Overexpression of cathepsin K during silica-induced lung fibrosis and control by TGF-beta.
BACKGROUND
Lung fibrosis is characterized by tissue remodeling resulting from an imbalance between synthesis and degradation of extracellular organic matrices. To examine whether cathepsin(s) (Cat) are important in the development of pulmonary fibrosis, we assessed the expression of four Cat known for their collagenolytic activity in a model of silica-induced lung fibrosis.


METHODS
Different strains of mice were transorally instilled with 2.5 mg crystalline silica or other particles. Cat expression (Cat K, S, L and B) was quantified in lung tissue and isolated pulmonary cells by quantitative RT-PCR. In vitro, we assessed the effect of different cytokines, involved in lung inflammatory and fibrotic responses, on the expression of Cat K by alveolar macrophages and fibroblasts.


RESULTS
In lung tissue, Cat K transcript was the most strongly upregulated in response to silica, and this upregulation was intimately related to the fibrotic process. In mouse strains known for their differential response to silica, we showed that the level of Cat K expression following silica treatment was inversely related to the level of TGF-beta expression and the susceptibility of these strains to develop fibrosis. Pulmonary macrophages and fibroblasts were identified as Cat K overproducing cells in the lung of silicotic mice. In vitro, Cat K was downregulated in mouse and human lung fibroblasts by the profibrotic growth factor TGF-beta1.


CONCLUSIONS
Altogether, these data suggest that while Cat K may contribute to control lung fibrosis, TGF-beta appears to limit its overexpression in response to silica particles.
van den Brûle
Sybille
S
Université Catholique de Louvain, Clos Chapelle-aux-Champs, 30.54, 1200 Brussels, Brussels, Belgium. Sybille.VandenBrule@toxi.ucl.ac.be
Misson
Pierre
P
Bühling
Frank
F
Lison
Dominique
D
Huaux
François
F
D000818:Animals; D056657:Cathepsin K; D002403:Cathepsins / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000378:metabolism*; D012822:Silicon Dioxide; D012829:Silicosis / Q000209:etiology / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation
C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D012822:Silicon Dioxide; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C534132:Ctsk protein, mouse