Rapamycin Prevents Transforming Growth Factor-α–Induced Pulmonary Fibrosis

Korfhagen, Thomas R.; Cras, Timothy D. Le; Davidson, Cynthia; Schmidt, Stephanie; Ikegami, Machiko; Whitsett, Jeffrey A.; Hardie, William D.

doi:10.1165/rcmb.2008-0377oc

Cited by 94 publications

(87 citation statements)

References 37 publications

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“…Our study also showed that RAPA treatment could not block the trend of body weight loss and may even worsen it. This result was inconsistent with some previous studies (Korfhagen et al, 2009;Madala et al, 2011). We speculate that this discrepancy may be caused mainly by the different animal models established: TGF-α-and bleomycin-induced pulmonary fibrosis might have less severe lung damage and a lower incidence of multiple organ dysfunction syndrome (MODS).…”

Section: Discussioncontrasting

confidence: 67%

“…In rat models of liver fibrosis, low-dose RAPA treatment can reduce collagen deposition (Neef et al, 2006). More recently, several studies have revealed that RAPA can prevent the progression of bleomycin-or transforming growth factor-α (TGF-α)-induced pulmonary fibrosis (Korfhagen et al, 2009;Madala et al, 2011). As a result, we hypothesized that RAPA treatment may be an effective therapy to ameliorate PQ-induced pulmonary fibrosis.…”

Section: Introductionmentioning

confidence: 99%

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Effects of rapamycin against paraquat-induced pulmonary fibrosis in mice

Shao

Luo

et al. 2015

J. Zhejiang Univ. Sci. B

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Background and aims: Ingestion of paraquat (PQ), a widely used herbicide, can cause severe toxicity in humans, leading to a poor survival rate and prognosis. One of the main causes of death by PQ is PQ-induced pulmonary fibrosis, for which there are no effective therapies. The aim of this study was to evaluate the effects of rapamycin (RAPA) on inhibiting PQ-induced pulmonary fibrosis in mice and to explore its possible mechanisms. Methods: Male C57BL/6J mice were exposed to either saline (control group) or PQ (10 mg/kg body weight, intraperitoneally; test group). The test group was divided into four subgroups: a PQ group (PQ-exposed, non-treated), a PQ+RAPA group (PQ-exposed, treated with RAPA at 1 mg/kg intragastrically), a PQ+MP group (PQ-exposed, treated with methylprednisolone (MP) at 30 mg/kg intraperitoneally), and a PQ+MP+RAPA group (PQ-exposed, treated with MP at 30 mg/kg intraperitoneally and with RAPA at 1 mg/kg intragastrically). The survival rate and body weight of all the mice were recorded every day. Three mice in each group were sacrificed at 14 d and the rest at 28 d after intoxication. Lung tissues were excised and stained with hematoxylin-eosin (H&E) and Masson's trichrome stain for histopathological analysis. The hydroxyproline (HYP) content in lung tissues was detected using an enzyme-linked immunosorbent assay (ELISA) kit. The expression of transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA) in lung tissues was detected by immunohistochemical staining and Western blotting. Results: A mice model of PQ-induced pulmonary fibrosis was established. Histological examination of lung tissues showed that RAPA treatment moderated the pathological changes of pulmonary fibrosis, including alveolar collapse and interstitial collagen deposition. HYP content in lung tissues increased soon after PQ intoxication but had decreased significantly by the 28th day after RAPA treatment. Immunohistochemical staining and Western blotting showed that RAPA treatment significantly down-regulated the enhanced levels of TGF-β1 and α-SMA in lung tissues caused by PQ exposure. However, RAPA treatment alone could not significantly ameliorate the lower survival rate and weight loss of treated mice. MP treatment enhanced the survival rate, but had no significant effects on attenuating PQ-induced pulmonary fibrosis or reducing the expression of TGF-β1 and α-SMA. Conclusions: This study demonstrates that RAPA treatment effectively suppresses PQ-induced alveolar collapse and collagen deposition in lung tissues through reducing the expression of TGF-β1 and α-SMA. Thus, RAPA has potential value in the treatment of PQ-induced pulmonary fibrosis.

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Section: Discussioncontrasting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Effects of rapamycin against paraquat-induced pulmonary fibrosis in mice

Shao

Luo

et al. 2015

J. Zhejiang Univ. Sci. B

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“…7,25 However, mTOR is universally expressed regardless of cell types, so rapamycin was gradually used in anti-cancer and anti-fibrotic therapies. 11,26,27 We used N-and F-HLFs to demonstrate that rapamycin potently exerts direct profibrotic activities by promoting CCN2 expression in a Smad-independent and PI3K-dependent manner. In our sister paper, 28 we also showed rapamycin potentiates CCN2 expression in alveolar epithelial cells by PI3K pathway.…”

Section: Discussionmentioning

confidence: 99%

“…8 In addition to immunosuppressive effects, rapamycin also showed to be effective in preventing fibrogenesis in animal models. [11][12][13] However, the exact molecular mechanisms underlying the effects of rapamycin on preventing organ fibrosis remain poorly understood. Furthermore, the antifibrotic effect of rapamycin was seriously challenged by other studies, which showed that rapamycin had no significant improvements on fibrotic process.…”

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confidence: 99%

Rapamycin increases CCN2 expression of lung fibroblasts via phosphoinositide 3-kinase

Dai

Geng

et al. 2015

Laboratory Investigation

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Excessive production of connective tissue growth factor (CTGF, CCN2) and increased motor ability of the activated fibroblast phenotype contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, molecules and signal pathways regulating CCN2 expression and migration of lung fibroblasts are still elusive. We hypothesize that rapamycin, via binding and blocking mammalian target of rapamycin (mTOR) complex (mTORC), affects CCN2 expression and migration of lung fibroblasts in vitro. Primary normal and fibrotic human lung fibroblasts were isolated from lung tissues of three patients with primary spontaneous pneumothorax and three with IPF. Cells were incubated with regular medium, or medium containing rapamycin, human recombinant transforming growth factor (TGF)-β1, or both. CCN2 and tissue inhibitor of metalloproteinase (TIMP)-1 expression in cells or supernatant was detected. Wound healing and migration assay was used to measure the migratory potential. TGF-β type I receptor (TβRI)/Smad inhibitor, SB431542 and phosphoinositide 3-kinase (PI3K) inhibitor, LY294002 were used to determine rapamycin's mechanism of action. We demonstrated that rapamycin amplified basal or TGF-β1-induced CCN2 mRNA and protein expression in normal or fibrotic fibroblasts by Smad-independent but PI3K-dependent pathway. Additionally, rapamycin also enhanced TIMP-1 expression as indicated by ELISA. However, wound healing and migrating assay showed rapamycin did not affect the mobility of fibroblasts. Collectively, this study implies a significant fibrogenic induction activity of rapamycin by activating AKT and inducing CCN2 expression in vitro and provides the possible mechanisms for the in vivo findings which previously showed no antifibrotic effect of rapamycin on lung fibrosis.

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“…Artesunate treatment resulted in decreased collagen-IV protein in lung tissues and decreased collagen-IV mRNA in primary lung fibroblast cells, indicating that the anti-fibrotic effect of artesunate might be involve, at least partially, downregulation collagen-IV expression. MMP-2 and MMP-9 are well-known owing to their ability to degrade collagen-IV, and their increased activity leads to various pulmonary diseases including pulmonary fibrosis (Krämer et al, 2008;Bridle et al, 2009;Korfhagen et al, 2009). MMP-2 and MMP-9 play an important role in the inefficient remodeling of damaged lung tissue (Checa et al, 2008;Yamashita et al, 2011;Song et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Artesunate modulates expression of matrix metalloproteinases and their inhibitors as well as collagen-IV to attenuate pulmonary fibrosis in rats

Wang¹,

Huang²,

Mo³

et al. 2016

Genet. Mol. Res.

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ABSTRACT. The aim of this study was to determine the effect of artesunate on extracellular matrix (ECM) accumulation and the expression of collagen-IV, matrix metalloproteinase (MMP), and tissue inhibitor of matrix metalloproteinase (TIMP) to understand the pharmacological role of artesunate in pulmonary fibrosis. Eighty Sprague-Dawley rats were randomly assigned to four groups that were administered saline alone, bleomycin (BLM) alone, BLM + artesunate, or artesunate alone for 28 days. Lung tissues from 10 rats in each group were used to obtain lung fibroblast (LF) primary cells, and the rest were used to analyze protein expression. The mRNA expression of collagen-IV, MMP-2, MMP-9, TIMP-1, and TIMP-2 in lung fibroblasts was detected by real-time quantitative reverse transcriptase polymerase chain reaction. The protein levels of collagen-IV, MMP-2, MMP-9, TIMP-1, and TIMP-2 protein in lung tissues were analyzed by western blotting. Artesunate treatment alleviated alveolitis and pulmonary fibrosis induced by bleomycin in rats, as indicated by a decreased lung coefficient and improvement of lung tissue morphology. Artesunate treatment also led to decreased collagen-IV protein levels, which might be a result of its downregulated expression and increased MMP-2 and MMP-9 protein and mRNA levels. Increased TIMP-1 and TIMP-2 protein and mRNA levels were detected after artesunate treatment in lung tissues and primary lung fibroblast cells and may contribute to enhanced activity of MMP-2 and -9. These findings suggested that artesunate attenuates alveolitis and pulmonary fibrosis by regulating expression of collagen-IV, TIMP-1 and 2, as well as MMP-2 and -9, to reduce ECM accumulation.

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Rapamycin Prevents Transforming Growth Factor-α–Induced Pulmonary Fibrosis

Cited by 94 publications

References 37 publications

Effects of rapamycin against paraquat-induced pulmonary fibrosis in mice

Effects of rapamycin against paraquat-induced pulmonary fibrosis in mice

Rapamycin increases CCN2 expression of lung fibroblasts via phosphoinositide 3-kinase

Artesunate modulates expression of matrix metalloproteinases and their inhibitors as well as collagen-IV to attenuate pulmonary fibrosis in rats

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