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


CONCLUSIONS
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.
Srivastava
Mrigank
M
Department of Pulmonary Medicine, Laboratory for Experimental Lung Research, Hannover School of Medicine, Hannover, Germany. srivastava.mrigank@mh-hannover.de
Steinwede
Kathrin
K
Kiviranta
Riku
R
Morko
Jukka
J
Hoymann
Heinz-Gerd
HG
Länger
Florian
F
Buhling
Frank
F
Welte
Tobias
T
Maus
Ulrich A
UA
D000818:Animals; D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D056657:Cathepsin K; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism*; D004195:Disease Models, Animal; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology
D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D003094:Collagen; D002403:Cathepsins; D056657:Cathepsin K; C534132:Ctsk protein, mouse