An essential role for CCAAT/enhancer binding protein beta in bleomycin-induced pulmonary fibrosis.
Pulmonary fibrosis is characterized by inflammation, genesis of myofibroblasts, and abnormal tissue repair. Despite extensive research, its pathogenesis remains incompletely understood. Previously, the transcription factor CCAAT/enhancer binding protein beta (C/EBPbeta) was found to be a key regulator of myofibroblast differentiation in vitro, and to be involved in the acute phase and inflammatory responses. In an attempt to test the role of C/EBPbeta in the development of pulmonary fibrosis, experiments using C/EBPbeta null mice and their wild-type littermates were conducted. Our findings indicated that, compared to wild-type mice, animals deficient in C/EBPbeta showed significantly reduced fibrotic lesions and collagen deposition in the lung upon endotracheal injection of bleomycin. Further studies on the mechanisms by which C/EBPbeta regulates fibrosis indicated that knockout of C/EBPbeta attenuates inflammatory cytokine expression in bleomycin-treated mice. The reduced alpha-smooth muscle actin gene expression in either isolated lung fibroblasts or lung tissue from bleomycin or saline-treated C/EBPbeta deficient mice suggests that C/EBPbeta regulates myofibroblast differentiation during fibrosis. Consistent with this finding, cells from C/EBPbeta deficient mice exhibited higher proliferative rates than those from wild-type mice. These data suggest that C/EBPbeta plays an essential role in pulmonary fibrosis and that this role appears to be multifactorial with respect to cytokine expression, cell differentiation, and proliferation.
Hu
B
B
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109-2200, USA.
Ullenbruch
M R
MR
Jin
H
H
Gharaee-Kermani
M
M
Phan
S H
SH
D000199:Actins; D000818:Animals; D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000032:analysis* / Q000172:deficiency; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D003094:Collagen / Q000032:analysis; D016207:Cytokines / Q000032:analysis; D005347:Fibroblasts / Q000502:physiology; D015870:Gene Expression; D005838:Genotype; D008168:Lung / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009130:Muscle, Smooth / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000032:analysis
D000199:Actins; D000903:Antibiotics, Antineoplastic; D022782:CCAAT-Enhancer-Binding Protein-beta; D016207:Cytokines; D012333:RNA, Messenger; D001761:Bleomycin; D003094:Collagen