Increased telomerase expression in fibroblasts occurs earlier than myofibroblast alfa-smooth muscle actin expression in the remodeling process of usual interstitial pneumonia

Abstract

Objective: To identify potential markers associated with fibroblast telomerase and interstitial myfibroblast alpha-smooth muscle actin (α-AMS) expression in patients with idiopathic pulmonary fibrosis/usual intersticial pneumonia (IPF/UIP). Methods: Pulmonary specimens included 34 surgical lung biopsies, histologically classified as UIP, from patients clinically diagnosed with IPF. Fibroblast telomerase expression, interstitial myofibroblast α-AMS expression and IL-4 (interleukin 4), TGF-β (transforming growth factor beta) and bFGF (basic fibroblast growth factor) tissue expression were evaluated by immunohistochemistry and quantified in collapsed (COL), mural fibrosis (MF) and honeycombing areas (HC). Results: Telomerase expression was significantly higher in COL areas than in MF and HC areas. The same was observed for b-FGF. Interleukin-4 and α-AMS expression were significantly higher in MF areas. TGF-β expression ws higher in COL and HC areas. We observed a positive correlation between telomerase and bFGF expression in COL, MF and HC areas. The same was noted for α-AMS and IL-4. In MF areas, a negative correlation between IL-4 and b-FGF was obtained and TGF-β tended to positively correlate with α-AMS. In multivariate analysis, IL-4 tissue and α-AMS myofibroblast expression in MF areas were independently predictive of mortality in a statistically significant model including age, tobacco use and FVC (full vital capacity). Patients with IL-4 expression lower than 13.5% in MF areas had better survival. The same was noted for α-AMS expression lower than 8.5%. Conclusion: Fibroblast multiplicative capacity, characterized by telomerase expression and associated with bFGF tissue expression, seems to predominate in the early remodeling process of IPF/UIP, whereas myofibroblast differentiation, characterized by alpha-smooth muscle actin expression and associated with IL-4 tissue expression, seems to lead to the later fibrotic response. Patient survival seems to be influenced by the intensity of this process