PloS one, 2012-04, Vol.7 (4), p.e35926
2012
Details
- Autor(en) / Beteiligte
- Titel
- Lipopolysaccharide induces lung fibroblast proliferation through Toll-like receptor 4 signaling and the phosphoinositide3-kinase-Akt pathway
- Ist Teil von
- PloS one, 2012-04, Vol.7 (4), p.e35926
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2012
- Link zum Volltext
- Quelle
- EZB-FREE-00999 freely available EZB journals
- Beschreibungen/Notizen
- Pulmonary fibrosis is characterized by lung fibroblast proliferation and collagen secretion. In lipopolysaccharide (LPS)-induced acute lung injury (ALI), aberrant proliferation of lung fibroblasts is initiated in early disease stages, but the underlying mechanism remains unknown. In this study, we knocked down Toll-like receptor 4 (TLR4) expression in cultured mouse lung fibroblasts using TLR4-siRNA-lentivirus in order to investigate the effects of LPS challenge on lung fibroblast proliferation, phosphoinositide3-kinase (PI3K)-Akt pathway activation, and phosphatase and tensin homolog (PTEN) expression. Lung fibroblast proliferation, detected by BrdU assay, was unaffected by 1 mug/mL LPS challenge up to 24 hours, but at 72 hours, cell proliferation increased significantly. This proliferation was inhibited by siRNA-mediated TLR4 knockdown or treatment with the PI3K inhibitor, Ly294002. In addition, siRNA-mediated knockdown of TLR4 inhibited the LPS-induced up-regulation of TLR4, down-regulation of PTEN, and activation of the PI3K-Akt pathway (overexpression of phospho-Akt) at 72 hours, as detected by real-time PCR and Western blot analysis. Treatment with the PTEN inhibitor, bpV(phen), led to activation of the PI3K-Akt pathway. Neither the baseline expression nor LPS-induced down-regulation of PTEN in lung fibroblasts was influenced by PI3K activation state. PTEN inhibition was sufficient to exert the LPS effect on lung fibroblast proliferation, and PI3K-Akt pathway inhibition could reverse this process. Collectively, these results indicate that LPS can promote lung fibroblast proliferation via a TLR4 signaling mechanism that involves PTEN expression down-regulation and PI3K-Akt pathway activation. Moreover, PI3K-Akt pathway activation is a downstream effect of PTEN inhibition and plays a critical role in lung fibroblast proliferation. This mechanism could contribute to, and possibly accelerate, pulmonary fibrosis in the early stages of ALI/ARDS.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0035926Titel-ID: cdi_plos_journals_1324595976
- Format
- –
- Schlagworte
- 1-Phosphatidylinositol 3-kinase, Aberration, AKT protein, Anesthesiology, Animals, Apoptosis, Biology, Cell cycle, Cell proliferation, Cell Proliferation - drug effects, Cells, Cultured, Chromones - pharmacology, Collagen, Critical care, Cytokines, Desulfovibrio desulfuricans, Down-regulation, Down-Regulation - drug effects, Fibroblasts, Fibroblasts - cytology, Fibroblasts - metabolism, Fibrosis, Growth factors, Homology, Hyperoxia, Inhibition, Inhibitors, Kinases, Laboratory animals, Lipopolysaccharides, Lipopolysaccharides - toxicity, Lung - cytology, Lung - metabolism, Lung cancer, Lung diseases, Medicine, Mice, Mice, Inbred C57BL, Mitogens, Morpholines - pharmacology, Organometallic Compounds - pharmacology, Phenanthrolines - pharmacology, Phosphatase, Phosphatases, Phosphatidylinositol 3-Kinases - antagonists & inhibitors, Phosphatidylinositol 3-Kinases - metabolism, Proto-Oncogene Proteins c-akt - metabolism, PTEN Phosphohydrolase - antagonists & inhibitors, PTEN Phosphohydrolase - genetics, PTEN Phosphohydrolase - metabolism, PTEN protein, Pulmonary fibrosis, RNA Interference, RNA, Small Interfering - metabolism, Rodents, Secretion, Signal transduction, Signal Transduction - drug effects, Signaling, siRNA, Tensin, TLR4 protein, Toll-Like Receptor 4 - antagonists & inhibitors, Toll-Like Receptor 4 - genetics, Toll-Like Receptor 4 - metabolism, Toll-like receptors, Up-Regulation - drug effects