Background/Purpose:  Pulmonary fibrosis is a severe complication of systemic sclerosis (SSc). Changes in the expression levels of sirtuins (SIRTs), a family of NAD⁺-dependent histone deacetylases, have been reported recently in patients with SSc and other fibrotic diseases, implying a possible pathophysiologic role. Out of 7 known human SIRTs, SIRT1 has received the most attention. We have comparatively assessed the mRNA and protein expression of all SIRTs in primary lung fibroblasts from scleroderma patients with pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), and from healthy controls, and begun addressing mechanistic implications of the observed differences.

Methods:  mRNA levels of SIRT1-7 were measured by RT-qPCR in lung tissue and fibroblasts from scleroderma patients with lung fibrosis and patients with IPF, as well as from healthy controls; protein levels were measured by western blotting. Intracellular delivery of SIRT7-encoding plasmid constructs and SIRT7-inhibiting siRNA to cultured adult normal human lung fibroblasts was performed by electroporation. The effects of SIRT7 on mRNA of collagen chains COL1A1, COL1A2, and COL3A1 and on protein levels of type I collagen, with and without stimulation with recombinant TGF-β, were assessed.

Results:  mRNA and protein levels of all SIRTs tended to be lower in lung tissues and fibroblasts from patients with fibrosis compared to controls, but the levels of SIRT7 mRNA and protein in pulmonary fibroblasts were significantly lower, particularly in scleroderma (p<0.001 for SIRT7 mRNA and p=0.019 for SIRT7 protein). SIRT7 overexpression in fibroblast cultures inhibited basal and TGF-β-induced levels of collagen, reducing COL1A1 mRNA levels by 5 to 10 fold, COL1A2 mRNA by 2 to 3 fold, and COL3A1 by 3 to 5 fold; the levels of collagen protein were reduced by ~3 fold. SIRT7 silencing increased collagen protein by ~2 fold.

Conclusion:  Pulmonary fibrosis is characterized by lower levels of sirtuins, with a particularly notable decrease in SIRT7 in scleroderma. Overexpression of SIRT7 decreases collagen mRNA and protein levels in cultured lung fibroblasts and attenuates TGF-β-induced increases in collagen. These findings identify SIRT7 as a pathophysiologic contributor to lung fibrosis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/decreased-expression-of-sirtuin-7-by-lung-fibroblasts-from-patients-with-scleroderma-contributes-to-elevated-collagen-production/