Mammalian Target of Rapamycin Inhibition With Rapamycin Mitigates Radiation-Induced Pulmonary Fibrosis in a Murine Model

Abstract

Background Radiation-induced pulmonary fibrosis (RIPF) is a late toxicity of therapeutic radiation. mTOR signaling drives several processes implicated in RIPF, including inflammatory cytokine production, fibroblast proliferation, and epithelial senescence. We sought to determine if mTOR inhibition with rapamycin would mitigate RIPF. Methods/Materials C57BL/6NCr mice received a diet formulated with rapamycin (14 mg/kg food) or control diet two days before and continuing for 16 weeks after exposure to 5 daily fractions of 6 Gy thoracic irradiation (IR). Fibrosis was assessed with Masson-Trichrome staining and hydroxyproline assay. Cytokine expression was evaluated by quantitative real time PCR. Senescence was assessed by staining for beta-galactosidase activity. Results Administration of rapamycin extended the median survival of irradiated mice compared to control diet from 116 days to 156 days (log rank p=0.006). Treatment with rapamycin reduced hydroxyproline content compared to control diet (IR+vehicle: 45.9±11.8, IR+rapamycin: 21.4±6.0, p=0.001) and reduced visible fibrotic foci. Rapamycin treatment attenuated IL-1β and TGF-β induction in irradiated lung compared to control diet. Type II pneumocyte senescence after IR was reduced with rapamycin treatment at 16 weeks (three-fold reduction at 16 weeks, p<0.001). Conclusion Rapamycin protected against RIPF in a murine model. Rapamycin treatment reduced inflammatory cytokine expression, extra cellular matrix production, and senescence in type II pneumocytes.

Nebulisation of synthetic lamellar lipids mitigates radiation-induced lung injury in a large animal model

“…In a murine model of radiation-induced fibrosis, type II pneumocyte senescence occurred in a time and dose-dependent fashion following whole thorax irradiation, which was thought to reduce the stem cell compartment 71 . There is a complex set of pro-inflammatory, immunomodulatory and mitogenic cytokines that comprise the secretory profile of senescence (SASP), including TGF-β1, IL-1β, and IL-6 that have implications on RILI 72 , 73 . In a more recent murine study of radiation-induced lung fibrosis, rapamcyin effectively mitigated type II pneumocyte senescence, inflammatory cytokine expression, and collagen production 72 .…”

“…There is a complex set of pro-inflammatory, immunomodulatory and mitogenic cytokines that comprise the secretory profile of senescence (SASP), including TGF-β1, IL-1β, and IL-6 that have implications on RILI 72 , 73 . In a more recent murine study of radiation-induced lung fibrosis, rapamcyin effectively mitigated type II pneumocyte senescence, inflammatory cytokine expression, and collagen production 72 . Further study is warranted to determine whether the enlarged type II pneumocytes in the present study represent cells that have undergone radiation-induced early senescence.…”

Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles

“…Accordingly, rapamycin treatment partially protects mice from IPF caused by bleomycin 241 or radiation 244 , as well as from hypoxia-induced PAH 245 . Similarly, the intranasal delivery of a Becn1 -coding lentivirus successfully restores autophagy and limits inflammation in Cftr F508Δ mice (a model of cystic fibrosis) 243 , as does the genetic inactivation of Rptor or Mtor in mouse models of hyperoxia-induced or lipopolysaccharide-induced acute lung injury 246,247 .…”

Rapamycin protects against paraquat‑induced pulmonary epithelial‑mesenchymal transition via the Wnt/β‑catenin signaling pathway

“…However, whether mTOR is associated with the regulation of PQ-induced EMT requires further study to confirm. Using a murine model, Chung et al (22) demonstrated that rapamycin treatment reduced inflammatory cytokine expression, extracellular matrix production and senescence in type II pneumocytes, and that rapamycin protected against radiation-induced pulmonary fibrosis. Phosphoinositide 3-kinase (PI3K) was reported as a promising therapeutic target for idiopathic pulmonary fibrosis (23).…”