communications

authors

Mammoto A,Mammoto T,Kanapathipillai M,Wing Yung C,Jiang E,Jiang A,Lofgren K,Gee EP,Ingber DE

doi

10.1038/ncomms2774

subject

Has Abstract

pub_date

2013-01-01 00:00:00

pages

1759

issn

2041-1723

pii

ncomms2774

journal_volume

4

pub_type

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