title: Antifibrotic effects of curcumin are associated with overexpression of cathepsins K and L in bleomycin treated mice and human fibroblasts.
abstract: BACKGROUND
  Lung fibrosis is characterized by fibroblast proliferation and the deposition of collagens. Curcumin, a polyphenol antioxidant from the spice tumeric, has been shown to effectively counteract fibroblast proliferation and reducing inflammation and fibrotic progression in animal models of bleomycin-induced lung injury. However, there is little mechanistic insight in the biological activity of curcumin. Here, we study the effects of curcumin on the expression and activity of cathepsins which have been implicated in the development of fibrotic lung diseases.
  
  
  METHODS
  We investigated the effects of curcumin administration to bleomycin stimulated C57BL/6 mice and human fetal lung fibroblasts (HFL-1) on the expression of cathepsins K and L which have been implicated in matrix degradation, TGF-β1 modulation, and apoptosis. Lung tissues were evaluated for their contents of cathepsins K and L, collagen, and TGF-β1. HFL-1 cells were used to investigate the effects of curcumin and cathepsin inhibition on cell proliferation, migration, apoptosis, and the expression of cathepsins K and L and TGF-β1.
  
  
  RESULTS
  Collagen deposition in lungs was decreased by 17-28% after curcumin treatment which was accompanied by increased expression levels of cathepsins L (25%-39%) and K (41%-76%) and a 30% decrease in TGF-β1 expression. Moreover, Tunel staining of lung tissue revealed a 33-41% increase in apoptotic cells after curcumin treatment. These in vivo data correlated well with data obtained from the human fibroblast line, HFL-1. Here, cathepsin K and L expression increased 190% and 240%, respectively, in the presence of curcumin and the expression of TGF-β1 decreased by 34%. Furthermore, curcumin significantly decreased cell proliferation and migration and increased the expression of surrogate markers of apoptosis. In contrast, these curcumin effects were partly reversed by a potent cathepsin inhibitor.
  
  
  CONCLUSIONS
  This study demonstrates that curcumin increases the expression of cathepsins K and L in lung which an effect on lung fibroblast cell behavior such as proliferation, migration and apoptosis rates and on the expression of TGF-β1 in mouse lung and HFL-1 cells. These results suggest that cathepsin-inducing drugs such as curcumin may be beneficial in the treatment of lung fibrosis.
authors: Department of Oral and Biological Science, Faculty of Dentistry, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
authors: Dongwei
authors: D
authors: Zhang
authors: Chuangfang
authors: C
authors: Huang
authors: Changfu
authors: C
authors: Yang
authors: Renzuo J
authors: RJ
authors: Liu
authors: Jifeng
authors: J
authors: Wang
authors: Jianzhao
authors: J
authors: Niu
authors: Dieter
authors: D
authors: Brömme
mesh_terms: D000818:Animals; D000933:Antifibrinolytic Agents / Q000494:pharmacology; D001761:Bleomycin; D056657:Cathepsin K / Q000378:metabolism*; D056668:Cathepsin L / Q000378:metabolism*; D002478:Cells, Cultured; D003474:Curcumin / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000378:metabolism* / Q000517:prevention & control; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000933:Antifibrinolytic Agents; D001761:Bleomycin; D056668:Cathepsin L; D056657:Cathepsin K; D003474:Curcumin