Development of pulmonary fibrosis through a pathway involving the transcription factor Fra-2/AP-1.
Studies using genetically modified mice have revealed fundamental functions of the transcription factor Fos/AP-1 in bone biology, inflammation, and cancer. However, the biological role of the Fos-related protein Fra-2 is not well defined in vivo. Here we report an unexpected profibrogenic function of Fra-2 in transgenic mice, in which ectopic expression of Fra-2 in various organs resulted in generalized fibrosis with predominant manifestation in the lung. The pulmonary phenotype was characterized by vascular remodeling and obliteration of pulmonary arteries, which coincided with expression of osteopontin, an AP-1 target gene involved in vascular remodeling and fibrogenesis. These alterations were followed by inflammation; release of profibrogenic factors, such as IL-4, insulin-like growth factor 1, and CXCL5; progressive fibrosis; and premature mortality. Genetic experiments and bone marrow reconstitutions suggested that fibrosis developed independently of B and T cells and was not mediated by autoimmunity despite the marked inflammation observed in transgenic lungs. Importantly, strong expression of Fra-2 was also observed in human samples of idiopathic and autoimmune-mediated pulmonary fibrosis. These findings indicate that Fra-2 expression is sufficient to cause pulmonary fibrosis in mice, possibly by linking vascular remodeling and fibrogenesis, and suggest that Fra-2 has to be considered a contributing pathogenic factor of pulmonary fibrosis in humans.
Eferl
Robert
R
Research Institute of Molecular Pathology, Doktor Bohr-Gasse 7, A-1030 Vienna, Austria.
Hasselblatt
Peter
P
Rath
Martina
M
Popper
Helmut
H
Zenz
Rainer
R
Komnenovic
Vukoslav
V
Idarraga
Maria-Helena
MH
Kenner
Lukas
L
Wagner
Erwin F
EF
D000818:Animals; D054365:Chemokine CXCL5 / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D051921:Fos-Related Antigen-2 / Q000096:biosynthesis*; D006801:Humans; D007249:Inflammation; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008168:Lung / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000235:genetics* / Q000473:pathology*; D018808:Transcription Factor AP-1 / Q000378:metabolism*
C486263:CXCL5 protein, human; D054365:Chemokine CXCL5; D051921:Fos-Related Antigen-2; D018808:Transcription Factor AP-1; D015847:Interleukin-4; D007334:Insulin-Like Growth Factor I