Genetic variants in the plasminogen activator inhibitor‐1 gene are associated with an increased risk of radiation pneumonitis in lung cancer patients

Liu, Bo; Tang, Yang; Yi, Minxiao; Liu, Qingxu; Xiong, Huihua; Hu, Guangyuan; Yuan, Xianglin

doi:10.1002/cam4.1011

Cited by 17 publications

(10 citation statements)

References 40 publications

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“…To further validate the involvement of immune enhancement in LDR‐induced tumor inhibition, HDR pretreatment was carried out before LDR treatment to impair the immune function as an inverse validation. The dose of HDR was 1 Gy, which was considered insufficient to directly inhibit tumor growth because the effective dose of radiation to treat Lewis lung cancer in mice is 13 Gy or more . As expected, we found that HDR markedly impaired immune function, resulting in decreased splenocyte proliferation and cytokine production.…”

Section: Discussionsupporting

confidence: 77%

Validating the pivotal role of the immune system in low‐dose radiation‐induced tumor inhibition in Lewis lung cancer‐bearing mice

Zhou

Zhang

et al. 2018

Cancer Medicine

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Although low‐dose radiation (LDR) possesses the two distinct functions of inducing hormesis and adaptive responses, which result in immune enhancement and tumor inhibition, its clinical applications have not yet been elucidated. The major obstacle that hinders the application of LDR in the clinical setting is that the mechanisms underlying induction of tumor inhibition are unclear, and the risks associated with LDR are still unknown. Thus, to overcome this obstacle and elucidate the mechanisms mediating the antitumor effects of LDR, in this study, we established an in vivo lung cancer model to investigate the participation of the immune system in LDR‐induced tumor inhibition and validated the pivotal role of the immune system by impairing immunity with high‐dose radiation (HDR) of 1 Gy. Additionally, the LDR‐induced adaptive response of the immune system was also observed by sequential HDR treatment in this mouse model. We found that LDR‐activated T cells and natural killer cells and increased the cytotoxicity of splenocytes and the infiltration of T cells in the tumor tissues. In contrast, when immune function was impaired by HDR pretreatment, LDR could not induce tumor inhibition. However, when LDR was administered before HDR, the immunity could be protected from impairment, and tumor growth could be inhibited to some extent, indicating the induction of the immune adaptive response by LDR. Therefore, we demonstrated that immune enhancement played a key role in LDR‐induced tumor inhibition. These findings emphasized the importance of the immune response in tumor radiotherapy and may help promote the application of LDR as a novel approach in clinical practice.

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Section: Discussionsupporting

confidence: 77%

Validating the pivotal role of the immune system in low‐dose radiation‐induced tumor inhibition in Lewis lung cancer‐bearing mice

Zhou

Zhang

et al. 2018

Cancer Medicine

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“…Radiation (IR)-induced pulmonary fibrosis is a frequently occurred complication from radiotherapy threatening the health and life of patients [1, 2]. The time of onset and severity of lung fibrosis after radiotherapy depend on many factors, including the volume of irradiated parenchyma, dose of absorbed IR, and number of fractions [3–5].…”

Section: Introductionmentioning

confidence: 99%

Identification of molecular signatures involved in radiation-induced lung fibrosis

et al. 2018

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In radiotherapy, radiation (IR)-induced lung fibrosis has severe and dose-limiting side effects. To elucidate the molecular effects of IR fibrosis, we examined the fibrosis process in irradiated mouse lung tissues. High focal IR (90 Gy) was exposed to a 3-mm volume of the left lung in C57BL6 mice. In the diffused irradiation, 20 Gy dose delivered with a 7-mm collimator almost covered the entire left lung. Histological examination for lung tissues of both irradiated and neighboring regions was done for 4 weeks after irradiation. Long-term effects (12 months) of 20Gy IR were compared on a diffuse region of the left lung and non-irradiated right lung. Fibrosis was initiated as early as 2 weeks after IR in the irradiated lung region and neighboring region. Upregulation of gtse1 in both 90Gy-irradiated and neighboring regions was observed. Upregulation of fgl1 in both 20Gy diffused irradiated and non-irradiated lungs was identified. When gtse1 or flg1 was knock-downed, TGFβ or IR-induced epithelial-mesenchymal transition was inhibited, accompanied with the inhibition of cellular migration, suggesting fibrosis responsible genes. Immunofluorescence analysis using mouse fibrotic lung tissues suggested that fibrotic regions showed increased expressions of Gtse1 and Fgl1, indicating novel molecular signatures of gtse1and fgl1 for IR-induced lung fibrosis. Even though their molecular mechanisms and IR doses or irradiated volumes for lung fibrosis may be different, these genes may be novel targets for understanding IR-induced lung fibrosis and in treatment strategies.Key messages Upregulation of gtse1 by 90Gy focal irradiation and upregulation of fgl1 by 20Gy diffused irradiation are identified in mouse lung fibrosis model.Gtse1 and Fgl1 are involved in radiation or TGFβ-induced epithelial-mesenchymal transition.Radiation-induced fibrotic regions of mouse lungs showed increased expressions of Gtse1 and Fgl1.Gtse1 and Fgl1 are suggested to be novel targets for radiation-induced lung fibrosis. Electronic supplementary materialThe online version of this article (10.1007/s00109-018-1715-9) contains supplementary material, which is available to authorized users.

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“…Liu et al found that rs7242 GT/GG genotypes located in the 3ÚTR of PAI-1 were associated with a signi cantly increased risk of RP. 40 Overall, our ndings suggest a potential biological predisposition to lung damage and altered wound healing in RILI development, which would deserve a depth study to better understand pathogenesis.…”

Section: Discussionmentioning

confidence: 73%

Severity of radiation pneumonitis, from clinical, dosimetric and biological features: a pilot study.

Aso

Navarro-Martín

Castillo

et al. 2020

Preprint

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Background and objective: Radiation pneumonitis (RP) could be a lethal complication of lung cancer treatment. No reliable predictors of RP severity have been recognized. This prospective pilot study was performed to identify early predictors of high grade lung toxicity and to evaluate clinical, biological or dosimetric features associated with different grades of toxicity.Method: Sixteen patients with non-small cell lung cancer with indication of concurrent chemoradiotherapy using 60Gy/2Gy/fraction starting at cycle one of platinum based chemotherapy were included. Bronchoalveolar lavage (BAL), pulmonary function testing (PFT), and 18F-2-fluoro-2-deoxy-D-glucose positron-emission tomography was performed before radiotherapy (RT), after three weeks of treatment, and two months post-RT. For analysis, patients were grouped by grade (low [G1-G2] vs. high [G3-G5]). The two groups were compared to identify predictors of RP. Protein expression BAL and lung tissue metabolism was evaluated in two patients (RP-G1 vs. RP-G3). Categorical variables such as comorbidities, stages and locations were summarized as percentages. Radiation doses, pulmonary function values and time to RP were summarized by medians with ranges or as means with standard deviation. Longitudinal analysis PFT was performed by a T-test. Results: All 16 patients developed RP, as follows: G1 (5 pts; 31.3%); G2 (5 pts; 31.3%); G3 (5 pts; 31.3%); and G5 (1 pts; 6.1%). Patients with high grade RP presented significant decrease (p=0.02) in diffusing lung capacity for carbon monoxide (DLCO) after three week of RT. No correlation between dosimetric values and RP grades was observed. BAL analysis of the selected patients showed that CXCL-1, CD154, IL-1ra, IL-23, MIF, PAI-1 and IFN-g were overexpressed in the lungs of the RP-G3 patient, even before treatment. The pre-RT SUVmax value in the RP-G3 patient was non-significantly higher than in the patient with RP-G1. Conclusions: RT induces some degree of RP. Our data suggest that decrease in DLCO% is the most sensitive parameter for the early detection of RP. Moreover, we detect biological differences between the two grades of pneumonitis, highlighting the potential value of some cytokines as a prognostic marker for developing high grade lung toxicity. Further multicenter studies with larger sample size are essential to validate these findings.

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Genetic variants in the plasminogen activator inhibitor‐1 gene are associated with an increased risk of radiation pneumonitis in lung cancer patients

Cited by 17 publications

References 40 publications

Validating the pivotal role of the immune system in low‐dose radiation‐induced tumor inhibition in Lewis lung cancer‐bearing mice

Validating the pivotal role of the immune system in low‐dose radiation‐induced tumor inhibition in Lewis lung cancer‐bearing mice

Identification of molecular signatures involved in radiation-induced lung fibrosis

Severity of radiation pneumonitis, from clinical, dosimetric and biological features: a pilot study.

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