Pathophysiological mechanisms underlying phenotypic differences in pulmonary radioresponse

Abstract

Differences in the pathogenesis of radiation-induced lung injury among murine strains offer a unique opportunity to elucidate the molecular mechanisms driving the divergence in tissue response from repair and recovery to organ failure. Here, we utilized two well-characterized murine models of radiation pneumonitis/fibrosis to compare and contrast differential gene expression in lungs 24 hours after exposure to a single dose of whole thorax lung irradiation sufficient to cause minor to major morbidity/mortality. Expression of 805 genes was altered as a general response to radiation; 42 genes were identified whose expression corresponded to the threshold for lethality. Three genes were discovered whose expression was altered within the lethal, but not the sublethal, dose range. Time-course analysis of the protein product of the most promising gene, resistin-like molecule alpha, demonstrated a significant difference in expression between radiosensitive versus radiotolerant strains, suggesting a unique role for this protein in acute lung injury.

Acute Proteomic Changes in the Lung After WTLI in a Mouse Model: Identification of Potential Initiating Events for Delayed Effects of Acute Radiation Exposure

“…Radiation doses of 8, 10, 12, and 14 Gy WTLI were assayed at 1, 3, and 6 days post-exposure. We selected the time course of the current proteomic study based upon recent publications from our team (Jackson et al 2016;. One of the recent studies in the murine WTLI model reported that ultrastructural damage and gene expression profiles suggest the response to radiation within the first 24 h post-exposure determines tissue fate .…”

“…One of the recent studies in the murine WTLI model reported that ultrastructural damage and gene expression profiles suggest the response to radiation within the first 24 h post-exposure determines tissue fate . The other recent study interrogated gene expression changes and interpreted them in terms of pathophysiological mechanisms (Jackson et al 2016). The study design of the proteomics study described herein was intended to assay proteomic changes on a similar timescale as these gene expression studies.…”

“…Initiation of cellular damage from irradiation (IR) exposure results in chronic oxidative stress, tissue hypoxia, inflammation, and fibro-proliferation in various tissues where lung is particularly radiosensitive to the development of fibrosis (Rodemann and Blaese 2007;Ding et al 2013). Efforts to characterize the molecular mechanisms of RILI have included histological, cytokine, and gene expression analyses, however, the molecular mechanisms that lead to RILI remain incompletely understood (Finkelstein et al 1994;Chen et al 2001;Chen et al 2002;Stone et al 2003;Jackson et al 2016;Ghandhi et al 2018). Additionally, whereas there are medical countermeasures in development to treat radiationinduced lung injury, there are no FDA-approved medical countermeasures (MCM) to treat RILI (DiCarlo et al 2012;Ding et al 2013).…”

“…Several recent studies have conducted gene expression profiles in mouse lung after WTLI (Jackson et al 2016; and in peripheral blood cells after WTLI (Ghandhi et al 2018). Radiation-induced lung inflammation and toxicity in cancer patients has been explored via proteomics (Cai et al 2011;Oh et al 2011).…”

Study logistics that can impact medical countermeasure efficacy testing in mouse models of radiation injury

“…In WTLI studies, there was no difference in 180-day survival between males and females in C57L/J mice. In contrast, a clear sex difference was observed in the C57BL/6J mice exposed to WTLI, with females 3.54 times more likely to succumb to mortality compared to 1.62 in males (Jackson et al 2016). A marked sex-bias has also been observed when other endpoints are queried (Narendran et al 2019).…”