Small interfering RNAs (siRNAs) targeting TGF-beta1 mRNA suppress asbestos-induced expression of TGF-beta1 and CTGF in fibroblasts.

Abstract

Interstitial lung disease (ILD) afflicts millions of people worldwide. ILD can be caused by a number of agents, including inhaled asbestos, and may ultimately result in respiratory failure and death. Currently, there are no effective treatments for ILD. Transforming growth factor-beta1 (TGF-beta1) is thought to play an important role in the development of pulmonary fibrosis, and asbestos has been shown to induce TGF-beta1 expression in a murine model of ILD. To better define the role of TGF-beta1 in ILD, we developed several small interfering RNAs (siRNAs) that target TGF-beta1 mRNA for degradation. To assess the efficacy of each siRNA in reducing asbestos-induced TGF-beta1 expression, Swiss 3T3 fibroblasts were transfected with TGF-beta1 siRNAs and then treated with chrysotile asbestos for 48 h. Two independent siRNAs targeting TGF-beta1 mRNA knocked-down asbestos-induced expression of TGF-beta1 mRNA by 72-89% and protein by 70-84%. Interestingly, siRNA knockdown of TGF-beta1 also reduced asbestos-induced expression of connective tissue growth factor (CTGF). CTGF can be upregulated by TGF-beta1 and appears to play an important role in the development of pulmonary fibrosis. These results suggest that siRNAs could be effective in preventing or possibly arresting the progression of pulmonary fibrosis. Studies are underway in vivo to test this postulate.