Mice lacking neutrophil elastase are resistant to bleomycin-induced pulmonary fibrosis.
Neutrophil elastase is a serine protease stored in the azurophilic granules of leukocytes. It has been implicated in the pathology of several lung diseases and is generally presumed to contribute to the tissue destruction and extracellular matrix damage associated with these conditions. To delineate the role of neutrophil elastase in pulmonary inflammation and fibrosis, neutrophil elastase-null mice were intratracheally instilled with bleomycin. In neutrophil elastase-null mice, biochemical and morphological characteristics of pulmonary fibrosis were attenuated for at least 60 days after bleomycin administration despite a typical response to bleomycin as evidenced by assessment of indices of DNA and cell damage. Neutrophil burden of bleomycin-treated wild-type and neutrophil elastase-null mice was comparable, and marked neutrophilic alveolitis was manifest in bleomycin-treated neutrophil elastase-null mice. An absence of immunostaining for active transforming growth factor (TGF)-beta in lung tissue from bleomycin-treated neutrophil elastase-null mice suggested a defect in TGF-beta activation, which was confirmed by biochemical assessment of TGF-beta levels in bronchoalveolar lavage fluid and lung tissue. These data point to novel and unexpected fibrogenic consequences of neutrophil elastase activity in the inflamed lung.
Chua
Felix
F
Department of Medicine, Royal Free and University College Medical School, London United Kingdom.
Dunsmore
Sarah E
SE
Clingen
Peter H
PH
Mutsaers
Steven E
SE
Shapiro
Steven D
SD
Segal
Anthony W
AW
Roes
Jürgen
J
Laurent
Geoffrey J
GJ
D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D001992:Bronchoalveolar Lavage Fluid; D004249:DNA Damage / Q000187:drug effects; D004351:Drug Resistance / Q000235:genetics; D019272:Leukocyte Elastase / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism
D016212:Transforming Growth Factor beta; D001761:Bleomycin; D019272:Leukocyte Elastase