Haplodeletion of Follistatin-Like 1 Attenuates Radiation-Induced Pulmonary Fibrosis in Mice.

Abstract

Radiation-induced pulmonary fibrosis (RIPF) is a severe and life-threatening complication of radiation therapy in patients with thoracic cancer; however, the exact molecular mechanisms remain unknown, and there is no effective treatment method in clinic. Here, we assessed the role of follistatin-like 1 (Fstl1) in RIPF. Protein and messenger RNA levels of Fstl1 in lung tissues from symptomatic RIPF patients, Rhesus macaques, and mice were assessed. Fibrotic and inflammatory responses to radiation-induced lung injury and accumulation of myofibroblasts in Fstl1 haplodeficient (Fstl1^+/-) mice were determined. Finally, radiation-induced differentiation and activation of fibroblasts in primary Fstl1^+/- lung fibroblasts were evaluated. FSTL1 amounts were significantly increased in serum and/or radiation-injured lung specimens from symptomatic RIPF patients, Rhesus macaques, and mice. Haplodeletion of Fstl1 in Fstl1^+/- mice was protective against x-ray-induced lung injury in mice in vivo, as well as myofibroblast activation in vitro. These findings suggest that Fstl1 plays an important role in lung fibrosis and may offer a potential approach to attenuate RIPF in radiation therapy of patients with thoracic cancer.