Upregulation of RGS2

A new mechanism for pirfenidone amelioration of pulmonary fibrosis

Yan Xie, Haihong Jiang, Qian Zhang, Suneet Mehrotra, Peter W. Abel, Myron L. Toews, Dennis W. Wolff, Stephen Rennard, Reynold A. Panettieri, Thomas B. Casale, Yaping Tu

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background: Pirfenidone was recently approved for treatment of idiopathic pulmonary fibrosis. However, the therapeutic dose of pirfenidone is very high, causing side effects that limit its doses and therapeutic effectiveness. Understanding the molecular mechanisms of action of pirfenidone could improve its safety and efficacy. Because activated fibroblasts are critical effector cells associated with the progression of fibrosis, this study investigated the genes that change expression rapidly in response to pirfenidone treatment of pulmonary fibroblasts and explored their contributions to the anti-fibrotic effects of pirfenidone. Methods: We used the GeneChip microarray to screen for genes that were rapidly up-regulated upon exposure of human lung fibroblast cells to pirfenidone, with confirmation for specific genes by real-time PCR and western blots. Biochemical and functional analyses were used to establish their anti-fibrotic effects in cellular and animal models of pulmonary fibrosis. Results: We identified Regulator of G-protein Signaling 2 (RGS2) as an early pirfenidone-induced gene. Treatment with pirfenidone significantly increased RGS2 mRNA and protein expression in both a human fetal lung fibroblast cell line and primary pulmonary fibroblasts isolated from patients without or with idiopathic pulmonary fibrosis. Pirfenidone treatment or direct overexpression of recombinant RGS2 in human lung fibroblasts inhibited the profibrotic effects of thrombin, whereas loss of RGS2 exacerbated bleomycin-induced pulmonary fibrosis and mortality in mice. Pirfenidone treatment reduced bleomycin-induced pulmonary fibrosis in wild-type but not RGS2 knockout mice. Conclusions: Endogenous RGS2 exhibits anti-fibrotic functions. Upregulated RGS2 contributes significantly to the anti-fibrotic effects of pirfenidone.

Original languageEnglish (US)
Article number103
JournalRespiratory Research
Volume17
Issue number1
DOIs
StatePublished - Aug 22 2016

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GTP-Binding Protein Regulators
Pulmonary Fibrosis
Up-Regulation
Fibroblasts
Lung
Idiopathic Pulmonary Fibrosis
Bleomycin
Therapeutics
pirfenidone
RGS Proteins
Genes
Knockout Mice
Thrombin
Real-Time Polymerase Chain Reaction

All Science Journal Classification (ASJC) codes

  • Pulmonary and Respiratory Medicine

Cite this

Upregulation of RGS2 : A new mechanism for pirfenidone amelioration of pulmonary fibrosis. / Xie, Yan; Jiang, Haihong; Zhang, Qian; Mehrotra, Suneet; Abel, Peter W.; Toews, Myron L.; Wolff, Dennis W.; Rennard, Stephen; Panettieri, Reynold A.; Casale, Thomas B.; Tu, Yaping.

In: Respiratory Research, Vol. 17, No. 1, 103, 22.08.2016.

Research output: Contribution to journalArticle

Xie, Y, Jiang, H, Zhang, Q, Mehrotra, S, Abel, PW, Toews, ML, Wolff, DW, Rennard, S, Panettieri, RA, Casale, TB & Tu, Y 2016, 'Upregulation of RGS2: A new mechanism for pirfenidone amelioration of pulmonary fibrosis', Respiratory Research, vol. 17, no. 1, 103. https://doi.org/10.1186/s12931-016-0418-4
Xie, Yan ; Jiang, Haihong ; Zhang, Qian ; Mehrotra, Suneet ; Abel, Peter W. ; Toews, Myron L. ; Wolff, Dennis W. ; Rennard, Stephen ; Panettieri, Reynold A. ; Casale, Thomas B. ; Tu, Yaping. / Upregulation of RGS2 : A new mechanism for pirfenidone amelioration of pulmonary fibrosis. In: Respiratory Research. 2016 ; Vol. 17, No. 1.
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AU - Abel, Peter W.

AU - Toews, Myron L.

AU - Wolff, Dennis W.

AU - Rennard, Stephen

AU - Panettieri, Reynold A.

AU - Casale, Thomas B.

AU - Tu, Yaping

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N2 - Background: Pirfenidone was recently approved for treatment of idiopathic pulmonary fibrosis. However, the therapeutic dose of pirfenidone is very high, causing side effects that limit its doses and therapeutic effectiveness. Understanding the molecular mechanisms of action of pirfenidone could improve its safety and efficacy. Because activated fibroblasts are critical effector cells associated with the progression of fibrosis, this study investigated the genes that change expression rapidly in response to pirfenidone treatment of pulmonary fibroblasts and explored their contributions to the anti-fibrotic effects of pirfenidone. Methods: We used the GeneChip microarray to screen for genes that were rapidly up-regulated upon exposure of human lung fibroblast cells to pirfenidone, with confirmation for specific genes by real-time PCR and western blots. Biochemical and functional analyses were used to establish their anti-fibrotic effects in cellular and animal models of pulmonary fibrosis. Results: We identified Regulator of G-protein Signaling 2 (RGS2) as an early pirfenidone-induced gene. Treatment with pirfenidone significantly increased RGS2 mRNA and protein expression in both a human fetal lung fibroblast cell line and primary pulmonary fibroblasts isolated from patients without or with idiopathic pulmonary fibrosis. Pirfenidone treatment or direct overexpression of recombinant RGS2 in human lung fibroblasts inhibited the profibrotic effects of thrombin, whereas loss of RGS2 exacerbated bleomycin-induced pulmonary fibrosis and mortality in mice. Pirfenidone treatment reduced bleomycin-induced pulmonary fibrosis in wild-type but not RGS2 knockout mice. Conclusions: Endogenous RGS2 exhibits anti-fibrotic functions. Upregulated RGS2 contributes significantly to the anti-fibrotic effects of pirfenidone.

AB - Background: Pirfenidone was recently approved for treatment of idiopathic pulmonary fibrosis. However, the therapeutic dose of pirfenidone is very high, causing side effects that limit its doses and therapeutic effectiveness. Understanding the molecular mechanisms of action of pirfenidone could improve its safety and efficacy. Because activated fibroblasts are critical effector cells associated with the progression of fibrosis, this study investigated the genes that change expression rapidly in response to pirfenidone treatment of pulmonary fibroblasts and explored their contributions to the anti-fibrotic effects of pirfenidone. Methods: We used the GeneChip microarray to screen for genes that were rapidly up-regulated upon exposure of human lung fibroblast cells to pirfenidone, with confirmation for specific genes by real-time PCR and western blots. Biochemical and functional analyses were used to establish their anti-fibrotic effects in cellular and animal models of pulmonary fibrosis. Results: We identified Regulator of G-protein Signaling 2 (RGS2) as an early pirfenidone-induced gene. Treatment with pirfenidone significantly increased RGS2 mRNA and protein expression in both a human fetal lung fibroblast cell line and primary pulmonary fibroblasts isolated from patients without or with idiopathic pulmonary fibrosis. Pirfenidone treatment or direct overexpression of recombinant RGS2 in human lung fibroblasts inhibited the profibrotic effects of thrombin, whereas loss of RGS2 exacerbated bleomycin-induced pulmonary fibrosis and mortality in mice. Pirfenidone treatment reduced bleomycin-induced pulmonary fibrosis in wild-type but not RGS2 knockout mice. Conclusions: Endogenous RGS2 exhibits anti-fibrotic functions. Upregulated RGS2 contributes significantly to the anti-fibrotic effects of pirfenidone.

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