Epithelial Pten Controls Acute Lung Injury and Fibrosis by Regulating Alveolar Epithelial Cell Integrity

Miyoshi, Kahori; Yanagi, Shigehisa; Kawahara, Kohichi; Nishio, Makoto; Tsubouchi, Hironobu; Imazu, Yoshifumi; Koshida, Ryusuke; Matsumoto, Nobuhiro; Taguchi, Akiko; Yamashita, Shizuya; Suzuki, Akira; Nakazato, Masamitsu

doi:10.1164/rccm.201205-0851oc

Cited by 73 publications

(84 citation statements)

References 45 publications

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“…Exactly how this pattern of inhibition is achieved is unclear, but the inhibitory effects of methacycline on several non-Smad pathways imply that methacycline is acting very proximally in TGF-b1 signaling. The observed protective effects of inhibition of the non-Smad arm of TGF-b1 signaling is consistent with prior reports that Jun kinase, phosphoinositide 3-kinase (PI3K)/Akt, and p38 activities are each required for damaging fibrogenesis after bleomycin-induced lung injury (20,32,33). In addition, consistent with our observations, mice deficient in Jun kinase show suppression of fibrosis, but not inflammation after bleomycin-induced injury (32).…”

Section: Discussionsupporting

confidence: 92%

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Inhibition of Epithelial-to-Mesenchymal Transition and Pulmonary Fibrosis by Methacycline

Tan

Brumwell

et al. 2014

Am J Respir Cell Mol Biol

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A high-throughput small-molecule screen was conducted to identify inhibitors of epithelial-mesenchymal transition (EMT) that could be used as tool compounds to test the importance of EMT signaling in vivo during fibrogenesis. Transforming growth factor (TGF)-b1-induced fibronectin expression and E-cadherin repression in A549 cells were used as 48-hour endpoints in a cell-based imaging screen. Compounds that directly blocked Smad2/3 phosphorylation were excluded. From 2,100 bioactive compounds, methacycline was identified as an inhibitor of A549 EMT with the half maximal inhibitory concentration (IC50) of roughly 5 mM. In vitro, methacycline inhibited TGF-b1-induced a-smooth muscle actin, Snail1, and collagen I of primary alveolar epithelial cells . Methacycline inhibited TGF-b1-induced non-Smad pathways, including c-Jun N-terminal kinase, p38, and Akt activation, but not Smad or b-catenin transcriptional activity. Methacycline had no effect on baseline c-Jun N-terminal kinase, p38, or Akt activities or lung fibroblast responses to TGF-b1. In vivo, 100 mg/kg intraperitoneal methacycline delivered daily beginning 10 days after intratracheal bleomycin improved survival at Day 17 (P , 0.01).Bleomycin-induced canonical EMT markers, Snail1, Twist1, collagen I, as well as fibronectin protein and mRNA, were attenuated by methacycline (Day 17). Methacycline did not attenuate inflammatory cell accumulation or alter TGF-b1-responsive genes in alveolar macrophages. These studies identify a novel inhibitor of EMT as a potent suppressor of fibrogenesis, further supporting the concept that EMT signaling is important to lung fibrosis. The findings also provide support for testing the impact of methacycline or doxycycline, an active analog, on progression of human pulmonary fibrosis.

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Section: Discussionsupporting

confidence: 92%

“…Recent evidence linking signaling pathways promoting EMT in vitro with fibrogenesis in vivo supports an important role for EMT signaling in fibrosis (5,6,(17)(18)(19)(20)(21)(22). Moreover, epithelial-specific expression of the canonical EMT transcription factor, Snail1, is required for experimental hepatic fibrosis (23).…”

mentioning

confidence: 98%

Inhibition of Epithelial-to-Mesenchymal Transition and Pulmonary Fibrosis by Methacycline

Tan

Brumwell

et al. 2014

Am J Respir Cell Mol Biol

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“…It is also surprising that Fgf2 2/2 mice do not have increased amounts of bleomycin-induced pulmonary fibrosis, as a link between epithelial injury and fibroproliferation in response to bleomycin is well described (57)(58)(59). For example, epithelial-specific knockout of b-catenin causes increased epithelial injury in response to bleomycin, and subsequently leads to increased fibrosis (58).…”

Section: Our Results Show That Fgf2mentioning

confidence: 99%

Fibroblast Growth Factor 2 Is Required for Epithelial Recovery, but Not for Pulmonary Fibrosis, in Response to Bleomycin

Guzy

Stoilov

Elton³

et al. 2015

Am J Respir Cell Mol Biol

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The pathogenesis of pulmonary fibrosis involves lung epithelial injury and aberrant proliferation of fibroblasts, and results in progressive pulmonary scarring and declining lung function. In vitro, fibroblast growth factor (FGF) 2 promotes myofibroblast differentiation and proliferation in cooperation with the profibrotic growth factor, transforming growth factor-b1, but the in vivo requirement for FGF2 in the development of pulmonary fibrosis is not known. The bleomycin model of lung injury and pulmonary fibrosis was applied to Fgf2 knockout (Fgf2 2/2) and littermate control mice. Weight loss, mortality, pulmonary fibrosis, and histology were analyzed after a single intranasal dose of bleomycin. Inflammation was evaluated in bronchoalveolar lavage (BAL) fluid, and epithelial barrier integrity was assessed by measuring BAL protein and Evans Blue dye permeability. Fgf2 is expressed in mouse and human lung epithelial and inflammatory cells, and, in response to bleomycin, Fgf2 2/2 mice have significantly increased mortality and weight loss. Analysis of BAL fluid and histology show that pulmonary fibrosis is unaltered, but Fgf2 2/2 mice fail to efficiently resolve inflammation, have increased BAL cellularity, and, importantly, deficient recovery of epithelial integrity. Fgf2 2/2 mice similarly have deficient recovery of club cell secretory protein 1 bronchial epithelium in response to naphthalene. We conclude that FGF2 is not required for bleomycin-induced pulmonary fibrosis, but rather is essential for epithelial repair and maintaining epithelial integrity after bleomycin-induced lung injury in mice. These data identify that FGF2 acts as a protective growth factor after lung epithelial injury, and call into question the role of FGF2 as a profibrotic growth factor in vivo.Keywords: fibroblast growth factor 2; bleomycin; pulmonary fibrosis; lung injury; alveolar epithelial repair Clinical RelevanceFibroblast growth factors (FGFs) and, in particular, FGF2, are implicated in the pathogenesis of pulmonary fibrosis and recovery from airway epithelial cell (AEC) injury; however, the in vivo requirement for FGF2 in the development of pulmonary fibrosis is not known. In this study, we have found that mice lacking FGF2 do not show altered levels of fibrosis in response to bleomycin, indicating that FGF2 is dispensable for the generation of bleomycin-induced pulmonary fibrosis. In addition, we show that FGF2 knockout mice have increased mortality and weight loss in response to bleomycin, accompanied by deficient recovery of mature alveolar epithelium and epithelial barrier function. These findings suggest that FGF2 is required for lung epithelial recovery, that pharmacological inhibition of FGF signaling could impair the response to lung injury, and that FGF2 administration or augmentation may have therapeutic benefit for lung injury.Lung alveolar epithelial cell (AEC) injury can be caused by a variety of insults, including infection, trauma, aspiration, and sepsis. Chronic AEC injury of unknown origin is central to ...

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“…Mice with constitutive deficiency of PTEN develop spontaneous fibrosis by intrinsic defects in fibroblasts and negative regulation of their proliferative response (51,52). Furthermore, conditional targeted deletion of PTEN in lung epithelium exacerbated injury and fibrosis after bleomycin treatment by an increase of active TGF-β and loss of epithelial integrity (53). In support of a role for PTEN in PINK1 deficiency in IPF lungs, microarray analyses of the Lung Genomics Research Consortium (LGRC) cohort (http://www.lung-genomics.org/) showed that PINK1 expression correlated directly with expression levels of the gene set of the PTEN pathway (Supplemental Table 3).…”

Section: C) Mitochondrial Morphology In Pink1mentioning

confidence: 99%

PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis

Bueno¹,

Lai²,

Romero³

et al. 2014

J. Clin. Invest.

500

554

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Epithelial Pten Controls Acute Lung Injury and Fibrosis by Regulating Alveolar Epithelial Cell Integrity

Abstract: Our results highlight epithelial Pten as a crucial gatekeeper controlling ALI and lung fibrosis by modulating AEC integrity, and the Pten/PI3K/Akt pathway as a potential therapeutic target in these intractable diseases.

Cited by 73 publications

References 45 publications

Inhibition of Epithelial-to-Mesenchymal Transition and Pulmonary Fibrosis by Methacycline

Inhibition of Epithelial-to-Mesenchymal Transition and Pulmonary Fibrosis by Methacycline

Fibroblast Growth Factor 2 Is Required for Epithelial Recovery, but Not for Pulmonary Fibrosis, in Response to Bleomycin

PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis

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