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Published in: Respiratory Research 1/2008

Open Access 01-12-2008 | Research

Overexpression of cathepsin K in mice decreases collagen deposition and lung resistance in response to bleomycin-induced pulmonary fibrosis

Authors: Mrigank Srivastava, Kathrin Steinwede, Riku Kiviranta, Jukka Morko, Heinz-Gerd Hoymann, Florian Länger, Frank Buhling, Tobias Welte, Ulrich A Maus

Published in: Respiratory Research | Issue 1/2008

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Abstract

Background

Lung fibrosis is a devastating pulmonary disorder characterized by alveolar epithelial injury, extracellular matrix deposition and scar tissue formation. Due to its potent collagenolytic activity, cathepsin K, a lysosomal cysteine protease is an interesting target molecule with therapeutic potential to attenuate bleomycin-induced pulmonary fibrosis in mice. We here tested the hypothesis that over-expression of cathepsin K in the lungs of mice is protective in bleomycin-induced pulmonary fibrosis.

Methods

Wild-type and cathepsin K overexpressing (cathepsin K transgenic; cath K tg) mice were challenged intratracheally with bleomycin and sacrificed at 1, 2, 3 and 4 weeks post-treatment followed by determination of lung fibrosis by estimating lung collagen content, lung histopathology, leukocytic infiltrates and lung function. In addition, changes in cathepsin K protein levels in the lung were determined by immunohistochemistry, real time RT-PCR and western blotting.

Results

Cathepsin K protein levels were strongly increased in alveolar macrophages and lung parenchymal tissue of mock-treated cathepsin K transgenic (cath K tg) mice relative to wild-type mice and further increased particularly in cath K tg but also wild-type mice in response to bleomycin. Moreover, cath K tg mice responded with a lower collagen deposition in their lungs, which was accompanied by a significantly lower lung resistance (RL) compared to bleomycin-treated wild-type mice. In addition, cath K tg mice responded with a lower degree of lung fibrosis than wild-type mice, a process that was found to be independent of inflammatory leukocyte mobilization in response to bleomycin challenge.

Conclusion

Over-expression of cathepsin K reduced lung collagen deposition and improved lung function parameters in the lungs of transgenic mice, thereby providing at least partial protection against bleomycin-induced lung fibrosis.
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Metadata
Title
Overexpression of cathepsin K in mice decreases collagen deposition and lung resistance in response to bleomycin-induced pulmonary fibrosis
Authors
Mrigank Srivastava
Kathrin Steinwede
Riku Kiviranta
Jukka Morko
Heinz-Gerd Hoymann
Florian Länger
Frank Buhling
Tobias Welte
Ulrich A Maus
Publication date
01-12-2008
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2008
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/1465-9921-9-54

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