Clinicopathologic and Transcriptomic Analysis of Radiation-Induced Lung Injury in Nonhuman Primates.
Int J Radiat Oncol Biol Phys
; 111(1): 249-259, 2021 09 01.
Article
en En
| MEDLINE
| ID: mdl-33848608
ABSTRACT
PURPOSE:
Radiation-induced lung injury (RILI) is a progressive condition with an early phase (radiation pneumonitis) and a late phase (lung fibrosis). RILI may occur after partial-body ionizing radiation exposures or internal radioisotope exposure, with wide individual variability in timing and extent of lung injury. This study aimed to provide new insights into the pathogenesis and progression of RILI in the nonhuman primate (NHP) rhesus macaque model. METHODS AND MATERIALS We used an integrative approach to understand RILI and its evolution at clinical and molecular levels in 17 NHPs exposed to 10 Gy of whole-thorax irradiation in comparison with 3 sham-irradiated control NHPs. Clinically, we monitored respiratory rates, computed tomography (CT) scans, plasma cytokine levels, and bronchoalveolar lavage (BAL) over 8 months and lung samples collected at necropsy for molecular and histopathologic analyses using RNA sequencing and immunohistochemistry.RESULTS:
Elevated respiratory rates, greater CT density, and more severe pneumonitis with increased macrophage content were associated with early mortality. Radiation-induced lung fibrosis included polarization of macrophages toward the M2-like phenotype, TGF-ß signaling, expression of CDKN1A/p21 in epithelial cells, and expression of α-SMA in lung stroma. RNA sequencing analysis of lung tissue revealed SERPINA3, ATP12A, GJB2, CLDN10, TOX3, and LPA as top dysregulated transcripts in irradiated animals. In addition to transcriptomic data, we observed increased protein expression of SERPINA3, TGF-ß1, CCL2, and CCL11 in BAL and plasma samples.CONCLUSIONS:
Our combined clinical, imaging, histologic, and transcriptomic analysis provides new insights into the early and late phases of RILI and highlights possible biomarkers and potential therapeutic targets of RILI. Activation of TGF-ß and macrophage polarization appear to be key mechanisms involved in RILI.
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Base de datos:
MEDLINE
Asunto principal:
Traumatismos Experimentales por Radiación
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Perfilación de la Expresión Génica
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Lesión Pulmonar
Tipo de estudio:
Etiology_studies
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Prognostic_studies
Idioma:
En
Revista:
Int J Radiat Oncol Biol Phys
Año:
2021
Tipo del documento:
Article