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CCAAT/enhancer binding protein-? regulates the protease/antiprotease balance required for bronchiolar epithelium regeneration.

ABSTRACT: 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-? (C/EBP?), a transcription factor critical for perinatal lung maturation, regulates genes required for the normal repair of the bronchiolar epithelium after injury. Transgenic Cebp?(?/?) mice, in which Cebpa was conditionally deleted from Clara cells and Type II cells after birth, 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? did not influence lung structure and function under unstressed conditions, C/EBP? was required for the normal repair of terminal bronchiolar epithelium after naphthalene injury. To identify cellular processes that are influenced by C/EBP? 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?. The defective deposition of fibronectin in Cebp?(?/?) 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?(?/?) mice with the serine protease inhibitor. In conclusion, C/EBP? 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.

SUBMITTER: Sato A

PROVIDER: S-EPMC3488626 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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CCAAT/enhancer binding protein-α regulates the protease/antiprotease balance required for bronchiolar epithelium regeneration.

Sato Atsuyasu A Xu Yan Y Whitsett Jeffrey A JA Ikegami Machiko M

American journal of respiratory cell and molecular biology 20120531 4

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-α (C/EBPα), a transcription factor critical for perinatal lung maturation, regulates genes required for the normal repair of the bronchiolar epithelium after injury. Transgenic Cebpα(Δ/Δ) mice, in which Cebpa was conditionally deleted from Clara cells and Type II cells after birth, were used in this study. ...[more]

PMID: 22652201

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Project description:BACKGROUND: The imbalance between proteases and antiproteases has been proposed to participate to the pathogenesis of chronic obstructive pulmonary disease (COPD) and emphysema. Gene level variation in different metalloproteinases, metalloproteinase inhibitors, and cytokines affecting them may contribute to this imbalance and destruction of the lung parenchyma. We investigated whether polymorphisms in selected protease-antiprotease balance pathway genes predispose to different emphysema subtypes (centrilobular, paraseptal, panlobular, and bullae) and airflow limitation among Finnish construction workers. METHODS: Eleven single nucleotide polymorphisms (SNPs) from seven genes (GC: rs7041 and rs4588; MMP1: rs1799750; MMP9: rs3918242; MMP12: rs652438; TIMP2: rs2277698; TNF: rs1799724 and rs1800629; TGFB1: rs1800469, rs1800470, and rs2241718) were analyzed from 951 clinically and radiologically characterized construction workers. The genotype and haplotype data was compared to different emphysematous signs confirmed with high resolution computed tomography (HRCT), forced vital capacity (FVC), forced expiratory volume in one second (FEV?), and maximal expiratory flow at 50% of FVC (MEF50) by using linear and logistic regression analyses, adjusted for potential confounders. RESULTS: The TIMP2 rs2277698 SNP was associated with overall (p = 0.022) and paraseptal (p = 0.010) emphysema, as well as with FEV?/FVC ratio (p = 0.035) and MEF50 (p = 0.008). The TGFB1 rs2241718 and MMP9 rs3918242 SNPs were associated with centrilobular emphysema (p = 0.022 and p = 0.008), and the TNF rs1800629 SNP with paraseptal emphysema (p = 0.017). In stratified analysis, individuals with at least one TIMP2 rs2277698 or TNF rs1800629 variant allele were found to be at around two-fold risk for pathological paraseptal changes (OR 1.94, 95% CI 1.14-3.30; OR 2.10, 95% CI 1.24-3.56). On the contrary, the risk for pathological centrilobular changes was halved for individuals with at least one MMP9 rs3918242 (OR 0.51, 95% CI 0.30-0.86) or TGFB1 rs2241718 (OR 0.53, 95% CI 0.30-0.90) variant allele, or TGFB1 rs1800469-rs1800470 AT-haplotype (OR 0.55, 95% CI 0.33-0.93). MEF50, in turn, was significantly reduced among individuals with at least one TIMP2 rs2277698 variant allele (p = 0.011). CONCLUSION: Our findings strengthen the hypothesis of the importance of protease-antiprotease balance in pathogenesis of emphysema and shed light on the aetiology of different emphysema subtypes by associating MMP9 and TGFB1 to centrilobular emphysema, and TIMP2 and TNF to paraseptal emphysema and/or airflow obstruction.

Dataset Information

CCAAT/enhancer binding protein-? regulates the protease/antiprotease balance required for bronchiolar epithelium regeneration.

Publications

CCAAT/enhancer binding protein-α regulates the protease/antiprotease balance required for bronchiolar epithelium regeneration.

Similar Datasets

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