Suppression of plasminogen activator inhibitor-1 by RNA interference attenuates pulmonary fibrosis

Senoo, Tadashi; Hattori, Noboru; Tanimoto, Takuya; Furonaka, Makoto; Ishikawa, Nobuhisa; Fujitaka, Kazunori; Haruta, Yoshinori; Murai, Hiroshi; Yokoyama, Akihito; Kohno, Nobuoki

doi:10.1136/thx.2009.119974

Cited by 107 publications

(106 citation statements)

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“…Hu et al observed that hepatic fibrosis in rats could be ameliorated by downregulating the expression of PAI-1 [18] . Furthermore, Senoo et al reported that intranasal administration of PAI-1 siRNA attenuated the progression of pulmonary fibrosis [10] and therefore suggested that PAI-1 might be an important factor capable of accelerating lung fibrosis. The present study provided additional direct evidence to support this assumption by observing the expression of PAI-1 in the fibrotic pulmonary tissue of BLM-treated rats.…”

Section: Discussionmentioning

confidence: 99%

“…However, it remains unclear whether silencing PAI-1 expression could ameliorate lung fibrosis. In 2010, Senoo et al reported that PAI-1 siRNA prevented pulmonary fibrosis by inhibition of the epithelialto-mesenchymal transition (EMT) [10] . However, whether PAI-1 siRNA inhibits the proliferation of fibroblasts directly and its effects on the related signalling pathways have not been determined.…”

Section: Introductionmentioning

confidence: 99%

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siRNA against plasminogen activator inhibitor-1 ameliorates bleomycin-induced lung fibrosis in rats

Zhang

Wang

et al. 2012

Acta Pharmacol Sin

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Aim: Plasminogen activator inhibitor-1 (PAI-1) is involved in the progression of pulmonary fibrosis. The present study was undertaken to examine the effects on pulmonary fibrosis of silencing PAI-1 expression with small interfering RNA (siRNA) and to assess the possible underlying mechanisms. Methods: Male Wistar rats were subjected to intratracheal injection of bleomycin (BLM, 5 mg/kg, 0.2 mL) to induce pulmonary fibrosis. Histopathological changes of lung tissue were examined with HE or Masson's trichrome staining. The expression levels of α-smooth muscle actin (α-SMA), collagen type-I and type-III, caspase-3, as well as p-ERK1/2 and PI3K/Akt in the lung tissue were evaluated using immunohistochemistry and Western blot analysis. The fibroblasts isolated from BLM-induced fibrotic lung tissue were cultured and transfected with pcDNA-PAI-1 or PAI-1 siRNA. The expression level of PAI-1 in the fibroblasts was measured using real time RT-PCR and Western blot analysis. The fibroblast proliferation was evaluated using MTT assay. Results: Intratracheal injection of PAI-1 siRNA (7.5 nmoL/0.2 mL) significantly alleviated alveolitis and collagen deposition, reduced the expression of PAI-1, α-SMA, collagen type-I and collagen type-III, and increased the expression of caspase-3 in BLM-induced fibrotic lung tissue. In consistence with the in vivo results, the proliferation of the cultured fibroblasts from BLM-induced fibrotic lung tissue was inhibited by transfection with PAI-1 siRNA, and accelerated by overexpression of PAI-1 by transfection with pcDNA-PAI-1. The expression of caspase-3 was increased as a result of PAI-1 siRNA transfection, and decreased after transfection with pcDNA-PAI-1. In addition, the levels of p-ERK1/2 and PI3K/Akt in the fibrogenic lung tissue were reduced after treatment with PAI-1 siRNA.Conclusion: The data demonstrate that PAI-1 siRNA inhibits alveolitis and pulmonary fibrosis in BLM-treated rats via inhibiting the proliferation and promoting the apoptosis of fibroblasts. Suppression ERK and AKT signalling pathways might have at least partly contributed to this process. Targeting PAI-1 is a promising therapeutic strategy for pulmonary fibrosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

siRNA against plasminogen activator inhibitor-1 ameliorates bleomycin-induced lung fibrosis in rats

Zhang

Wang

et al. 2012

Acta Pharmacol Sin

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“…33 A previous murine model of lung fibrogenesis caused by injurious mechanical ventilation showed that TGF-b1 induced the production of PAI-1 and administering PAI-1 RNA interference inhibited EMT and the progression of pulmonary fibrogenesis. 8,9,15 TGF-b1 can inhibit collagen degradation by inducing PAI-1 expression and thus inhibiting the activities of plasmin and tPA. 15 We demonstrated that high-V T mechanical ventilation increased lung injury, collagen deposition, fibroblast accumulation, increased expression of mesenchymal markers a-SMA and type I collagen, but decreased epithelial marker ZO-1, and PAI-1 and TGF-b1 production.…”

Section: Discussionmentioning

confidence: 99%

Mechanical ventilation augments bleomycin-induced epithelial–mesenchymal transition through the Src pathway

Liu

Kao

et al. 2014

Laboratory Investigation

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Mechanical ventilation used in patients with acute respiratory distress syndrome (ARDS) can damage pulmonary epithelial cells by producing inflammatory cytokines and depositing excess collagen. Src participates in plasminogen activator inhibitor-1 (PAI-1) and transforming growth factor-b1(TGF-b1) production during the fibroproliferative phase of ARDS, which involves a process of epithelial-mesenchymal transition (EMT). The mechanisms regulating interactions between mechanical ventilation and EMT are unclear. We hypothesized that EMT induced by high-tidal volume (V T ) mechanical stretch-augmented lung inflammation occurs through upregulation of the Src pathway. Five days after administering bleomycin to simulate acute lung injury (ALI), male C57BL/6 mice, either wild-type or Src-deficient, aged 3 months, weighing between 25 and 30 g, were exposed to low-V T (6 ml/kg) or high-V T (30 ml/kg) mechanical ventilation with room air for 1-5 h. Nonventilated mice were used as control subjects. We observed that high-V T mechanical ventilation increased microvascular permeability, PAI-1 and TGF-b1 protein levels, Masson's trichrome staining, extracellular collagen levels, collagen gene expression, fibroblast accumulation, positive staining of a-smooth muscle actin and type I collagen, activation of Src signaling and epithelial apoptotic cell death in wild-type mice (Po0.05). Decreased staining of the epithelial marker, Zonula occludents-1, was also observed. Mechanical stretch-augmented EMT and epithelial apoptosis were attenuated in Src-deficient mice and pharmacological inhibition of Src activity by PP2 (Po0.05). Our data suggest that high-V T mechanical ventilation-augmented EMT after bleomycin-induced ALI partially depends on the Src pathway. Acute respiratory distress syndrome (ARDS) is a disorder of acute respiratory failure and manifests as non-cardiogenic pulmonary edema, respiratory distress and hypoxemia. 1,2 Mechanical ventilation with high-tidal volume (V T ) causes severe lung injury (ventilator-induced lung injury (VILI)) characterized by an initial inhomogeneous inflammatory reaction or epithelial injury that is followed by a fibroproliferative phase with fibroblast proliferation. 3-8 Epithelialmesenchymal transition (EMT) is the differentiation of epithelial cells into myofibroblast-like cells, which contributes to the fibroproliferative phase. 3-8 Upregulating Src, the plasminogen activator inhibitor-1 (PAI-1), and the transforming growth factor-b1(TGF-b1) has recently been demonstrated to regulate EMT. 9-14 However, the mechanisms regulating the interactions between mechanical ventilation and EMT remain unclear.PAI-1, a member of the serine protease inhibitor (serpin) gene family, rapidly inhibits both the urokinase-type plasminogen activator and the tissue-type plasminogen activator (tPA). 15 Mice with homozygous deletion of PAI-1 were relatively protected from bleomycin-induced pulmonary fibrogenesis, whereas overexpression of PAI-1 enhanced pulmonary fibrogenesis. 9 As a primary profibrogenic cytokine...

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“…There are four canonical signaling pathways induced by RTKs, including the mitogen- Knockdown of PAI-1 by siRNA also inhibited TGF-β-induced EMT in mouse lung epithelial LA-4 cells (Senoo, Hattori et al 2010). In summary, the role of PAI-1 in EMT is likely related to its ability in modulating remodeling of extracellular matrix and cell migration.…”

Section: Tgf-β Also Synergizes With Other Ligands Of Tyrosine Kinasementioning

confidence: 99%

“…For instance, inhibition of PAI-1 by decoy peptides attenuated tubulointerstitial (Gonzalez, Klein et al 2009). Suppression of PAI-1 by siRNA protects affected mice from the development and progression of pulmonary fibrosis (Senoo, Hattori et al 2010). A positive feedback loop between TGF-β and PAI-1 is involved in the development of renal fibrosis in diabetes (Seo, Park et al 2009).…”

Section: Pai-1 Over Expression In Diseasementioning

confidence: 99%

Plasminogen activator inhibitor 1: Mechanisms of its synergistic regulation by growth factors

Song

2010

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Suppression of plasminogen activator inhibitor-1 by RNA interference attenuates pulmonary fibrosis

Cited by 107 publications

References 28 publications

siRNA against plasminogen activator inhibitor-1 ameliorates bleomycin-induced lung fibrosis in rats

siRNA against plasminogen activator inhibitor-1 ameliorates bleomycin-induced lung fibrosis in rats

Mechanical ventilation augments bleomycin-induced epithelial–mesenchymal transition through the Src pathway

Plasminogen activator inhibitor 1: Mechanisms of its synergistic regulation by growth factors

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