title: Administration of a specific inhibitor of neutrophil elastase attenuates pulmonary fibrosis after acute lung injury in mice.
abstract: Excess production of neutrophil elastase contributes to the pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). However, the role of neutrophil elastase in the repair process following ALI/ARDS is not well understood. The objective of this study was to evaluate the effect of neutrophil elastase on the process of tissue repair after acute lung injury in mice. C57BL/6 mice were exposed to sublethal irradiation followed by intranasal instillation of lipopolysaccharide (LPS) to generate a model of impaired lung repair. The authors assessed the histopathology, lung mechanics, and total lung collagen content 7 days after irradiation and/or LPS-induced injury with daily administration of a neutrophil elastase inhibitor. The number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) was also evaluated. In addition, the concentration of activated transforming growth factor (TGF)-β1 in the BALF and the expression of phospho-SMAD2/3 were investigated. Irradiated and LPS-treated mice developed pulmonary fibrosis after injury. The neutrophil elastase inhibitor significantly decreased the collagen deposition in lung parenchyma and improved the static lung compliance of injured lungs. Administration of the neutrophil elastase inhibitor also decreased the accumulation of neutrophils in the BALF, TGF-β1 activation, and expression of phospho-SMAD2/3. The authors conclude that inhibiting neutrophil elastase protects against the development of lung fibrosis after acute injury. In addition, these data suggest that this neutrophil elastase inhibitor has therapeutic potential for the fibroproliferative phase of ALI/ARDS.
authors.affiliation: Department of Advanced Preventive Medicine for Infectious Disease, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Fujino
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kubo
authors.forename: Tomoko
authors.initials: T
authors.lastname: Suzuki
authors.forename: Mei
authors.initials: M
authors.lastname: He
authors.forename: Takaya
authors.initials: T
authors.lastname: Suzuki
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yamada
authors.forename: Toru
authors.initials: T
authors.lastname: Takahashi
authors.forename: Chiharu
authors.initials: C
authors.lastname: Ota
authors.forename: Mutsuo
authors.initials: M
authors.lastname: Yamaya
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012128:Respiratory Distress Syndrome / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D015842:Serine Proteinase Inhibitors; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D013449:Sulfonamides; D053773:Transforming Growth Factor beta1; D003094:Collagen; C069195:sivelestat; D019272:Leukocyte Elastase; D005998:Glycine