title: Attenuation of lipopolysaccharide-induced lung vascular stiffening by lipoxin reduces lung inflammation.
abstract: Reversible changes in lung microstructure accompany lung inflammation, although alterations in tissue micromechanics and their impact on inflammation remain unknown. This study investigated changes in extracellular matrix (ECM) remodeling and tissue stiffness in a model of LPS-induced inflammation and examined the role of lipoxin analog 15-epi-lipoxin A4 (eLXA4) in the reduction of stiffness-dependent exacerbation of the inflammatory process. Atomic force microscopy measurements of live lung slices were used to directly measure local tissue stiffness changes induced by intratracheal injection of LPS. Effects of LPS on ECM properties and inflammatory response were evaluated in an animal model of LPS-induced lung injury, live lung tissue slices, and pulmonary endothelial cell (EC) culture. In vivo, LPS increased perivascular stiffness in lung slices monitored by atomic force microscopy and stimulated expression of ECM proteins fibronectin, collagen I, and ECM crosslinker enzyme, lysyl oxidase. Increased stiffness and ECM remodeling escalated LPS-induced VCAM1 and ICAM1 expression and IL-8 production by lung ECs. Stiffness-dependent exacerbation of inflammatory signaling was confirmed in pulmonary ECs grown on substrates with high and low stiffness. eLXA4 inhibited LPS-increased stiffness in lung cross sections, attenuated stiffness-dependent enhancement of EC inflammatory activation, and restored lung compliance in vivo. This study shows that increased local vascular stiffness exacerbates lung inflammation. Attenuation of local stiffening of lung vasculature represents a novel mechanism of lipoxin antiinflammatory action.
authors.affiliation: 1 Lung Injury Center, Section of Pulmonary and Critical Care Medicine, Department of Medicine, and.
authors.forename: Fanyong
authors.initials: F
authors.lastname: Meng
authors.forename: Isa
authors.initials: I
authors.lastname: Mambetsariev
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Tian
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Beckham
authors.forename: Angelo
authors.initials: A
authors.lastname: Meliton
authors.forename: Alan
authors.initials: A
authors.lastname: Leff
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Gardel
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Allen
authors.forename: Konstantin G
authors.initials: KG
authors.lastname: Birukov
authors.forename: Anna A
authors.initials: AA
authors.lastname: Birukova
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D016209:Interleukin-8 / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D044045:Lipoxins / Q000627:therapeutic use*; D055370:Lung Injury / Q000139:chemically induced; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016209:Interleukin-8; D008070:Lipopolysaccharides; D044045:Lipoxins; C040527:lipoxin A4
keywords: endothelium; lipoxin; lung inflammation; stiffness; vascular leak