Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 180, Issue 6, Pages 2257-2267Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2012.02.010
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Funding
- NIH [HL28737, HL31963, HL52285, HL77297, HL91775]
- National Institute of Diabetes and Digestive and Kidney Diseases [DK020572]
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The CCAAT/enhancer-binding protein beta (C/EBP beta) regulates a variety of factors and cellular responses associated with pulmonary fibrosis. To distinguish its role in the mesenchyme from that in other compartments, the effects of mesenchymal-specific deletion of C/EBP beta on pulmonary fibrosis was examined. Crossing of mice with the foxed C/EBP beta gene with alpha 2(I) collagen enhancer-CreER(T)-bearing mice successfully generated progeny with a conditional knockout (CKO) of C/EBP beta in collagen I-expressing (mesenchymal) cells only on treatment with tamoxifen (C/EBP beta CKO). When treated with an endotracheal bleomycin injection, C/EBP beta CKO mice showed significant attenuation of pulmonary fibrosis relative to control C/EBP beta-intact mice. C/EBP beta CKO mice also had reduced myofibroblasts in the lung. However, no significant differences in inflammatory/immune cell influx were noted in the mutant mice relative to the control mice. DNA microarray and real-time PCR analyses identified a series of myofibroblast differentiation regulators as novel target genes of C/EBP beta. Interestingly, C/EBP beta deficiency caused a marked induction of matrix metalloproteinase 12 expression, suggesting its potential role as a repressor, which could account for the noted reduction in fibrosis in the C/EBP beta-deficient mice. Thus, these findings indicate an essential role for C/EBP beta in the mesenchymal compartment in pulmonary fibrosis that is independent of its effects on inflammation or immune cell infiltration. (Am J Path, 2012, 180:22572267; http://dx.doi.org/10.1016/j.ajpath.2012.02.010)
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