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

: Srivastava, M.; Steinwede, K.; Kiviranta, R.; Morko, J.; Hoymann, H.-G.; Länger, F.; Buhling, F.; Welte, T.; Maus, U.A.

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Respiratory research. Online journal 9 (2008), No.1, pp.54
ISSN: 1465-993X
ISSN: 1465-9921
Journal Article, Electronic Publication
Fraunhofer ITEM ()
Bbleomycin; Collagen; fibrosis; fibrosis model; lung resistance; pulmonary function; mouse

BACKGROUND: Lung fibrosis is a devastating pulmonary disorder characterized by alveolar epithelial injury, deposition of extracellular matrix 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 transgenic (cath K tg) mice on a FVB/N background were treated with bleomycin (i.t.) for 1, 2, 3 and 4 weeks and progress in fibrosis was monitored at different levels by estimating lung collagen content, lung histopathology, leukocytic infiltrates and lung function. Additionally, changes in cathepsin K were observed by immunohistochemical analysis of the lung, real time RT-PCR and western blotting. RESULTS: Cathepsin K protein levels were strongly increased in alveolar macrophages and lung parenchymal tissue but not type II alveolar epithelial cells of mock-treated cathepsin K transgenic (cath K tg) mice but not wild-type mice and further increased particularly in cath K tg and wild-type mice in response to bleomycin challenge. Moreover, cath K tg mice responded with a lower collagen deposition in their lungs post bleomycin challenge, which was accompanied by a significantly decreased lung resistance (RL) when compared to bleomycin-treated wild-type mice. In addition, cath K tg mice developed fewer pulmonary fibrotic lesions than wild-type mice during the observation period of four weeks, a process 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.