Susceptibility of signal transducer and activator of transcription-1-deficient mice to pulmonary fibrogenesis.
The signal transducer and activator of transcription (Stat)-1 mediates growth arrest and apoptosis. We postulated that lung fibrosis characterized by excessive proliferation of lung fibroblasts would be enhanced in Stat1-deficient (Stat1-/-) mice. Two weeks after bleomycin aspiration (3 U/kg), Stat1-/- mice exhibited a more severe fibroproliferative response and significantly elevated total lung collagen compared to wild-type mice. Growth factors [epidermal growth factor (EGF) or platelet-derived growth factor (PDGF)] enhanced [3H]thymidine uptake in lung fibroblasts isolated from Stat1-/- mice compared to wild-type mice. Interferon (IFN)-gamma, which signals growth arrest via Stat1, inhibited EGF- or PDGF-stimulated mitogenesis in wild-type fibroblasts but enhanced [3H]thymidine uptake in Stat1-/- fibroblasts. Moreover, IFN-gamma treatment in the absence of growth factors induced a concentration-dependent increase in [3H]thymidine uptake in Stat1-/- but not wild-type fibroblasts. Mitogen-activated protein kinase (ERK-1/2) phosphorylation in response to PDGF or EGF did not differ among Stat1-/- and wild-type fibroblasts. However, Stat3 phosphorylation induced by PDGF, EGF, or IFN-gamma increased twofold in Stat1-/- fibroblasts compared to wild-type fibroblasts. Our findings indicate that Stat1-/- mice are more susceptible to bleomycin-induced lung fibrosis than wild-type mice due to 1) enhanced fibroblast proliferation in response to growth factors (EGF and PDGF), 2) stimulation of fibroblast growth by a Stat1-independent IFN-gamma signaling pathway, and 3) increased activation of Stat3.
Walters
Dianne M
DM
CIIT Centers for Health Research, P.O. Box 12137, Research Triangle Park, NC 27709, USA.
Antao-Menezes
Aurita
A
Ingram
Jennifer L
JL
Rice
Annette B
AB
Nyska
Abraham
A
Tani
Yoshiro
Y
Kleeberger
Steven R
SR
Bonner
James C
JC
D000818:Animals; D001761:Bleomycin / Q000633:toxicity; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000032:analysis; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005347:Fibroblasts / Q000473:pathology; D006131:Growth Inhibitors / Q000494:pharmacology; D006909:Hydroxyproline / Q000032:analysis; D007371:Interferon-gamma / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism
D006131:Growth Inhibitors; D010982:Platelet-Derived Growth Factor; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D001761:Bleomycin; D004815:Epidermal Growth Factor; D007371:Interferon-gamma; D003094:Collagen; D048052:Mitogen-Activated Protein Kinase 3; D006909:Hydroxyproline; D013936:Thymidine