Access Type

Open Access Dissertation

Date of Award

January 2015

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Immunology and Microbiology

First Advisor

Gilda G. Hillman

Abstract

Radiation-induced lung injury (RILI) is caused by an early inflammatory process triggered by damage to lung parenchyma, epithelial cells, vascular endothelial cells and stroma. Initially, oxidative injuries after radiation induce altered expression of pro-inflammatory cytokines. Infiltrating inflammatory cells are stimulated and activated, producing additional mediators, resulting in a cytokine cascade. The expansion and perpetual activation of inflammatory cells, as well as lung parenchyma, lead to clinical pneumonitis. Activated cells produce molecular mediators and growth factors that affect the proliferation and gene expression of lung fibroblasts. This process leads to increased collagen synthesis and deposition, eventually leading to the development of lung fibrosis. These adverse events after radiotherapy affect patients’ breathing and their quality of life. Various strategies to decrease the extent of pneumonitis have been investigated but need further research efforts.

We have previously demonstrated in mice receiving a single high dose of thoracic irradiation that supplementation with a mixture soy isoflavones (genistein, daidzein, and glycitein) has the dual capability of protecting normal lung tissue from radiation injury while simultaneously enhancing radiation damage in the tumor. However, mechanisms of radioprotection by soy isoflavones in normal tissues remained to be elucidated. We hypothesized that soy isoflavones mediate radioprotection via the modulation of radiation-induced inflammatory processes involving macrophages, neutrophils, and myeloid-derived suppressor cells.

The major findings of this work suggest that soy isoflavones can inhibit inflammatory responses triggered by a single dose of thoracic irradiation in the lung, including NF-κB and pro-inflammatory cytokine production. We reveal that soy isoflavones inhibit the infiltration and activation of macrophages and neutrophils in the lung induced by radiation. Radiation induced a pro-inflammatory M1 macrophage phenotype in lungs, while mice receiving soy isoflavones and radiation switched to an anti-inflammatory M2 macrophage subtype. Soy isoflavones had a protective effect on regulatory interstitial macrophages (IM) after irradiation, while inhibiting alveolar macrophage (AM) infiltration and activation induced by radiation. Interestingly, we show that soy isoflavones promote granulocytic myeloid-derived suppressor cells that express Arg-1 after radiation, resulting in subsequent downregulation inflammatory mediators. These data indicate that lung radioprotection by soy isoflavones may occur via the modulation of cellular and molecular mediators involved in the inflammatory response induced by radiation.

Download

Share

COinS