Research

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

Mrigank Srivastava¹ , Kathrin Steinwede¹ , Riku Kiviranta² , Jukka Morko² , Heinz-Gerd Hoymann³ , Florian Länger⁴ , Frank Buhling⁵ , Tobias Welte¹ and Ulrich A Maus¹

¹Department of Pulmonary Medicine, Laboratory for Experimental Lung Research, Hannover School of Medicine, Hannover, Germany

²Department of Medical Biochemistry and Molecular Biology, University of Turku, Turku, Finland

³Division of Pre-clinical Airway Research, Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany

⁴Department of Pathology, Hannover School of Medicine, Hannover, Germany

⁵Institute of Clinical Chemistry and Laboratory Diagnostics, Carl-Thiem-Klinikum, Cottbus, Germany

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Respiratory Research 2008, 9:54doi:10.1186/1465-9921-9-54

Published:	18 July 2008

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 (R_L) 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.