Inhibitory effects of pitavastatin on fibrogenic mediator production by human lung fibroblasts

Aims: Idiopathic pulmonary fibrosis continues to be a devastating clinical disorder for which there are few therapeutic options, and the pathogenesis of this disease remains largely unknown. Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in cholesterol biosynthesis, and they have been reported to exert pleiotropic effects on the cellular signaling involved in tissue inflammation and in organ fibrosis/remodeling. We examined the preventive effects of statins on fibrogenic mediator expression and production in normal human lung fibroblasts (NHLF). Main methods: NHLF were pretreated with 100 nM pitavastatin or medium alone (control), and were then stimulated with transforming growth factor-beta 1 (TGF-beta 1). mRNA expression and protein secretion of several mediators from cells were analyzed by real-time polymerase chain reaction, enzyme-linked immunosorbent assay or multiplex assay. Key findings: TGF-beta 1-induced expression or production of mediators, such as collagen-1, vascular endothelial growth factor and chemokine C-X-C motif ligand 8, in NHLF pretreated with pitavastatin was significantly suppressed with inhibition of Smad-3 phosphorylation, as compared to untreated controls. In addition, the inhibitory effects of pitavastatin were negated by addition of mevalonate. Significance: Pitavastatin appeared to inhibit TGF-beta 1-induced fibrogenic mediator production from lung fibroblasts via the mevalonic cascade. Although further evaluation of the signaling pathways for these phenomena is necessary, our results suggest the potential benefits of pitavastatin. (C) 2013 Elsevier Inc. All rights reserved.