CCAAT/Enhancer Binding Protein-α Regulates the Protease/Antiprotease Balance Required for Bronchiolar Epithelium Regeneration

Many transcription factors that regulate lung morphogenesis during development are reactivated to mediate repairs of the injured adult lung. We hypothesized that CCAAT/enhancer binding protein-alpha (C/EBP alpha), a transcription factor critical for perinatal lung maturation, regulates genes required for the normal repair of the bronchiolar epithelium after injury. Transgenic Cebp alpha(Delta/Delta) mice, in which CEBP alpha was conditionally deleted from Clara cells and Type II cells afterbirth, were used in this study. Airway injury was induced in mice by the intraperitoneal administration of naphthalene to ablate bronchiolar epithelial cells. Although the deletion of C/EBP alpha did not influence lung structure and function under unstressed conditions, C/EBP alpha was required for the normal repair of terminal bronchiolar epithelium after naphthalene injury. To identify cellular processes that are influenced by C/EBP alpha during repair, mRNA microarray was performed on terminal bronchiolar epithelial cells isolated by laser-capture microdissection. Normal repair of the terminal bronchiolar epithelium was highly associated with the mRNAs regulating antiprotease activities, and their induction required C/EBP alpha. The defective deposition of fibronectin in Cebp alpha(Delta/Delta) mice was associated with increased protease activity and delayed differentiation of FoxJ1-expressing ciliated cells. The fibronectin and ciliated cells were restored by the intratracheal treatment of Cebp alpha(Delta/Delta) mice with the serine protease inhibitor. In conclusion, C/EBP alpha regulates the expression of serine protease inhibitors that are required for the normal increase of fibronectin and the restoration of ciliated cells after injury. Treatment with serine protease inhibitor may aid in the recovery of injured bronchiolar epithelial cells, and prevent common chronic lung diseases.