Gene expression profiles among murine strains segregate with distinct differences in the progression of radiation-induced lung disease

Abstract

Molecular mechanisms underlying development of acute pneumonitis and/or late fibrosis following thoracic irradiation remain poorly understood. Here, we hypothesize that heterogeneity in disease progression and phenotypic expression of radiation-induced lung disease (RILD) across murine strains presents an opportunity to better elucidate mechanisms driving tissue response toward pneumonitis and/or fibrosis. Distinct differences in disease progression were observed in age- and sex-matched CBA/J, C57L/J and C57BL/6J mice over 1 year after graded doses of whole-thorax lung irradiation (WTLI). Separately, comparison of gene expression profiles in lung tissue 24 h post-exposure demonstrated >5000 genes to be differentially expressed (P<0.01; >twofold change) between strains with early versus late onset of disease. An immediate divergence in early tissue response between radiation-sensitive and -resistant strains was observed. In pneumonitis-prone C57L/J mice, differentially expressed genes were enriched in proinflammatory pathways, whereas in fibrosis-prone C57BL/6J mice, genes were enriched in pathways involved in purine and pyrimidine synthesis, DNA replication and cell division. At 24 h post-WTLI, different patterns of cellular damage were observed at the ultrastructural level among strains but microscopic damage was not yet evident under light microscopy. These data point toward a fundamental difference in patterns of early pulmonary tissue response to WTLI, consistent with the macroscopic expression of injury manifesting weeks to months after exposure. Understanding the mechanisms underlying development of RILD might lead to more rational selection of therapeutic interventions to mitigate healthy tissue damage.

Modeling and multiscale characterization of the quantitative imaging based fibrosis index reveals pathophysiological, transcriptome and proteomic correlates of lung fibrosis induced by fractionated irradiation

“…Most recently it was shown that depletion of interstitial macrophages (IMs) by a neutralizing antibody abrogating the CSF-CSF1R signaling inhibits RILF, whereas depletion of alveolar macrophages (AMs) by Clodrosome was not effective further underscoring the relevance of leukocyte subtypes in RILF development. 26 A brief collection of recent studies investigating potential impact of different leukocyte subsets in RILF [27][28][29][30][31][32][33][34][35][36] is provided in supplemental Table S1, Supporting Information. Segregated-nucleuscontaining atypical monocytes (SatM) with granulocyte characteristics regulated by CCAAT/enhancer binding protein β (C/EBPβ) as well as release of neutrophil extracellular traps (NETosis) consisting of extracellular chromatin orchestrated by peptidylarginine deiminase 4 (PAD4) in age related organ fibrosis.…”

Targeting the Immunomodulatory CD73/Adenosine System to Improve the Therapeutic Gain of Radiotherapy

“…Otherwise, the high radio sensitivity of the normal lung tissue limits the application of curative radiation doses to the thoracic region and therapy intensification efforts of RCT (9, 11). Technical advances in image guidance and modern radiation techniques have significantly increased the safety profile of thoracic radiotherapy (12–14); but radiation-induced lung disease (RILD) still represents a serious normal tissue complication associated with radio(chemo)therapy of thoracic neoplasms or total body irradiation in conditioning regimens for hematopoietic stem cell transplantation (15–17). Moreover, toxicity rates can increase or new toxicities can be observed when using molecularly targeted drugs in combination with radiotherapy (18–21).…”

The Th1/Th17 balance dictates the fibrosis response in murine radiation-induced lung disease

“…The pneumonitis and fibrosis responses evident clinically have been modelled in mice, which show strain and genotype dependent presentations of these traits 13 – 19 . Specifically, we 13 , 15 , 16 and others 14 , 19 – 21 have documented that following thoracic irradiation inbred strains of mice vary in the times at which respiratory distress is evident, and at distress certain strains have developed pneumonitis, while others are prone to pneumonitis with fibrosis.Investigations of these lung response phenotypes have revealed post irradiation gene expression profiles associated with the pneumonitis and pneumonitis with fibrosis responding mouse strains 18 , 22 . Further in mouse models, we demonstrated combined toll-like receptor 2 ( Tlr2 ) and Tlr 4 deficient mice develop an enhanced fibrotic response, of earlier onset, relative to that of wild type C57BL/6J mice, in response to thoracic irradiation 17 and thus are a useful model for severe fibrosis.…”