Dataset Information

Overexpression of fibroblast growth factor-10 during both inflammatory and fibrotic phases attenuates bleomycin-induced pulmonary fibrosis in mice.

ABSTRACT:

Rationale

Fibroblast growth factor-10 (FGF10) controls survival, proliferation, and differentiation of distal-alveolar epithelial progenitor cells during lung development.

Objectives

To test for the protective and regenerative effect of Fgf10 overexpression in a bleomycin-induced mouse model of pulmonary inflammation and fibrosis.

Methods

In SP-C-rtTA; tet(O)Fgf10 double-transgenic mice, lung fibrosis was induced in 2-month-old transgenic mice by subcutaneous delivery of bleomycin (BLM), using an osmotic minipump for 1 week. Exogenous Fgf10 expression in the alveolar epithelium was induced for 7 days with doxycycline during the first, second, and third weeks after bleomycin pump implantation, and lungs were examined at 28 days.

Measurements and main results

Fgf10 overexpression during Week 1 (inflammatory phase) resulted in increased survival and attenuated lung fibrosis score and collagen deposition. In these Fgf10-overexpressing mice, an increase in regulatory T cells and a reduction in both transforming growth factor-beta(1) and matrix metalloproteinase-2 activity were observed in bronchoalveolar lavage fluids whereas the number of surfactant protein C (SP-C)-positive, alveolar epithelial type II cells (AEC2) was markedly elevated. Analysis of SP-C and TUNEL (terminal deoxynucleotidyltransferase dUTP nick end labeling) double-positive cells and isolation of AEC2 from lungs overexpressing Fgf10 demonstrated increased AEC2 survival. Expression of Fgf10 during Weeks 2 and 3 (fibrotic phase) showed significant attenuation of the lung fibrosis score and collagen deposition.

Conclusions

In the bleomycin model of lung inflammation and fibrosis, Fgf10 overexpression during both the inflammatory and fibrotic phases results in a greatly reduced extent of lung fibrosis, suggesting that FGF10 may be useful as a novel approach to the treatment of pulmonary fibrosis.

SUBMITTER: Gupte VV

PROVIDER: S-EPMC2742760 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Overexpression of fibroblast growth factor-10 during both inflammatory and fibrotic phases attenuates bleomycin-induced pulmonary fibrosis in mice.

Gupte Varsha V VV Ramasamy Suresh K SK Reddy Raghava R Lee Jooeun J Weinreb Paul H PH Violette Shelia M SM Guenther Andreas A Warburton David D Driscoll Barbara B Minoo Parviz P Bellusci Saverio S

American journal of respiratory and critical care medicine 20090604 5

<h4>Rationale</h4>Fibroblast growth factor-10 (FGF10) controls survival, proliferation, and differentiation of distal-alveolar epithelial progenitor cells during lung development.<h4>Objectives</h4>To test for the protective and regenerative effect of Fgf10 overexpression in a bleomycin-induced mouse model of pulmonary inflammation and fibrosis.<h4>Methods</h4>In SP-C-rtTA; tet(O)Fgf10 double-transgenic mice, lung fibrosis was induced in 2-month-old transgenic mice by subcutaneous delivery of bl ...[more]

PMID: 19498056

Similar Datasets

Project description:ObjectiveSecretoglobin (SCGB) 3A2 is a novel lung-enriched cytokine, previously shown to exhibit anti-inflammatory, growth factor, and anti-fibrotic activities. The latter activity was demonstrated using exogenously-administered recombinant SCGB3A2 in the bleomycin (BLM)-induced pulmonary fibrosis model. Whether SCGB3A2 exhibits anti-fibrotic activity in vivo is not known.MethodsMice null for the Scgb3a2 gene were subjected to the BLM-induced pulmonary fibrosis model, and the severity of pulmonary fibrosis determined using histological and biochemical methods.ResultsBLM treatment caused weight loss of both Scgb3a2-null and wild-type mice, however, the loss was far more pronounced in BLM-treated Scgb3a2-null than wild-type mice, and the weight of day 21 of BLM-treated Scgb3a2-null mice was about half of that of BLM-treated wild-type mice. Hematoxylin & Eosin, Masson Trichrome, and Sirius Red staining of lung sections, Ashcroft fibrosis scores, hydroxyproline contents, and the levels of mRNAs encoding various collagens demonstrated that BLM-treated Scgb3a2-null mouse lungs had more severe fibrosis than those of wild-type mouse lungs. Total and differential inflammatory cell numbers in bronchoalveolar lavage fluids, and levels of lung mRNAs including those encoding Th2 cytokines such as IL-4 and profibrotic cytokines such as TGF? were higher in BLM-treated Scgb3a2-null mouse lungs as compared to those of wild-type mouse lungs. In contrast, mRNAs encoding surfactant proteins A, B, C, and D, and SCGB1A1 did not differ between BLM-treated Scgb3a2-null and wild-type mouse lungs.ConclusionThe role of SCGB3A2 in fibrosis was revisited using Scgb3a2-null mice and littermate controls in the BLM-induced pulmonary fibrosis model. The pulmonary fibrosis in the Scgb3a2-null mice was more severe than the wild-type controls, thus establishing that SCGB3A2 has anti-fibrotic activity in vivo. Importantly, surfactant proteins and SCGB1A1 appear not to be involved in the susceptibility of Scgb3a2-null mice to BLM-induced pulmonary fibrosis.

Project description:Fibroblast growth factor (FGF) signaling has been implicated in the pathogenesis of pulmonary fibrosis. Mice lacking FGF2 have increased mortality and impaired epithelial recovery after bleomycin exposure, supporting a protective or reparative function following lung injury. To determine whether FGF2 overexpression reduces bleomycin-induced injury, we developed an inducible genetic system to express FGF2 in type II pneumocytes. Double-transgenic (DTG) mice with doxycycline-inducible overexpression of human FGF2 (SPC-rtTA;TRE-hFGF2) or single-transgenic controls were administered intratracheal bleomycin and fed doxycycline chow, starting at either day 0 or day 7. In addition, wild-type mice received intratracheal or intravenous recombinant FGF2, starting at the time of bleomycin treatment. Compared to controls, doxycycline-induced DTG mice had decreased pulmonary fibrosis 21 days after bleomycin, as assessed by gene expression and histology. This beneficial effect was seen when FGF2 overexpression was induced at day 0 or day 7 after bleomycin. FGF2 overexpression did not alter epithelial gene expression, bronchoalveolar lavage cellularity or total protein. In vitro studies using primary mouse and human lung fibroblasts showed that FGF2 strongly inhibited baseline and TGF?1-induced expression of alpha smooth muscle actin (?SMA), collagen, and connective tissue growth factor. While FGF2 did not suppress phosphorylation of Smad2 or Smad-dependent gene expression, FGF2 inhibited TGF?1-induced stress fiber formation and serum response factor-dependent gene expression. FGF2 inhibition of stress fiber formation and ?SMA requires FGF receptor 1 (FGFR1) and downstream MEK/ERK, but not AKT signaling. In summary, overexpression of FGF2 protects against bleomycin-induced pulmonary fibrosis in vivo and reverses TGF?1-induced collagen and ?SMA expression and stress fiber formation in lung fibroblasts in vitro, without affecting either inflammation or epithelial gene expression. Our results suggest that in the lung, FGF2 is antifibrotic in part through decreased collagen expression and fibroblast to myofibroblast differentiation. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Dataset Information

Overexpression of fibroblast growth factor-10 during both inflammatory and fibrotic phases attenuates bleomycin-induced pulmonary fibrosis in mice.

Rationale

Objectives

Methods

Measurements and main results

Conclusions

Publications

Overexpression of fibroblast growth factor-10 during both inflammatory and fibrotic phases attenuates bleomycin-induced pulmonary fibrosis in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets