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MacKenzie, B.* ; Henneke, I.* ; Hezel, S.* ; Al Alam, D.* ; El Agha, E.* ; Chao, C.M.* ; Quantius, J.* ; Wilhelm, J.* ; Jones, M.* ; Goth, K.* ; Li, X.* ; Seeger, W.* ; Königshoff, M. ; Herold, S.* ; Rizvanov, A.A.* ; Günther, A.* ; Bellusci, S.*

Attenuating endogenous Fgfr2b ligands during bleomycin-induced lung fibrosis does not compromise murine lung repair.

Am. J. Physiol. Lung Cell Mol. Physiol. 308, L1014-L1024 (2015)

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Fibroblast growth factors (Fgfs) mediate organ repair. Lung epithelial cell overexpression of Fgf10 post-bleomycin injury is both protective and therapeutic, characterized by increased survival and attenuated fibrosis. Exogenous administration of FGF7 (Palifermin) also showed prophylactic survival benefits in mice. The role of endogenous Fgfr2b ligands upon bleomycin-induced lung fibrosis is still elusive. This study reports the expression of endogenous Fgfr2b ligands, receptors and signaling targets in wild type mice following bleomycin lung injury. In addition, the impact of attenuating endogenous Fgfr2b-ligands following bleomycin-induced fibrosis was tested using a doxycycline (dox)-based inducible, soluble, dominant-negative form of the Fgfr2b receptor. Double transgenic (DTG) Rosa26(rtTA/+);tet(O)solFgfr2b mice were validated for the expression and activity of soluble Fgfr2b (failure to regenerate maxillary incisors, attenuated recombinant FGF7 signal in the lung). As previously reported, no defects in lung morphometry were detected in DTG (+dox) mice exposed from post-natal (PN) 1 through PN105. Female single transgenic (STG) and DTG mice were subjected to various levels of bleomycin injury (1.0, 2.0, and 3.0U/kg). Fgfr2b ligands were attenuated either throughout injury (d0-d11; d0-28) or during later stages (d6-d28 and d14-d28). No significant changes in survival, weight, lung function, confluent areas of fibrosis, or hydroxyproline deposition were detected in DTG mice. These results indicate that endogenous Fgfr2b ligands do not significantly protect against bleomycin injury, nor do they expedite the resolution of bleomycin lung induced injury in mice.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Fgf ; Ipf ; Bleomycin ; Genetics ; Lung Fibrosis; Keratinocyte Growth-factor; Idiopathic Pulmonary-fibrosis; Gene-expression; Mouse Lung; Mice; Receptor; Injury; Cells; Morphogenesis; Epithelium

ISSN (print) / ISBN 1040-0605

e-ISSN 1522-1504

Journal American Journal of Physiology - Lung Cellular and Molecular Physiology

Quellenangaben Volume: 308, Issue: 10, Pages: L1014-L1024

Publisher American Physiological Society

Publishing Place Bethesda, Md. [u.a.]

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Lung Health and Immunity (LHI)