Detection of epithelial to mesenchymal transition in airways of a bleomycin induced pulmonary fibrosis model derived from an α-smooth muscle actin-Cre transgenic mouse

Wu, Zhuang; Yang, Leilei; Cai, Lin; Zhang, Min; Chen, Xuan; Yang, Xiao; Xu, Jianping

doi:10.1186/1465-9921-8-1

Cited by 147 publications

(116 citation statements)

References 26 publications

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“…Significantly, this response was largely absent in lung from JNK12/2 mice. The emerging role of EMT in pulmonary fibrosis has recently been suggested (69,70), and compelling observations that EMT occurs in the bleomycin model of fibrosis that were based upon lineage tracing have been published (71). However, recent studies have failed to support a role for EMT in IPF or the bleomycin model of fibrosis (72).…”

Section: Discussionmentioning

confidence: 98%

c-Jun N-Terminal Kinase 1 Is Required for the Development of Pulmonary Fibrosis

Alcorn¹,

Velden²,

Brown³

et al. 2009

Am J Respir Cell Mol Biol

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Collagen deposition is observed in a diverse set of pulmonary diseases, and the unraveling of the molecular signaling pathways that facilitate collagen deposition represents an ongoing area of investigation. The stress-activated protein kinase, c-Jun N-terminal kinase 1 (JNK1), is activated by a large variety of cellular stresses and environmental insults. Recent work from our laboratory demonstrated the critical role of JNK1 in epithelial to mesenchymal transition. The goal of the present study was to examine the involvement of JNK1 in subepithelial collagen deposition in mice subjected to models of allergic airways disease and interstitial pulmonary fibrosis. Activation of JNK was slightly enhanced in lungs from mice subjected to sensitization and challenge with ovalbumin (Ova), and predominant localization of phospho-JNK was observed in the bronchial epithelium. While mice lacking JNK1 (JNK12/2 mice) displayed enhanced lung inflammation and cytokine production compared with wild-type (WT) mice, JNK12/2 mice accumulated less subepithelial collagen deposition in response to antigen, and showed decreased expression of profibrotic genes compared with WT animals. Furthermore, transforming growth factor (TGF)-b1 content in the bronchoalveolar lavage was diminished in JNK12/2 mice compared with WT animals subjected to antigen. Finally, we demonstrated that mice lacking JNK1 were protected against TGF-b1 and bleomycin-induced pro-fibrotic gene expression and pulmonary fibrosis. Collectively, these findings demonstrate an important requirement for JNK1 in promoting collagen deposition in multiple models of fibrosis.

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Section: Discussionmentioning

confidence: 98%

c-Jun N-Terminal Kinase 1 Is Required for the Development of Pulmonary Fibrosis

Alcorn¹,

Velden²,

Brown³

et al. 2009

Am J Respir Cell Mol Biol

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“…Briefly, two loxP sites were inserted at each end of the first exon of the Mypt1 gene, and the resultant Mypt1 flox/flox mice were crossed with transgenic mice with Cre expression driven by a smooth muscle ␣-actin promoter (Mypt1 flox/flox : SMA-Cre mice, MYPT1 SMKO ) (28). The littermates of the Mypt1 flox/flox/ϩ :SMA-Cre mice were used as a control (both male and female mice of 4ϳ60 weeks old).…”

Section: Establishment Of Mypt1mentioning

confidence: 99%

Myosin Phosphatase Target Subunit 1 (MYPT1) Regulates the Contraction and Relaxation of Vascular Smooth Muscle and Maintains Blood Pressure

Qiao

Chen

et al. 2014

Journal of Biological Chemistry

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Background: MYPT1 is a regulatory subunit of myosin phosphatase. Results: Deleting MYPT1 in vascular smooth muscle enhances myosin phosphorylation, contractility, and blood pressure. Conclusion: Genetic evidence shows MYPT1 plays a role in modulating vascular smooth muscle contractility. Significance: Although MYPT1 is not essential for vascular smooth muscle contractility, it contributes to blood pressure maintenance in vivo through signaling to myosin phosphorylation.

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“…Although little is known about how the alveolar epithelium is injured, the ensuing fibrotic response is associated with unrestrained accumulation of fibroblasts and myofibroblasts that synthesize and deposit collagen fibrils within fibroblast foci located in the pulmonary parenchyma (2,3). Recent studies have suggested that pulmonary fibroblasts arise by several routes including increased migration and proliferation of resident pulmonary fibroblasts, mesenchymal transition of the alveolar epithelium, and recruitment of bone marrow-derived progenitor cells (4)(5)(6)(7). In the presence of TGF-b and other agonists, resident fibroblast subsets transdifferentiate into a-smooth muscle actinpositive myofibroblasts (8,9), produce increased amounts of collagen, and, through their contractile activities, distort the parenchymal lung architecture (9,10).…”

mentioning

confidence: 99%

Increased Cell Surface Fas Expression Is Necessary and Sufficient To Sensitize Lung Fibroblasts to Fas Ligation-Induced Apoptosis: Implications for Fibroblast Accumulation in Idiopathic Pulmonary Fibrosis

Wynes

Edelman

Kostyk

et al. 2011

The Journal of Immunology

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Idiopathic pulmonary fibrosis (IPF) is associated with the accumulation of collagen-secreting fibroblasts and myofibroblasts in the lung parenchyma. Many mechanisms contribute to their accumulation, including resistance to apoptosis. In previous work, we showed that exposure to the proinflammatory cytokines TNF-α and IFN-γ reverses the resistance of lung fibroblasts to apoptosis. In this study, we investigate the underlying mechanisms. Based on an interrogation of the transcriptomes of unstimulated and TNF-α– and IFN-γ–stimulated primary lung fibroblasts and the lung fibroblast cell line MRC5, we show that among Fas-signaling pathway molecules, Fas expression was increased ∼6-fold in an NF-κB– and p38mapk-dependent fashion. Prevention of the increase in Fas expression using Fas small interfering RNAs blocked the ability of TNF-α and IFN-γ to sensitize fibroblasts to Fas ligation-induced apoptosis, whereas enforced adenovirus-mediated Fas overexpression was sufficient to overcome basal resistance to Fas-induced apoptosis. Examination of lung tissues from IPF patients revealed low to absent staining of Fas in fibroblastic cells of fibroblast foci. Collectively, these findings suggest that increased expression of Fas is necessary and sufficient to overcome the resistance of lung fibroblasts to Fas-induced apoptosis. Our findings also suggest that approaches aimed at increasing Fas expression by lung fibroblasts and myofibroblasts may be therapeutically relevant in IPF.

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Detection of epithelial to mesenchymal transition in airways of a bleomycin induced pulmonary fibrosis model derived from an α-smooth muscle actin-Cre transgenic mouse

Cited by 147 publications

References 26 publications

c-Jun N-Terminal Kinase 1 Is Required for the Development of Pulmonary Fibrosis

c-Jun N-Terminal Kinase 1 Is Required for the Development of Pulmonary Fibrosis

Myosin Phosphatase Target Subunit 1 (MYPT1) Regulates the Contraction and Relaxation of Vascular Smooth Muscle and Maintains Blood Pressure

Increased Cell Surface Fas Expression Is Necessary and Sufficient To Sensitize Lung Fibroblasts to Fas Ligation-Induced Apoptosis: Implications for Fibroblast Accumulation in Idiopathic Pulmonary Fibrosis

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