Statins inhibit matrix metalloproteinase release from human lung fibroblasts.
Pleiotropic effects of statins have been reported to include inhibition of matrix metalloproteinase (MMP) release from macrophages and endothelial cells. We evaluated whether statins would inhibit MMP release from human lung fibroblasts, which play a major role in remodelling processes. Monolayer and three-dimensional (3D) collagen gel cultures of fibroblasts were used. Cytokines (tumour necrosis factor-alpha and interleukin-1alpha) were used to induce MMP release and mRNA expression. Collagen degradation induced by cytokines and neutrophil elastase (NE) was evaluated by quantifying hydroxyproline. Atorvastatin inhibited MMP-1 and -3 release and mRNA expression in both culture systems. Similar results were obtained with simvastatin and fluvastatin. In 3D cultures where cytokines also stimulated MMP-9 release, atorvastatin also inhibited MMP-9 release. In 3D cultures, cytokines together with NE induced collagen degradation, which was also inhibited by atorvastatin. The effect of atorvastatin was reversed by mevalonate and geranylgeranyl-pyrophosphate but not by farnesyl-pyrophosphate. The current data suggest that statins may modulate remodelling processes mediated by fibroblasts by inhibiting MMP release.
University of Nebraska Medical Center, Omaha, NE 68198-5910, USA.
K
K
Kamio
X D
XD
Liu
H
H
Sugiura
S
S
Togo
S
S
Kawasaki
X
X
Wang
Y
Y
Ahn
C
C
Hogaboam
S I
SI
Rennard
D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020782:Matrix Metalloproteinases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology* / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012333:RNA, Messenger; D020782:Matrix Metalloproteinases