Radiation and Cancer Biology

SS 19 - Biology 4 - Normal Tissue Radiobiology

146 - Deficiency of IGF-1 Receptor in Type II Pneumocytes Reduces Radiation-Induced Pulmonary Fibrosis in a Murine Model

Tuesday, October 23
7:55 AM - 8:05 AM
Location: Room 008

Deficiency of IGF-1 Receptor in Type II Pneumocytes Reduces Radiation-Induced Pulmonary Fibrosis in a Murine Model
E. J. Chung1, A. White1, S. Kwon1, U. T. Shankavaram2, and D. E. Citrin3; 1Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 2Radiation Oncology Branch, National Cancer Institute, Bethesda, MD, 3NCI, Bethesda, MD

Purpose/Objective(s): Fibrosis is a late toxicity of radiation in lung. Radiation-induced pulmonary fibrosis (RIPF) is characterized by senescence of stem cells, parenchymal depletion, chronic inflammation, fibroblast proliferation, and collagen deposition. Insulin-like Growth Factor-1 (IGF-1) signaling through IGF-1 receptor (IGF1r) has been implicated in fibroblast activation, epithelial regeneration and endothelial senescence in murine lungs. Recently, we reported that accelerated senescence of type II pneumocytes (AEC2), the alveolar stem cell, precedes RIPF. We sought to determine if IGF-1 signaling inhibition in AEC2 would mitigate RIPF.

Materials/Methods: To inactivate IGF-1 signaling specifically in AEC2, Sftpc-CreERT2 mice expressing a tamoxifen-inducible cre recombinase from the Sftpc locus (B6.129S-Sftpctm1(cre/ERT2)Blh/J; Brigid Hogan) were crossed with mice possessing loxP sites flanking exon 3 of the Igf1r gene (B6;129-Igf1rtm2Arge/J; Jackson Laboratory). AEC2-specific IGF1r knockout mice (IGF-1R F/F+ Sftpc-CreERT2) administered vehicle (Oil) or Tamoxifen (Tam), were exposed to thoracic irradiation in 5 daily fractions of 6 Gy (RT). Histologic changes were evaluated by Masson-Trichrome staining at 16 weeks after RT. Accumulation of classically (M1) and alternatively activated (M2) macrophages was assessed with immunohistochemistry. Collagen deposition was assessed with hydroxyproline assay. Inflammatory and senescence associated cytokine secretion by AEC2 was evaluated by antibody array and ELISA. Senescence was assessed by staining for beta-galactosidase activity.

Results: IGF1r deficiency in AEC2 reduced hydroxyproline content after irradiation compared to vehicle treated irradiated controls (RT+Oil: 71.9±19.1, RT+Tam: 37.1±8.9, unirradiated+Oil: 30.9±8.0, or unirradiated+Tam: 37.1±8.9 μg/lung respectively, p<0.001). Mice exposed to RT+Oil had dense foci of subpleural fibrosis at 16 weeks, a finding absent in RT+Tam treated mice. Deficiency of IGF1r diminished the levels of inflammatory and senescence associated cytokines (MIP-1α, sTNFRI, and sTNFRII), but increased pro-MMP9 in cultures of AEC2 collected lungs at 4 weeks after RT. Accumulation of M2 macrophages in response to thoracic radiation was significantly reduced by IGF1r deficiency in lung tissue at 16 weeks after RT (3-fold decrease, p=0.005). Cellular senescence in AEC2 was also significantly decreased by IGF1r deficiency in lung tissue at 16 weeks after RT (2.6-fold decrease, p=0.001).

Conclusion: Inhibition of IGF-1 signaling in AEC2 protected against RIPF in murine lungs through a reduction in inflammatory cytokine expression, extra cellular matrix production, and senescence in AEC2. Modulation of IGF-1 signaling in AEC2 has the potential to be an effective therapy option for pulmonary fibrosis following thoracic radiation.

Author Disclosure: E.J. Chung: None. A. White: None. S. Kwon: Contractor; National Institutes of Health. U.T. Shankavaram: None. D.E. Citrin: Employee; US Army. Research Grant; National Institutes of Health. receive research funding; National Institute of Allergy and Infectious Disease. Deputy Director; Center for Cancer Research, NCI. Biology Track Chair; ASTRO.

Eun Chung, MD, PhD

Disclosure:
Employment
National Institutes of Health: Staff Scientist: Employee

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