NKT Deficient Mice are not Spared Lung Disease after Exposure to Thoracic Radiotherapy

Paun, Alexandra; Bergeron, Marie-Ève; Haston, Christina K.

doi:10.1667/rr13581.1

Cited by 4 publications

(1 citation statement)

References 35 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Zhou

Moustafa

Cao

et al. 2019

Intl Journal of Cancer

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Pulmonary fibrosis represents a leading cause of morbidity and mortality worldwide. Therapy induced lung fibrosis constitutes a pivotal dose‐limiting side effect of radiotherapy and other anticancer agents. We aimed to develop objective criteria for assessment of fibrosis and discover pathophysiological and molecular correlates of lung fibrosis as a function of fractionated whole thoracic irradiation. Dose–response series of fractionated irradiation was utilized to develop a non‐invasive and quantitative measure for the degree of fibrosis – the fibrosis index (FI). The correlation of FI with histopathology, blood‐gas, transcriptome and proteome responses of the lung tissue was analyzed. Macrophages infiltration and polarization was assessed by immunohistochemistry. Fibrosis development followed a slow kinetic with maximum lung fibrosis levels detected at 24‐week post radiation insult. FI favorably correlated with radiation dose and surrogates of lung fibrosis i.e., enhanced pro‐inflammatory response, tissue remodeling and extracellular matrix deposition. The loss of lung architecture correlated with decreased epithelial marker, loss of microvascular integrity with decreased endothelial and elevated mesenchymal markers. Lung fibrosis was further attributed to a switch of the inflammatory state toward a macrophage/T‐helper cell type 2‐like (M2/Th2) polarized phenotype. Together, the multiscale characterization of FI in radiation‐induced lung fibrosis (RILF) model identified pathophysiological, transcriptional and proteomic correlates of fibrosis. Pathological immune response and endothelial/epithelial to mesenchymal transition were discovered as critical events governing lung tissue remodeling. FI will be instrumental for deciphering the molecular mechanisms governing lung fibrosis and discovery of novel targets for treatment of this devastating disease with an unmet medical need.

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Section: Discussionmentioning

confidence: 99%

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

Zhou

Moustafa

Cao

et al. 2019

Intl Journal of Cancer

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Protective role of NKT cells and macrophage M2-driven phenotype in bleomycin-induced pulmonary fibrosis

et al. 2017

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Pulmonary fibrosis is a result of an abnormal wound healing in lung tissue triggered by an excessive accumulation of extracellular matrix proteins, loss of tissue elasticity, and debit of ventilatory function. NKT cells are a major source of Th1 and Th2 cytokines and may be crucial in the polarization of M1/M2 macrophages in pulmonary fibrogenesis. Although there appears to be constant scientific progress in that field, pulmonary fibrosis still exhibits no current cure. From these facts, we hypothesized that NKT cells could influence the development of pulmonary fibrosis via modulation of macrophage activation. Wild type (WT) and NKT type I cell-deficient mice (Jα18) were subjected to the protocol of bleomycin-induced pulmonary fibrosis with or without treatment with NKT cell agonists α-galactosylceramide and sulfatide. The participation of different cell populations, collagen deposition, and protein levels of different cytokines involved in inflammation and fibrosis was evaluated. The results indicate a benign role of NKT cells in Jα18 mice and in wild-type α-galactosylceramide-sulfatide-treated groups. These animals presented lower levels of collagen deposition, fibrogenic molecules such as TGF-β and vimentin and improved survival rates. In contrast, WT mice developed a Th2-driven response augmenting IL-4, 5, and 13 protein synthesis and increased collagen deposition. Furthermore, the arginase-1 metabolic pathway was downregulated in wild-type NKT-activated and knockout mice indicating lower activity of M2 macrophages in lung tissue. Hence, our data suggest that NKT cells play a protective role in this experimental model by down modulating the Th2 milieu, inhibiting M2 polarization and finally preventing fibrosis.

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A Chromosome 6, not Natural Killer Cell, Contribution to Radiation- and Bleomycin-Induced Lung Disease in Mice

Lemay

Haston

2018

Radiation Research

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NKT Deficient Mice are not Spared Lung Disease after Exposure to Thoracic Radiotherapy

Cited by 4 publications

References 35 publications

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

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

Protective role of NKT cells and macrophage M2-driven phenotype in bleomycin-induced pulmonary fibrosis

A Chromosome 6, not Natural Killer Cell, Contribution to Radiation- and Bleomycin-Induced Lung Disease in Mice

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