title: 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.
authors.affiliation: Vascular Biology Program, Departments of Pathology & Surgery, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Akiko
authors.initials: A
authors.lastname: Mammoto
authors.forename: Tadanori
authors.initials: T
authors.lastname: Mammoto
authors.forename: Mathumai
authors.initials: M
authors.lastname: Kanapathipillai
authors.forename: Chong
authors.initials: C
authors.lastname: Wing Yung
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Jiang
authors.forename: Amanda
authors.initials: A
authors.lastname: Jiang
authors.forename: Kristopher
authors.initials: K
authors.lastname: Lofgren
authors.forename: Elaine P S
authors.initials: EP
authors.lastname: Gee
authors.forename: Donald E
authors.initials: DE
authors.lastname: Ingber
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D004195:Disease Models, Animal; D004548:Elasticity; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D004731:Endotoxins; D005109:Extracellular Matrix / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism / Q000648:ultrastructure; D008168:Lung / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology* / Q000648:ultrastructure; D051379:Mice; D008249:Protein-Lysine 6-Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D011654:Pulmonary Edema / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology*; D012128:Respiratory Distress Syndrome / Q000150:complications / Q000503:physiopathology
chemical_list: D004731:Endotoxins; D008249:Protein-Lysine 6-Oxidase