The WNT/beta-catenin pathway : Profibrotic signaling in fibroblasts in idiopathic pulmonary fibrosis
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Idiopathic pulmonary fibrosis (IPF) is the most common and most severe form of theidiopathic interstitial pneumonias (IIP). Unresponsive to any currently available therapy itleads to architectural distortion of the lung parenchyma and rapidly to respiratory failure.Although the pathogenesis of the disease is not completely understood, it is well accepted thatinitial alveolar epithelial cell injury is followed by enhanced fibroblast proliferation andactivation to myofibroblasts. These fibroblasts are considered as key effector cells in IPF. Theso called fibroblast foci represent hallmark lesions of the disease as they are responsible forthe increased ECM deposition that leads to impaired gas exchange and ultimately to fibrosis.The present study aimed to reveal possible profibrotic paracrine effects of recently identifiedprofibrotic mediators that trigger the disturbed crosstalk between alveolar epithelial cells typeII (ATII) and fibroblasts. Recently, WNT/beta-catenin signaling has been demonstrated to beinvolved in the pathogenesis of IPF. In particular it has been reported that WNT3a andWNT1-inducible signaling protein (WISP) 1 are secreted by ATII cells in IPF.In the present project it was hypothesized that WNT3a and WISP1 act in a paracrine fashionon fibroblasts, thereby contributing to the impaired ATII cell ̶ fibroblast crosstalk in thepathogenesis of IPF.It was shown that active WNT/beta-catenin signaling takes place in NIH-3T3 fibroblasts in vitroas assessed by Western Blot analysis and quantitative RT-PCR. To reveal functional effects ofactive WNT/beta-catenin signaling, thymidine [H3] incorporation proliferation assay,immunofluorescence, Sircol Collagen Assay, as well as quantitative (q) RT-PCR wereperformed.WNT3a stimulation of fibroblasts caused a significantly increased production of theextracellular matrix component collagen and led to transcriptional upregulation of fibroblastactivation markers. Interestingly, WNT3a stimulation did not affect fibroblast proliferation.The paracrine effects of WISP-1, which is encoded by a WNT target gene, were analyzed in acomparable way. Like WNT3a, WISP-1 led to enhanced collagen deposition as well asupregulation of fibroblast activation markers. Proliferation of the fibroblasts remainedunaffected.These results provided evidence that both molecules, WNT3a and WISP1, are capable ofactivating lung fibroblasts and causing increased collagen production in these cells. Thereforeit is strongly suggested that WNT3a and WISP-1, which are aberrantly secreted by ATII cellsin IPF, are profibrotic mediators that act in a paracrine fashion on fibroblasts during thepathogenesis of this fatal disease.Verknüpfung zu Publikationen oder weiteren Datensätzen
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Giessen : VVB Laufersweiler