Linked Life Data

19188658

Source:http://linkedlifedata.com/resource/pubmed/id/19188658

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2009-9-16
pubmed:abstractText
Myofibroblast apoptosis is critical for the normal resolution of wound repair responses, and impaired myofibroblast apoptosis is associated with tissue fibrosis. Lung expression of endothelin (ET)-1, a soluble peptide implicated in fibrogenesis, is increased in murine models of pulmonary fibrosis and in the lungs of humans with pulmonary fibrosis. Mechanistically, ET-1 has been shown to induce fibroblast proliferation, differentiation, contraction, and collagen synthesis. In this study, we examined the role ET-1 in the regulation of lung fibroblast survival and apoptosis. ET-1 rapidly activates the prosurvival phosphatidylinositol 3'-OH kinase (PI3K)/AKT signaling pathway in normal and fibrotic human lung fibroblasts. ET-1-induced activation of PI3K/AKT is dependent on p38 mitogen-activated protein kinase (MAPK), but not extracellular signal-regulated kinase (ERK) 1/2, JNK, or transforming growth factor (TGF)-beta1. Activation of the PI3K/AKT pathway by ET-1 inhibits fibroblast apoptosis, and this inhibition is reversed by blockade of p38 MAPK or PI3K. TGF-beta1 has been shown to attenuate myofibroblast apoptosis through the p38 MAPK-dependent secretion of a soluble factor, which activates PI3K/AKT. In this study, we show that, although TGF-beta1 induces fibroblast synthesis and secretion of ET-1, TGF-beta1 activation of PI3K/AKT is not dependent on ET-1. We conclude that ET-1 and TGF-beta1 independently promote fibroblast resistance to apoptosis through signaling pathways involving p38 MAPK and PI3K/AKT. These findings suggest the potential for novel therapies targeting the convergence of prosurvival signaling pathways activated by these two profibrotic mediators.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
1535-4989
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
41
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
484-93
pubmed:dateRevised
2011-9-26
pubmed:meshHeading
pubmed-meshheading:19188658-Adult, pubmed-meshheading:19188658-Animals, pubmed-meshheading:19188658-Apoptosis, pubmed-meshheading:19188658-Cells, Cultured, pubmed-meshheading:19188658-Cycloheximide, pubmed-meshheading:19188658-Endothelin-1, pubmed-meshheading:19188658-Enzyme Activation, pubmed-meshheading:19188658-Fas Ligand Protein, pubmed-meshheading:19188658-Fibroblasts, pubmed-meshheading:19188658-Humans, pubmed-meshheading:19188658-Idiopathic Pulmonary Fibrosis, pubmed-meshheading:19188658-Lung, pubmed-meshheading:19188658-Phosphatidylinositol 3-Kinases, pubmed-meshheading:19188658-Phosphorylation, pubmed-meshheading:19188658-Protein Kinase Inhibitors, pubmed-meshheading:19188658-Protein Processing, Post-Translational, pubmed-meshheading:19188658-Proto-Oncogene Proteins c-akt, pubmed-meshheading:19188658-RNA, Small Interfering, pubmed-meshheading:19188658-Signal Transduction, pubmed-meshheading:19188658-Sus scrofa, pubmed-meshheading:19188658-Swine, pubmed-meshheading:19188658-Transforming Growth Factor beta1, pubmed-meshheading:19188658-p38 Mitogen-Activated Protein Kinases
pubmed:year
2009
pubmed:articleTitle
Endothelin-1 and transforming growth factor-beta1 independently induce fibroblast resistance to apoptosis via AKT activation.
pubmed:affiliation
Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109-5642, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural