Title

Fibroblast-Specific Expression of Adenylyl Cyclase 6 Reduces Myofibroblast Differentiation and Protects Against Bleomycin-Induced Pulmonary Fibrosis

Document Type

Abstract

Publication Date

2008

Abstract

Pulmonary fibroblasts (PF) regulate extracellular matrix production and degradation and are critical in maintenance of lung structure, function and repair. cAMP-elevating agents inhibit cytokine- and growth factor-stimulated myofibroblast differentiation and collagen synthesis in PF and overexpression of adenylyl cyclase 6 (AC6) enhances these responses. Thus, we generated transgenic mice that overexpress AC6 under a fibroblast-specific promoter, FTS1. FTS1-AC6+/– mice or littermate controls were given intratracheal instillation of saline or bleomycin (5 mg/Kg) and their lungs were removed after 14 days for pathological analysis and assay of collagen content. H&E and trichrome staining revealed normal lung histology in both FTS1-AC6+/– and WT mice receiving saline. The WT mice receiving bleomycin showed extensive peri-bronchial and interstitial fibrosis and collagen deposition. By contrast, FTS1-AC6+/– mice displayed more limited fibrotic development and lower total collagen content. Blinded pathological scoring of the degree of fibrosis (using a 0–8 scale with 8 being the most fibrotic) indicates a statistically significant effect of the FTS1-AC6 transgene (WT: 6.4 ± 0.2, FTS1-AC6+/–: 3.5 ± 0.4, p < 0.001). We conclude that AC6 overexpression inhibits fibrogenesis in the lung by reducing PF-mediated collagen synthesis and myofibroblast differentiation.

Comments

This abstract was originally published in FASEB Journal, volume 22, issue 1 (supplement), in 2008.

Copyright

Federation of American Society of Experimental Biology (FASEB)