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

Akiko Mammoto, Tadanori Mammoto, Mathumai Kanapathipillai, Chong Wing Yung, Elisabeth Jiang, Amanda Jiang, Kristopher Lofgren, Elaine P.S. Gee and Donald E. Ingber ()
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Akiko Mammoto: Vascular Biology Program, Children's Hospital and Harvard Medical School
Tadanori Mammoto: Vascular Biology Program, Children's Hospital and Harvard Medical School
Mathumai Kanapathipillai: Vascular Biology Program, Children's Hospital and Harvard Medical School
Chong Wing Yung: Vascular Biology Program, Children's Hospital and Harvard Medical School
Elisabeth Jiang: Vascular Biology Program, Children's Hospital and Harvard Medical School
Amanda Jiang: Vascular Biology Program, Children's Hospital and Harvard Medical School
Kristopher Lofgren: Vascular Biology Program, Children's Hospital and Harvard Medical School
Elaine P.S. Gee: Vascular Biology Program, Children's Hospital and Harvard Medical School
Donald E. Ingber: Vascular Biology Program, Children's Hospital and Harvard Medical School

Nature Communications, 2013, vol. 4, issue 1, 1-10

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms2774

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