title: Attenuating endogenous Fgfr2b ligands during bleomycin-induced lung fibrosis does not compromise murine lung repair.
abstract: Fibroblast growth factors (Fgfs) mediate organ repair. Lung epithelial cell overexpression of Fgf10 postbleomycin 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 on 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 by 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 postnatal days (PN) 1 through PN105. Female single-transgenic (STG) and DTG mice were subjected to various levels of bleomycin injury (1.0, 2.0, and 3.0 U/kg). Fgfr2b ligands were attenuated either throughout injury (days 0-11; days 0-28) or during later stages (days 6-28 and 14-28). 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-induced lung injury in mice.
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany;
authors.forename: BreAnne
authors.initials: B
authors.lastname: MacKenzie
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany;
authors.forename: Ingrid
authors.initials: I
authors.lastname: Henneke
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany;
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hezel
authors.affiliation: Developmental Biology Program, Division of Surgery, Saban Research Institute of Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, California;
authors.forename: Denise
authors.initials: D
authors.lastname: Al Alam
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany;
authors.forename: Elie
authors.initials: E
authors.lastname: El Agha
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany;
authors.forename: Cho-Ming
authors.initials: CM
authors.lastname: Chao
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Quantius
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany;
authors.forename: Jochen
authors.initials: J
authors.lastname: Wilhelm
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany;
authors.forename: Matthew
authors.initials: M
authors.lastname: Jones
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany;
authors.forename: Kerstin
authors.initials: K
authors.lastname: Goth
authors.affiliation: School of Pharmacy, Wenzhou Medical College, China;
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany;
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.affiliation: Comprehensive Pneumology Center, Ludwig Maximilians University, University Hospital Grosshadern, and Helmholtz Zentrum München, Munich, Bavaria, Germany;
authors.forename: Melanie
authors.initials: M
authors.lastname: Königshoff
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany;
authors.forename: Susanne
authors.initials: S
authors.lastname: Herold
authors.affiliation: Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia.
authors.forename: Albert A
authors.initials: AA
authors.lastname: Rizvanov
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany; AGAPLESION Lung Clinic Waldhof-Elgershausen, Greifenstein, Germany; German Center for Lung Research, Germany;
authors.forename: Andreas
authors.initials: A
authors.lastname: Günther
authors.affiliation: German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, Giessen, Hessen, Germany; Developmental Biology Program, Division of Surgery, Saban Research Institute of Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, California; Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia saverio.bellusci@innere.med.uni-giessen.de.
authors.forename: Saverio
authors.initials: S
authors.lastname: Bellusci
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000494:pharmacology; D001761:Bleomycin / Q000009:adverse effects* / Q000494:pharmacology; D005260:Female; D051523:Fibroblast Growth Factor 7 / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D051523:Fibroblast Growth Factor 7; D051497:Receptor, Fibroblast Growth Factor, Type 2
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