Levels of reactive oxygen species and primary antioxidant enzymes in WI38 versus transformed WI38 cells following bleomcyin treatment

Yen, Hsiu-Chuan; Chang, Hui-Ming; Majima, Hideyuki J.; Chen, Fan-Yi; Li, Sin-Hua

doi:10.1016/j.freeradbiomed.2004.12.022

Cited by 20 publications

(13 citation statements)

References 52 publications

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“…At low doses (0.1-10 mU/ml) bleomycin promoted cell growth, whereas at higher doses it induced apoptotic cell death (Figure 1). This latter effect of bleomycin was previously reported by Yen and coworkers (39) in human lung fibroblast W138 cells. In primary lung fibroblasts isolated from rats, Koslowski and colleagues (40) showed that bleomycin induced terminal differentiation of the cells at the same dose range that was shown in this study to stimulate cell growth.…”

Section: Discussionsupporting

confidence: 84%

“…Previous studies have shown that PI3K is involved in the activation of Akt under various physiologic and pathologic conditions (14,39,42); however, PI3K-independent mechanisms of Akt activation have also been reported (43,44). In this study, we found that PI3K is an important upstream regulator of bleomycin-induced Akt activation, and that ERK pathway plays a minor role in this process (Figure 3).…”

Section: Discussionsupporting

confidence: 53%

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Phosphatidylinositol-3-Kinase/Akt Regulates Bleomycin-Induced Fibroblast Proliferation and Collagen Production

Azad²,

Wang³

et al. 2010

Am J Respir Cell Mol Biol

110

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Abnormal repair and dysregulated angiogenesis have been implicated in the pathogenesis of pulmonary fibrosis, but the underlying mechanisms of regulation are not well understood. The present study investigated the role of phosphatidylinositol-3-kinase (PI3K)/ Akt in fibrogenesis of human lung fibroblasts and its regulation by reactive oxygen species (ROS). Exposure of lung fibroblasts to bleomycin, a known inducer of fibrosis, resulted in rapid activation of PI3K/Akt and a parallel increase in fibroblast proliferation and collagen production, characteristics of lung fibrosis. Bleomycin had no significant effect on total Akt protein expression but induced phosphorylation of the protein at threonine 308 and serine 473 positions. Inhibition of this phosphorylation by PI3K inhibitors or by dominant-negative Akt (T308A/S473A) expression abrogated the effects of bleomycin on fibroblast proliferation and collagen production, suggesting the role of PI3K/Akt in the fibrogenic process. Activation of PI3K/Akt by bleomycin also led to transcriptional activation and protein expression of hypoxia-inducible factor-1a (HIF-1a) and vascular endothelial growth factor, which contributed to the fibroproliferative and collagen-inducing effects of bleomycin. The fibrogenic effects of bleomycin were dependent on ROS generation, particularly superoxide anion and hydrogen peroxide, which were induced by bleomycin. Inhibition of ROS generation by antioxidant enzymes, catalase and superoxide dismutase mimetic MnTBAP, abrogated the fibrogenic effects of bleomycin as well as its induction of PI3K/Akt and HIF-1a activation. Together, our results indicate a novel role of PI3K/Akt in fibrogenesis of human lung fibroblasts and its regulation by ROS, which could be exploited for the treatment of pulmonary fibrosis and related disorders.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionsupporting

confidence: 53%

Phosphatidylinositol-3-Kinase/Akt Regulates Bleomycin-Induced Fibroblast Proliferation and Collagen Production

Azad²,

Wang³

et al. 2010

Am J Respir Cell Mol Biol

110

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“…It has been reported that ROS are involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and the animal model of bleomycin-induced lung fibrosis [27–31]. Exposure of cultured lung fibroblasts to high concentrations of oxygen leads to increased formation of ROS [32].…”

Section: Discussionmentioning

confidence: 99%

The role of RhoA and cytoskeleton in myofibroblast transformation in hyperoxic lung fibrosis

Dong

Han

et al. 2013

Free Radical Biology and Medicine

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Myofibroblast transformation is a key process in the pathogenesis of lung fibrosis. We have previously reported that hyperoxia induces RhoA activation in HFL-1 lung fibroblasts and RhoA mediates collagen synthesis in hyperoxic lung fibrosis. In the present study, we investigated the role of RhoA and actin cytoskeleton in hyperoxia-induced myofibroblast transformation. Exposure of HFL-1 lung fibroblasts to hyperoxia stimulated actin filament formation, shift of G-actin to F-actin, nuclear co-localization of myocardin-related transcription factor-A (MRTF-A), recruitment of MRTF-A to α-smooth muscle actin (α-SMA) gene promoter, myofibroblast transformation, and collagen-I synthesis. Inhibition of RhoA by C3 transferase CT-04 or dominant-negative RhoA mutant T19N, and inhibition of ROCK by Y27632 prevented myofibroblast transformation and collagen-I synthesis. Moreover, inhibition of RhoA by CT-04 prevented hyperoxia-induced actin filament formation, shift of G-actin to F-actin, and nuclear co-localization of MRTF-A. In addition, disrupting actin filaments by cytochalasin D or scavenging reactive oxygen species (ROS) by tiron attenuated actin filament formation, nuclear co-localization of MRTF-A, myofibroblast transformation, and collagen-I synthesis. Furthermore, overexpression of constitutively active RhoA mutant Q63L or stabilization of actin filaments recapitulated the effect of hyperoxia on actin cytoskeleton, and nuclear co-localization of MRTF-A, myofibroblast transformation and collagen-I synthesis. Interestingly, knocking-down MRTF-A prevented hyperoxia-induced increase in the recruitment of MRTF-A to serum response factor (SRF) transcriptional complex on α-SMA gene promoter, myofibroblast transformation and collagen-I synthesis. Finally, Y27632 and tiron attenuates hyperoxia-induced increases in α-SMA and collagen-I in mouse lungs. Together, these results indicate that the actin cytoskeletal reorganization due to ROS/RhoA-ROCK pathway mediates myofibroblast transformation and collagen synthesis in lung fibrosis of oxygen toxicity. MRTF-A contributes to the regulatory effect of actin cytoskeleton on myofibroblast transformation during hyperoxia.

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“…However, the effective use of BLM in chemotherapy is greatly limited because it causes dose-dependent interstitial pneumonitis that often progresses to interstitial PF (IPF) (Venkatesan et al, 1997;Yen et al, 2005). BLMinduced pulmonary fibrosis is a widely used animal model of idiopathic PF (Arslan et al, 2002;Snider et al, 1978).…”

Section: Research Articlementioning

confidence: 99%

The effect of octreotide, an analog of somatostatin, on bleomycin-induced interstitial pulmonary fibrosis in rats

Tuğ

Kara

Karaoğlu

et al. 2012

Drug and Chemical Toxicology

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In this study, octreotide (OCT), a synthetic somatostatin analog, was tested for its beneficial effects in the prevention of interstitial pulmonary fibrosis (IPF) induced by bleomycin (BLM) in rats by histological examination and by evaluating tissue OH-proline levels. Thirty male Wistar rats were divided randomly into three groups: group I: intratracheal (i.t.) BLM (7.5 mg/kg, single dose) + saline solution [0.9% NaCl, subcutaneously (s.c.), once-daily for 7 days]; group II: i.t. BLM (7.5 mg/kg, single dose) + OCT acetate (82.5 µg/kg, s.c., once-daily for 7 days); and the control group. At the end of the 7 days, lung tissues were excised and examined by histopathological methods. Levels of tissue hydroxyproline (OH-proline) were determined. BLM administration resulted in prominent histopathologic findings, such as diffuse alveolar damage and interstitial pulmonary fibrosis, as well as a significant increase in OH-proline level, as compared to controls. OCT application explicitly attenuated the histopathologic changes to a significant extent. OCT decreased paranchymal fibrosis and structural deformities in BLM-induced lung fibrosis. These results suggest that OCT administration to rats with BLM-induced IPF has a protective effect. Further studies are necessary to reveal the molecular mechanism(s) of OCT-induced protective effect.

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Levels of reactive oxygen species and primary antioxidant enzymes in WI38 versus transformed WI38 cells following bleomcyin treatment

Cited by 20 publications

References 52 publications

Phosphatidylinositol-3-Kinase/Akt Regulates Bleomycin-Induced Fibroblast Proliferation and Collagen Production

Phosphatidylinositol-3-Kinase/Akt Regulates Bleomycin-Induced Fibroblast Proliferation and Collagen Production

The role of RhoA and cytoskeleton in myofibroblast transformation in hyperoxic lung fibrosis

The effect of octreotide, an analog of somatostatin, on bleomycin-induced interstitial pulmonary fibrosis in rats

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