Hypoxia-induced alveolar epithelial-mesenchymal transition requires mitochondrial ROS and hypoxia-inducible factor 1

Zhou, Guofei; Dada, Laura A.; Wu, Minghua; Kelly, Aileen; Trejo, Humberto E.; Zhou, Qingwen; Varga, John; Sznajder, Jacob I.

doi:10.1152/ajplung.00007.2009

Cited by 205 publications

(202 citation statements)

References 54 publications

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“…Our present studies indicate that IL-17A is a potent inducer of EMT; in contrast, IL-17C and IL-17F fail to induce EMT in these cells. Here we observed that IL-17-mediated EMT is comparable in both normal primary human small airway epithelial and, using a well-documented EMT cell line, RLE-6TNs (20,39,50,54). These data provide more evidence demonstrating IL-17-mediated EMT similar to its effect in tumor-derived epithelial cells (36).…”

Section: L409 Il-17 Mediated Col(v) Overexpression and Emtsupporting

confidence: 62%

IL-17 induces type V collagen overexpression and EMT via TGF-β-dependent pathways in obliterative bronchiolitis

Vittal¹,

Fan²,

Greenspan³

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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erative bronchiolitis (OB), a fibrotic airway lesion, is the leading cause of death after lung transplantation. Type V collagen [col(V)] overexpression and IL-17-mediated anti-col(V) immunity are key contributors to OB pathogenesis. Here, we report a previously undefined role of IL-17 in inducing col(V) overexpression, leading to epithelial mesenchymal transition (EMT) and subsequent OB. We observed IL-17-mediated induction of col(V) ␣1 chains [␣1 (V)] in normal airway epithelial cells in vitro and detected ␣1 (V)-specific antibodies in bronchoalveolar lavage fluid of lung transplant patients. Overexpression of IL-17 and col(V) was detected in OB lesions in patient lung biopsies and in a murine OB model. IL-17 is shown to induce EMT, TGF-␤ mRNA expression, and SMAD3 activation, whereas downregulating SMAD7 expression in vitro. Pharmacological inhibition of TGF-␤RI tyrosine kinase, p38 MAPK, or focal adhesion kinase prevented col(V) overexpression and EMT. In murine orthotopic lung transplants, neutralizing IL-17 significantly decreased TGF-␤ mRNA and protein expression and prevented epithelial repair/ OB. Our findings highlight a feed-forward loop between IL-17 and TGF-␤, leading to induction of col(V) and associated epithelial repair, thus providing one possible link between autoimmunity and OB after lung transplantation. autoimmunity; p38 MAPK; focal adhesion kinase; small-airway epithelial cells; RLE-6TN; mouse transplant model; epithelial-mesenchymal transition OBLITERATIVE BRONCHIOLITIS (OB) is characterized by extensive peribronchiolar fibrosis with plugs of granulation tissues (fibroblasts and collagen) that occlude small airways. OB is the key reason that the 5-yr survival of lung transplant recipients is only 50%, the worst of all major solid organ transplants (42,48).Aberrant epithelial repair is a key event in the transplanted lung (1, 9) in which bronchioles lose resident epithelial cells and become occluded by granulation tissue. Abnormal epithelial repair eventually causes an epithelial-to-mesenchymal transition (EMT), a functional and phenotypic change of epithelial cells into spindle-shaped, migratory (43) and matrix-component-secreting mesenchymal cells (10, 41), and a process associated with lung fibrosis (15,27). However, the direct connection between EMT and the in vivo phenomena of fibrosis and fibro-obliterative disease remains controversial.We and others previously reported that OB is associated with dysregulation of two types of collagen: 1) marked increase in type V collagen [col(V)], a quantitatively minor lung collagen (8,14,40), and 2) a decrease in the major lung collagen type I [col(I)] (2, 53). We have shown that prospective monitoring of patients with human lung transplant revealed a critical role of col(V)-specific cellular immunity in OB pathogenesis (14,40). Although overexpression of col(V), an otherwise quantitatively minor collagen, is involved in OB pathology, mechanisms leading to col(V) overexpression are unknown. Thus a mechanistic understanding of the triggers of col(V)...

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Section: L409 Il-17 Mediated Col(v) Overexpression and Emtsupporting

confidence: 62%

IL-17 induces type V collagen overexpression and EMT via TGF-β-dependent pathways in obliterative bronchiolitis

Vittal¹,

Fan²,

Greenspan³

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Transforming growth factor‐β1 is a classical EMT‐promoting cytokine, and many studies have shown the relationship between HIF‐1α and TGF‐β1 in the process of EMT 13, 35, 36. We also found that TGF‐β1 has a positive correlation with HIF‐1α as well as Snail and β‐catenin in PQ poisoning‐induced pulmonary fibrosis, the latter of which are the two other EMT‐promoting cytokines in addition to TGF‐β1 26.…”

Section: Resultsmentioning

confidence: 99%

HIF‐1α regulates EMT via the Snail and β‐catenin pathways in paraquat poisoning‐induced early pulmonary fibrosis

Zhu

Tan

Xie

et al. 2016

J Cellular Molecular Medi

104

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Paraquat (PQ) poisoning‐induced pulmonary fibrosis is one of the primary causes of death in patients with PQ poisoning. Hypoxia‐inducible factor‐1α (HIF‐1α) and epithelial‐mesenchymal transition (EMT) are involved in the progression of pulmonary fibrosis. Snail and β‐catenin are two other factors involved in promoting EMT. However, the relationship among HIF‐1α, Snail and β‐catenin in PQ poisoning‐induced pulmonary fibrosis is not clear. Our research aimed to determine whether the regulation of HIF‐1α in EMT occurs via the Snail and β‐catenin pathways in PQ poisoning‐induced pulmonary fibrosis. Sixty‐six Sprague–Dawley rats were randomly and evenly divided into a control group and a PQ group. The PQ group was treated with an intragastric infusion of a 20% PQ solution (50 mg/kg) for 2, 6, 12, 24, 48 and 72 hrs. A549 and RLE‐6TN cell lines were transfected with HIF‐1α siRNA for 48 hrs before being exposed to PQ. Western blotting, real‐time quantitative PCR, immunofluorescence, immunohistochemistry and other assays were used in our research. In vivo, the protein levels of HIF‐1α and α‐SMA were increased at 2 hrs and the level of ZO‐1 (Zonula Occluden‐1) was reduced at 12 hrs. In vitro, the transient transfection of HIF‐1α siRNA resulted in a decrease in the degree of EMT. The expression levels of Snail and β‐catenin were significantly reduced when HIF‐α was silenced. These data demonstrate that EMT may be involved in PQ poisoning‐induced pulmonary fibrosis and regulated by HIF‐1α via the Snail and β‐catenin pathways. Hypoxia‐inducible factor‐1α may be a therapeutic target for the treatment of PQ poisoning‐induced pulmonary fibrosis.

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“…Previously, it was suggested that the hypoxic signal can be triggered through HIF, resulting in the occurrence of EMT (34). Tumor growth factor-β was initially confirmed as an inducer of EMT in normal mammary epithelial cells and has since been shown to mediate the EMT in tumorigenesis (35,36). various transcription factors are involved in TGFβ signals, including ZEB1 and SNAIL (37).…”

Section: Discussionmentioning

confidence: 99%

Krüppel-like factor 8 involved in hypoxia promotes the invasion and metastasis of gastric cancer via epithelial to mesenchymal transition

Liu¹,

Wang²,

Zhou³

et al. 2014

Oncology Reports

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Abstract. Previously, we reported that hypoxia was able to induce invasion and metastasis in gastric cancer and that hypoxia-inducible factor-1 (HIF-1) is a key factor involved in this tumor type. Krüppel-like factor 8 (KLF8) as a transcriptional repressor has been suggested as a promoter of tumor metastasis in breast cancer and an inducer of the epithelial-mesenchymal transition (EMT). KLF8 is also highly expressed in gastric cancer tissues, contributing to poor prognosis. However, the association between KLF8 and HIF-1 in regulating the progression of human gastric cancer in hypoxia is unclear. In the present study, we found that KLF8 was overexpressed in gastric cancer metastatic tissues and cells. Additionally, KLF8 siRNA significantly inhibited SGC7901 cell invasion and migration compared with SGC7901, SGC7901/Scr-si cells. Hypoxia is thus able to induce KLF8 expression and EMT in SGC7901 cells. However, following the examination of changes in cell morphology and epithelial and mesenchymal markers, it was found that KLF8 siRNA and HIF-1 siRNA strongly reversed EMT in cells undergoing hypoxia. Furthermore, hypoxia-induced KLF8 overexpression was attenuated by HIF-1 siRNA. Experiments using luciferase promoter constructs resulted in a marked increase in the activity of cells exposed to hypoxia and decreased activity in cells co-transfected with HIF-1 siRNA. The chromatin immunoprecipitation assay revealed proximal HRE at -133 is the main HIF-1 binding site in the KLF8 promoter.In conclusion, the results demonstrated that KLF8 is actively enhanced by hypoxia and is a novel HIF-1 target. KLF8 is a novel EMT regulating transcription factor that involved in the progression of gastric cancer. The specific anti-EMT drugs in combination with anti-hypoxia are new promising cancer therapies.

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Hypoxia-induced alveolar epithelial-mesenchymal transition requires mitochondrial ROS and hypoxia-inducible factor 1

Cited by 205 publications

References 54 publications

IL-17 induces type V collagen overexpression and EMT via TGF-β-dependent pathways in obliterative bronchiolitis

IL-17 induces type V collagen overexpression and EMT via TGF-β-dependent pathways in obliterative bronchiolitis

HIF‐1α regulates EMT via the Snail and β‐catenin pathways in paraquat poisoning‐induced early pulmonary fibrosis

Krüppel-like factor 8 involved in hypoxia promotes the invasion and metastasis of gastric cancer via epithelial to mesenchymal transition

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