Serine Protease Imbalance in the Small Airways and Development of Centrilobular Emphysema in Chronic Obstructive Pulmonary Disease

• Published in: American journal of respiratory cell and molecular biology Vol. 63; no. 1; pp. 67 - 78
• 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: New York American Thoracic Society 01.07.2020
• Subjects: Alveoli; CCAAT/enhancer-binding protein; Chronic obstructive pulmonary disease; Cigarette smoke; Clinical trials; Emphysema; Epithelial cells; Epithelium; Homeostasis; Lung diseases; Obstructive lung disease; Phenotypes; Proteases; Proteinase inhibitors; Serine; Serine proteinase; Sleep apnea; Zonula occludens-1 protein
• ISSN: 1044-1549; 1535-4989
• DOI: 10.1165/rcmb.2019-0377OC

Epithelial dysfunction in the small airways may cause the development of emphysema in chronic obstructive pulmonary disease. C/EBPα (CCAAT/enhancer binding protein-α), 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 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 zonula occludens-1 (Zo-1), and decreased alveolar attachments, were found in C/EBPα-knockout mice compared with control mice. We found that Spink5 (serine protease inhibitor kazal-type 5) gene (encoding lymphoepithelial Kazal-type-related inhibitor [LEKTI], an anti-serine protease) expression in the small airways is a key regulator of protease activity in this model.