Reemergence of hedgehog mediates epithelial-mesenchymal crosstalk in pulmonary fibrosis.

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TitleReemergence of hedgehog mediates epithelial-mesenchymal crosstalk in pulmonary fibrosis.
Publication TypeJournal Article
Year of Publication2015
AuthorsHu B, Liu J, Wu Z, Liu T, Ullenbruch MR, Ding L, Henke CA, Bitterman PB, Phan SH
JournalAm J Respir Cell Mol Biol
Volume52
Issue4
Pagination418-28
Date Published2015 Apr
ISSN1535-4989
Abstract

Hedgehog signaling plays important roles in cell development and differentiation. In this study, the ability of Sonic Hedgehog (SHH) to induce myofibroblast differentiation was analyzed in isolated human lung fibroblasts, and its in vivo significance was evaluated in rodent bleomycin-induced pulmonary fibrosis. The results showed that SHH could induce myofibroblast differentiation in human lung fibroblasts in a Smo- and Gli1-dependent manner. Gel shift analysis, chromatin immunoprecipitation assay, and site-directed mutagenesis revealed that a Gli1 binding consensus in the α-SMA gene promoter was important for mediating SHH-induced myofibroblast differentiation. Analysis of Hedgehog reemergence in vivo revealed that of all three Hedgehog isoforms, only SHH was significantly induced in bleomycin-injured lung along with Gli1. The induction of SHH was only noted in epithelial cells, and its expression was undetectable in lung fibroblasts or macrophages. transforming growth factor (TGF)-β induced SHH significantly in cultured alveolar epithelial cells, whereas SHH induced TGF-β in lung fibroblasts. Pulmonary fibrosis and α-smooth muscle actin (α-SMA) expression were significantly reduced in mice that were Smo deficient only in type I collagen-expressing cells. Thus, the reemergence of SHH in epithelial cells could result in induction of myofibroblast differentiation in a Smo-dependent manner and subsequent Gli1 activation of the α-SMA promoter.

DOI10.1165/rcmb.2014-0108OC
Alternate JournalAm. J. Respir. Cell Mol. Biol.
PubMed ID25140582
PubMed Central IDPMC4491120
Grant ListDK020572 / DK / NIDDK NIH HHS / United States
HL112880 / HL / NHLBI NIH HHS / United States
HL28737 / HL / NHLBI NIH HHS / United States
HL52285 / HL / NHLBI NIH HHS / United States
HL77297 / HL / NHLBI NIH HHS / United States
HL91775 / HL / NHLBI NIH HHS / United States
R01 HL052285 / HL / NHLBI NIH HHS / United States
R01 HL112880 / HL / NHLBI NIH HHS / United States
U24 DK097153 / DK / NIDDK NIH HHS / United States