Clinicopathologic and Transcriptomic Analysis of Radiation-Induced Lung Injury in Nonhuman Primates

Thakur, Priyanka; DeBo, Ryne J.; Dugan, Greg; Bourland, J. Daniel; Michalson, Kristofer T.; Olson, John D.; Register, Thomas C.; Kock, Nancy D.; Cline, J. Mark

doi:10.1016/j.ijrobp.2021.03.058

Cited by 20 publications

(16 citation statements)

References 52 publications

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“…Indeed, expression of SERPINA3 has been reported to be dysregulated in models of radiation-induced lung injury (RILI), and increased protein expression of SERPINA3 has been observed in bronchoalveolar lavage and plasma samples. 28 In addition, Uysal et al (2019) found that SERPINA3 was highly expressed in the plasma of chronic obstructive pulmonary disease (COPD) patients, and the increased expression of SERPINA3 might play an important role in airway remodeling in the pathogenesis of COPD. 29 Hence, SERPINA3, which has been reported in lung injury and other related lung diseases, as well as associated with inflammatory response, was chosen as a key gene for further research in this study.…”

Section: Discussionmentioning

confidence: 99%

Identification of biomarkers and candidate small-molecule drugs in lipopolysaccharide (LPS)-induced acute lung injury by bioinformatics analysis

Wang

Chen

2023

Allergol Immunopathol

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Background/objective: Acute lung injury (ALI) is a critical clinical syndrome with high rates of incidence and mortality. However, its molecular mechanism remains unclear. The current work aimed to explore the molecular mechanisms of ALI by identifying different expression genes (DEGs) and candidate drugs using a combination of chip analysis and experimental validation. Methods: Three microarray datasets were downloaded from Gene Expression Omnibus (GEO) database to obtain DEGs. We conducted a Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway-enrichment analyses of overlapping DEGs among three databases. The expression level of key gene was verified by Western blotting analysis in LPS-treated ALI cell models. Finally, we predicted the candidate drugs targeting the key gene that might be effective for ALI treatment, and the role of candidate drug in treating ALI was verified by investigation. Results: A total 29 overlapping DEGs were up-regulated in LPS-induced ALI groups. They were enriched in inflammation and inflammation-related pathways. Serpin family A member 3 (SERPINA3) was defined as a key gene because it was associated with inflammation pathway and up-regulated in microarray datasets in LPS-induced ALI. In LPS-induced human bronchial epithelial cells transformed with Ad12-SV40-2B (BEAS-2B) cells, SERPINA3 was enhanced. Pyridoxal phosphate as an upstream drug of SERPINA3 could improve cell viability and reduce expression inflammatory factors in LPS-treated BEAS-2B cells. Conclusion: Our study suggested that pyridoxal phosphate could be a candidate drug targeting SERPINA3 gene in LPS-induced ALI. It has protective and anti-inflammatory effects in BEAS-2B cells, and may become a potential novel treatment for ALI.

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Section: Discussionmentioning

confidence: 99%

Identification of biomarkers and candidate small-molecule drugs in lipopolysaccharide (LPS)-induced acute lung injury by bioinformatics analysis

Wang

Chen

2023

Allergol Immunopathol

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“…Interestingly, LPS treatment (induces macrophage polarization to M1 type) attenuates early radiation damage to the lung [ 37 ]. Radiation-induced early inflammation plays a minimal role in the later development of pneumonia [ 38 ]. TGF-β1 is a specific cytokine that induces extracellular matrix production [ 39 , 40 ], consistent with our findings.…”

Section: Discussionmentioning

confidence: 99%

Monophosphoryl lipid A ameliorates radiation-induced lung injury by promoting the polarization of macrophages to the M1 phenotype

Guo

et al. 2022

J Transl Med

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Background Radiation-induced lung injury (RILI) often occurs during clinical chest radiotherapy and acute irradiation from accidental nuclear leakage. This study explored the role of monophosphoryl lipid A (MPLA) in RILI. Materials and Methods The entire thoracic cavity of C57BL/6N mice was irradiated at 20 Gy with or without pre-intragastric administration of MPLA. HE staining, Masson trichrome staining, and TUNEL assay were used to assess lung tissue injury after treatment. The effect of irradiation on the proliferation of MLE-12 cells was analyzed using the Clonogenic assay. The effect of MPLA on the apoptosis of MLE-12 cells was analyzed using flow cytometry. Expression of γ-H2AX and epithelial-mesenchymal transition (EMT) markers in MLE-12 cells was detected by immunofluorescence and Western blot, respectively. Results MPLA attenuated early pneumonitis and late pulmonary fibrosis after thoracic irradiation and reversed radiation-induced EMT in C57 mice. MPLA further promoted proliferation and inhibited apoptosis of irradiated MLE-12 cells in vitro. Mechanistically, the radioprotective effect of MPLA was mediated by exosomes secreted by stimulated macrophages. Macrophage-derived exosomes modulated DNA damage in MLE-12 cells after irradiation. MPLA promoted the polarization of RAW 264.7 cells to the M1 phenotype. The exosomes secreted by M1 macrophages suppressed EMT in MLE-12 cells after irradiation. Conclusion MPLA is a novel treatment strategy for RILI. Exosomes derived from macrophages are key to the radioprotective role of MPLA in RILI.

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“…In addition, one patient who relapsed with ILD after receiving durvalumab did not have solitary shadows located only outside the irradiation eld at any time, indicating the possibility that local immune system changes in the lung due to radiation cannot be ruled out as the cause of relapse of ILD. Although various studies have been conducted on radiation therapy-induced changes in the immune system [19][20][21], much remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Clinical features and risk factors for interstitial lung disease spreading in low-dose irradiated areas after definitive radiotherapy with or without durvalumab consolidation therapy for patients with non-small cell lung cancer

Sakagami

Inokuchi²,

Mukumoto³

et al. 2022

Preprint

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Background: The current standard of care for patients with unresectable locally advanced non-small cell lung cancer (NSCLC) is chemoradiotherapy (CRT) combined with durvalumab consolidation therapy. However, radiotherapy (RT) always carries the risk of radiation pneumonitis (RP), which can preclude durvalumab continuation. In particular, the spread of interstitial lung disease (ILD) in low-dose areas or extending beyond the RT field often makes it difficult to determine the safety of continuation or rechallenging of durvalumab. Thus, we retrospectively analyzed ILD/RP after definitive RT with and without durvalumab, with assessment of radiologic features and dose distribution in RT.Methods: We retrospectively evaluated the clinical records, CT imaging, and radiotherapy planning data of 74 patients with NSCLC who underwent definitive RT at our institution between July 2016 and July 2020. Univariate analysis and propensity score analysis were performed to assess the risk factors for recurrence within one year and occurrence of ILD/RP.Results: In 68 patients followed up for more than one year, propensity score analysis showed that ≥7 cycles of durvalumab significantly reduced the risk of recurrence within one year (odds ratio: 0.232). Nineteen patients (26%) were diagnosed with ≥ Grade 2 and 7 (9.5%) with ≥ Grade 3 ILD/RP after completing RT. Propensity score analysis showed no significant correlation between durvalumab administration and ≥ Grade 2 ILD/RP. Twelve patients (16%) developed ILD/RP that spread outside the high-dose (>40 Gy) area, of whom 8 (67%) had ≥ Grade 2 and 3 (25%) had Grade 3 symptoms. Univariate analysis showed that high HbA1c level (>6.2%) was significantly associated with the ILD/RP distribution pattern. In propensity score analysis adjusted for risk factors for diabetes mellitus, high HbA1c level was also significantly correlated with ILD/RP pattern spreading outside the high-dose area (odds ratio: 9.865).Conclusions: Durvalumab improves 1-year progression-free survival without increasing the risk of ILD/RP. High HbA1c level was associated with ILD/RP distribution pattern spreading in the lower dose area or outside RT fields, with a high rate of symptoms. Further study of the clinical background of patients including diabetes is needed to safely increase the number of durvalumab doses after CRT.

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Clinicopathologic and Transcriptomic Analysis of Radiation-Induced Lung Injury in Nonhuman Primates

Cited by 20 publications

References 52 publications

Identification of biomarkers and candidate small-molecule drugs in lipopolysaccharide (LPS)-induced acute lung injury by bioinformatics analysis

Identification of biomarkers and candidate small-molecule drugs in lipopolysaccharide (LPS)-induced acute lung injury by bioinformatics analysis

Monophosphoryl lipid A ameliorates radiation-induced lung injury by promoting the polarization of macrophages to the M1 phenotype

Clinical features and risk factors for interstitial lung disease spreading in low-dose irradiated areas after definitive radiotherapy with or without durvalumab consolidation therapy for patients with non-small cell lung cancer

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