Serine Protease Imbalance in the Small Airways and Development of Centrilobular Emphysema in COPD

• Published in: American journal of respiratory cell and molecular biology
• Main Authors: Uemasu, Kiyoshi, Tanabe, Naoya, Tanimura, Kazuya, Hasegawa, Koichi, Mizutani, Tatsushi, Hamakawa, Yoko, Sato, Susumu, Ogawa, Emiko, Thomas, Matthew J, Ikegami, Machiko, Muro, Shigeo, Hirai, Toyohiro, Sato, Atsuyasu
• Format: Journal Article
• Language: English
• Published: United States 26.02.2020
• Subjects: C/EBPα; LEKTI; COPD; emphysema
• ISSN: 1535-4989

Epithelial dysfunction in the small airways may cause the development of emphysema in chronic obstructive pulmonary disease. CCAAT/enhancer binding protein-α (C/EBPα), a transcription factor, is required for lung maturation during development and is also important for lung homeostasis after birth, including the maintenance of serine protease/antiprotease balance in the bronchiolar epithelium. This study aimed to show the roles of C/EBPα in the distal airway during chronic cigarette smoke (CS) exposure in mice and in the small airways in smokers. In a model of chronic smoke exposure using epithelial cell-specific C/EBPα-knockout mice, significant pathological phenotypes, such as higher protease activity, impaired ciliated cell regeneration, epithelial cell barrier dysfunction via reduced Zo-1, and decreased alveolar attachments, were found in C/EBPα-knockout mice compared to control mice. We found that Spink5 gene (encoding Lympho-epithelial Kazal-type-related inhibitor (LEKTI), an anti-serine protease) expression in the small airways is a key regulator of protease activity in this model. Finally, we showed that daily antiprotease treatment counteracted the phenotypes of C/EBPα-knockout mice. In human studies, CEBPA expression in the lung was downregulated in patients with emphysema, and 6 smokers with centrilobular emphysema (CLE) showed a significant reduction in LEKTI in the small airways compared to 22 non-CLE smokers. LEKTI downregulation in the small airways was associated with disease development during murine small airway injury and CLE in humans, suggesting that LEKTI might be a key factor linking small airway injury to the development of emphysema.