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OP0216 Resveratrol Ameliorates Pulmonary Fibrosis and Inhibits Human Lung Fibroblasts Activation VIA Modulating SIRT1 and GLI1 Signaling
  1. L. Haobo,
  2. Z. Guangfeng,
  3. Z. Xiao
  1. Rheumatology, Guangdong General Hospital, Guangzhou City, China

Abstract

Background Connective tissue disease associated pulmonary fibrosis is a severe clinical application with poor prognosis, myofibroblasts which mostly evolved from lung fibroblasts plays a key role in the pathogenesis of pulmonary fibrosis. Resveratrol (RV) is a natural phytoalexin exhibits multiple pharmacological properties in treating tumors, atherosclerosis and inflammation. Recently some research have revealed that RV can also inhibit visceral fibrosis such as kidney, liver and lung, but the underlying mechanism through which RV inhibits pulmonary is not yet fully understood, and whether the pathogenesis of pulmonary fibrosis in human body share the same signaling pathway as illuminated in animal model remains to be confirmed.

Objectives The objective of this study is to illuminate the role of RV in regulating migration, invasion and proliferation of human lung fibroblast cells and the therapeutic effects of RV on bleomycin (BM)-mouse model of lung fibrosis. Besides, we aim to investigate SIRT1 and Gli1 signaling in connective tissue disease associated pulmonary fibrosis patients.

Methods Cultured human lung fibroblasts (HLFs) were isolated from normal adjacent tissues from patients with lung cancer. Lung tissues of CTD-ILD patients were obtained by CT guided percutaneous transthoracic biopsy. Migration and invastion of HLFs in vitro were measured by chamber and Matrigel Invasion Chamber respectively, apotosis and proliferation of HLFs were measured by MTT and Brdu experiment. 6-8 week-old male C57BL/6 mice were treated with BM by bronchial arterial infusion to establishing animal model. Immunofluorescence, immunohistochemistry, western blotting and PCR were used to detect SIRT1, Gli1, alpha-SMA and E-cadherin expression.

Results We demonstrate that RV can inhibit the EMT of HLFs through suppress the change of cell function of HLFs triggered by the TGF-beta. RV also diminished the formation of myofibroblast and accumulation of collagen in BM-mouse model of lung fibrosis. By detecting the Lung biopsy of patients with pulmonary fibrosis, we found out there is a dramatically upregulation of the transcription factor Gli1 while downregulation of SIRT1 expression in connective-tissue associated PF patients compared with control group, as well as in vivo model. BM-mouse model of lung fibrosis treated with RV can reverse these signaling expression. We also confirm that resveratrol preserved E-cadherin by inhibit the Gli1 and upregulated SIRT1 in HLFs when TGF-beta was presented.

Conclusions In conclusion, these studies support that RV can inhibit EMT of HLFs through regulating Gli1 and SIRT1, which are two vital pathways in the pathogenesis of lung fibrosis, and suggest that resveratrol may have a novel therapeutic effect for pulmonary fibrosis disease.

References

  1. Fischer A, du Bois R. Interstitial lung disease in connective tissue disorders. Lancet 2012 Aug 18;380(9842):689-98

  2. Athol U. Wells & Christopher P. Denton Interstitial lung disease in connective tissue disease mechanisms and management. Nat Rev Rheumatol. 2014 Dec;10(12):728-39

  3. Zerr P, Palumbo-Zerr K, et al. Sirt1 regulates canonical TGF-β signalling to control fibroblast activation and tissue fibrosis. Ann Rheum Dis 2014 Sep 1

  4. Zhou D, Li Y, et al. Sonic hedgehog is a novel tubule-derived growth factor for interstitial fibroblasts after kidney injuryJ Am Soc Nephrol. 2014 Oct;25(10):2187-200

Disclosure of Interest None declared

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