Notch Induces Myofibroblast Differentiation of Alveolar Epithelial Cells via Transforming Growth Factor- -Smad3 Pathway

Aoyagi-Ikeda, Kana; Maeno, Toshitaka; Matsui, Hiroki; Ueno, Masashi; Hara, Kenichiro; Aoki, Yasuhiro; Aoki, Fumiaki; Shimizu, Tomohiro; Doi, Hiroshi; Kawai-Kowase, Keiko; Iso, Tatsuya; Suga, Tatsuo; Arai, M.; Kurabayashi, Masahiko

doi:10.1165/rcmb.2010-0140oc

Cited by 73 publications

(52 citation statements)

References 42 publications

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“…Downregulation of TGF-β1 expression and modulation of TGF-β/Smad signaling may be effective in preventing organ fibrosis [24]. Investigators have previously demonstrated that TGF-β1 overexpression has been associated with enhanced myofibroblast differentiaon [25,26]. In our data it was observed that the expressions of TGF-β1 and p-Smad2/3 were markedly decreased in cultured CFs under LH treatment.…”

Section: Discussionsupporting

confidence: 56%

Low Molecular Weight Heparin Inhibits Circulating Fibrocytes Differentiation by Modulating Neuronal Nitric Oxide Synthase and TGF-�1/Smad Pathway

Xie

Zhu²,

Fu³

et al. 2012

Cell Physiol Biochem

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Background/Aims: Circulating fibrocytes (CFs) have been placed at the center of a number of fibrosing conditions. Recently, attention has been drawn to the non-anticoagulant activities of low molecular weight heparin (LH), especially its anti-fibrotic effects. The purpose of this study was to investigate the effects of LH on CFs differentiation and possible underlying mechanisms. Methods/Results: CFs were cultured from human peripheral blood mononuclear cells and identified by dual-immunofluorescence staining. Incubation with LH inhibited CFs trans-differentiation by upregulating CD34 and downregulating pro-Collagen I and a-SMA in a concentration- and time-dependent manner, all of which were detected by flow cytometry. Similar effects were observed after incubation with L-NAME, an inhibitor of NOS. NO production was measured by Griess methods and markedly decreased in CFs treated with LH. Three NOS isoforms were assessed by western blot and nNOS was the predominant isoform involved in this process. Additionally, LH and L-NAME had similar down-regulating effects on the expression of TGF-β1 and pSmad2/3, which indicated that TGF-β/Smad pathway might be a downstream signaling of nNOS/NO during LH treatment. Conclusion: These results suggested that LH could exhibit anti-fibrotic effects by inhibiting CFs transdifferentiation, in which the involvement of nNOS/NO and TGF-β/Smad pathway were identified.

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Section: Discussionsupporting

confidence: 56%

Low Molecular Weight Heparin Inhibits Circulating Fibrocytes Differentiation by Modulating Neuronal Nitric Oxide Synthase and TGF-�1/Smad Pathway

Xie

Zhu²,

Fu³

et al. 2012

Cell Physiol Biochem

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“…Some collagen-producing myofibroblasts contain S100A4 (fibroblast-specific protein 1, calvasculin), a prototypical marker for EMT (24) (Figure 4C). Codetection of FAP, a protease selectively induced in fibrotic foci (25), together with Notch ( Figure 4D) or b-catenin ( Figure 4E), two critical signaling proteins that control the EMT phenotype (26,27), as well as the observed induction of Snail 1 Slug transcription factor ( Figure 4F), suggest that EMT may play a role in lung fibrogenesis in our model.…”

Section: Proliferative Phasementioning

confidence: 78%

Acute Lung Injury and Fibrosis in a Baboon Model of Escherichia coli Sepsis

Keshari

Silasi‐Mansat

Zhu

et al. 2014

Am J Respir Cell Mol Biol

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Sepsis-induced inflammation of the lung leads to acute respiratory distress syndrome (ARDS), which may trigger persistent fibrosis. The pathology of ARDS is complex and poorly understood, and the therapeutic approaches are limited. We used a baboon model of Escherichia coli sepsis that mimics the complexity of human disease to study the pathophysiology of ARDS. We performed extensive biochemical, histological, and functional analyses to characterize the disease progression and the long-term effects of sepsis on the lung structure and function. Similar to humans, sepsis-induced ARDS in baboons displays an early inflammatory exudative phase, with extensive necrosis. This is followed by a regenerative phase dominated by proliferation of type 2 epithelial cells, expression of epithelial-to-mesenchymal transition markers, myofibroblast migration and proliferation, and collagen synthesis. Baboons that survived sepsis showed persistent inflammation and collagen deposition 6-27 months after the acute episodes. Long-term survivors had almost double the amount of collagen in the lung as compared with age-matched control animals. Immunostaining for procollagens showed persistent active collagen synthesis within the fibroblastic foci and interalveolar septa. Fibroblasts expressed markers of transforming growth factor-b and platelet-derived growth factor signaling, suggesting their potential role as mediators of myofibroblast migration and proliferation, and collagen deposition. In parallel, up-regulation of the inhibitors of extracellular proteases supports a deregulated matrix remodeling that may contribute to fibrosis. The primate model of sepsisinduced ARDS mimics the disease progression in humans, including chronic inflammation and long-lasting fibrosis. This model helps our understanding of the pathophysiology of fibrosis and the testing of new therapies.Keywords: lung; acute respiratory distress syndrome; sepsis; organ failure; fibrosis Clinical RelevanceSepsis-induced acute lung injury and subsequent persistent inflammation are potential triggers of the fibrotic response. We developed a baboon model of sepsis-induced acute respiratory distress syndrome that leads to long-term inflammation and fibrosis and thus recapitulates the pathophysiology of the human disease.

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“…Genome-wide transcriptome studies in healthy or mutated T-cells (Chadwick et al, 2009;Dohda et al, 2007;Palomero et al, 2006;Weerkamp et al, 2006), mouse embryonic stem (ES) cells (Main et al, 2010;Meier-Stiegen et al, 2010), alveolar epithelial cells (Aoyagi-Ikeda et al, 2011), endometrial stromal cells (Mikhailik et al, 2009), C2C12 mouse myoblast cells (Buas et al, 2009) and Drosophila myogenic cells (Krejci et al, 2009) have unraveled distinct sets of Notch target genes with rather limited overlap of the transcriptomes. This is the case even when comparing transcriptome studies that were carried out with relatively similar modes and durations of Notch induction (summarized in Fig.…”

Section: Reviewmentioning

confidence: 99%

Notch signaling: simplicity in design, versatility in function

2011

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Notch signaling is evolutionarily conserved and operates in many cell types and at various stages during development. Notch signaling must therefore be able to generate appropriate signaling outputs in a variety of cellular contexts. This need for versatility in Notch signaling is in apparent contrast to the simple molecular design of the core pathway. Here, we review recent studies in nematodes, Drosophila and vertebrate systems that begin to shed light on how versatility in Notch signaling output is generated, how signal strength is modulated, and how cross-talk between the Notch pathway and other intracellular signaling systems, such as the Wnt, hypoxia and BMP pathways, contributes to signaling diversity.Key words: Cis-inhibition, Delta-like, Signaling diversity, Jagged, Notch, Notch intracellular domain Introduction Cells need to sense cues from their extracellular environment and integrate this information into appropriate developmental or physiological responses. Although there are a number of mechanisms that relay information from the exterior of the cell to the interior, a relatively small set of highly evolutionarily conserved signaling pathways stand out as playing particularly crucial roles in this transmission of information. In this roster of 'elite' intracellular signaling mechanisms are the Wnt pathway, the sonic hedgehog (Shh) pathway, the bone morphogenetic protein/transforming growth factor  (BMP/TGF) pathway, phosphatidylinositol 3-kinase/thymoma viral proto-oncogene (PI3K/AKT) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling, and, the subject of this review, the Notch signaling pathway. Each of these pathways converts information about the concentration of extracellular ligands into specific transcriptional responses in the nucleus. In most cases, the signaling mechanism consists of the 'core' signaling pathway, i.e. the minimal set of protein components required for transducing the signal, and a more elaborate set of 'auxiliary' proteins, which, in various ways, impinge upon the core pathway and modify the signal but are not intrinsically necessary for relaying the signal.Among these highly conserved pathways (Gazave et al., 2009;Richards and Degnan, 2009), the Notch signaling pathway scores highly with regard to simplicity in molecular design, as it contains only a small number of core signaling components (Fig. 1). Despite this, Notch signaling affects cell differentiation decisions not only across a wide spectrum of metazoan species, but also across a broad range of cell types in a single organism and at different steps during cell lineage progression. The pleiotropic actions of Notch in different cell types and organs have recently been reviewed and are summarized in Table 1. In keeping with its important role in many cell types, the mutation of Notch genes leads to diseases in various organs and tissues (Table 2). These studies highlight the fact that the Notch pathway must be able to elicit appropriate responses in many spatially and temporally...

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Notch Induces Myofibroblast Differentiation of Alveolar Epithelial Cells via Transforming Growth Factor- -Smad3 Pathway

Cited by 73 publications

References 42 publications

Low Molecular Weight Heparin Inhibits Circulating Fibrocytes Differentiation by Modulating Neuronal Nitric Oxide Synthase and TGF-�1/Smad Pathway

Low Molecular Weight Heparin Inhibits Circulating Fibrocytes Differentiation by Modulating Neuronal Nitric Oxide Synthase and TGF-�1/Smad Pathway

Acute Lung Injury and Fibrosis in a Baboon Model of Escherichia coli Sepsis

Notch signaling: simplicity in design, versatility in function

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