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Mice Lacking Neutrophil Elastase Are Resistant to Bleomycin-Induced Pulmonary Fibrosis

https://doi.org/10.2353/ajpath.2007.060352Get rights and content

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)-β in lung tissue from bleomycin-treated neutrophil elastase-null mice suggested a defect in TGF-β activation, which was confirmed by biochemical assessment of TGF-β 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.

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Supported by the Medical Research Council (project grant 9715800 to S.E.M, J.R., A.W.S., and G.J.L.), the Wellcome Trust (training fellowship for Medical and Dental Graduates grant 061554 to F.C., S.E.D., and G.J.L.; and Senior Research Fellowship in Basic Biomedical Sciences grant 047608 to J.R.), the University of London Central Research Fund (to S.E.D.), the British Lung Foundation (research scientist grant P00/4 to S.E.D.), and the American Lung Association (grant RG-029-N to S.E.D.).

F.C. and S.E.D. contributed equally to this study; J.R. and G.J.L. share senior authorship.

Supplemental material for this article can be found on http://ajp.amjpathol.org.

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