Fibroblast-Specific Expression of Adenylyl Cyclase 6 Reduces Myofibroblast Differentiation and Protects Against Bleomycin-Induced Pulmonary Fibrosis
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.
X Liu, F Li and RS Ostrom. Fibroblast-specific expression of adenylyl cyclase 6 reduces myofibroblast differentiation and protects against bleomycin-induced pulmonary fibrosis. FASEB J, 22(1):928.5, 2008.
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