scholarly journals Crossed Pathways for Radiation-Induced and Immunotherapy-Related Lung Injury

2021 ◽  
Vol 12 ◽  
Author(s):  
Zengfu Zhang ◽  
Jialin Zhou ◽  
Vivek Verma ◽  
Xu Liu ◽  
Meng Wu ◽  
...  
Keyword(s):  
Lung Injury ◽  
Signaling Pathways ◽  
Radiation Pneumonitis ◽  
Checkpoint Inhibitors ◽  
Therapeutic Targets ◽  
Normal Lung ◽  
Injury Treatment ◽  
Radiation Induced ◽  
The Common ◽  
Underlying Mechanisms

Radiation-induced lung injury (RILI) is a form of radiation damage to normal lung tissue caused by radiotherapy (RT) for thoracic cancers, which is most commonly comprised of radiation pneumonitis (RP) and radiation pulmonary fibrosis (RPF). Moreover, with the widespread utilization of immunotherapies such as immune checkpoint inhibitors as first- and second-line treatments for various cancers, the incidence of immunotherapy-related lung injury (IRLI), a severe immune-related adverse event (irAE), has rapidly increased. To date, we know relatively little about the underlying mechanisms and signaling pathways of these complications. A better understanding of the signaling pathways may facilitate the prevention of lung injury and exploration of potential therapeutic targets. Therefore, this review provides an overview of the signaling pathways of RILI and IRLI and focuses on their crosstalk in diverse signaling pathways as well as on possible mechanisms of adverse events resulting from combined radiotherapy and immunotherapy. Furthermore, this review proposes potential therapeutic targets and avenues of further research based on signaling pathways. Many new studies on pyroptosis have renewed appreciation for the value and importance of pyroptosis in lung injury. Therefore, the authors posit that pyroptosis may be the common downstream pathway of RILI and IRLI; discussion is also conducted regarding further perspectives on pyroptosis as a crucial signaling pathway in lung injury treatment.

scholarly journals Inhibition of Rac1 attenuates radiation-induced lung injury while suppresses lung tumor in mice

2022 ◽  
Vol 8 (1) ◽  
Author(s):  
Ni An ◽  
Zhenjie Li ◽  
Xiaodi Yan ◽  
Hainan Zhao ◽  
Yajie Yang ◽  
...  
Keyword(s):  
Ionizing Radiation ◽  
Lung Injury ◽  
Mouse Model ◽  
Tumor Cells ◽  
Nuclear Translocation ◽  
Lung Tumor ◽  
Lung Epithelial Cells ◽  
Normal Lung ◽  
Limiting Factor ◽  
Radiation Induced

AbstractThe lung is one of the most sensitive tissues to ionizing radiation, thus, radiation-induced lung injury (RILI) stays a key dose-limiting factor of thoracic radiotherapy. However, there is still little progress in the effective treatment of RILI. Ras-related C3 botulinum toxin substrate1, Rac1, is a small guanosine triphosphatases involved in oxidative stress and apoptosis. Thus, Rac1 may be an important molecule that mediates radiation damage, inhibition of which may produce a protective effect on RILI. By establishing a mouse model of radiation-induced lung injury and orthotopic lung tumor-bearing mouse model, we detected the role of Rac1 inhibition in the protection of RILI and suppression of lung tumor. The results showed that ionizing radiation induces the nuclear translocation of Rac1, the latter then promotes nuclear translocation of P53 and prolongs the residence time of p53 in the nucleus, thereby promoting the transcription of Trp53inp1 which mediates p53-dependent apoptosis. Inhibition of Rac1 significantly reduce the apoptosis of normal lung epithelial cells, thereby effectively alleviating RILI. On the other hand, inhibition of Rac1 could also significantly inhibit the growth of lung tumor, increase the radiation sensitivity of tumor cells. These differential effects of Rac1 inhibition were related to the mutation and overexpression of Rac1 in tumor cells.

scholarly journals Radiation Induced Upregulation of DNA Sensing Pathways is Cell-Type Dependent and Can Mediate the Off-Target Effects

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3365
Author(s):  
Tanja Jesenko ◽  
Masa Bosnjak ◽  
Bostjan Markelc ◽  
Gregor Sersa ◽  
Katarina Znidar ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Checkpoint Inhibitors ◽  
Cell Types ◽  
Immunofluorescent Staining ◽  
Dna Sensing ◽  
Radiation Induced ◽  
Underlying Mechanisms ◽  
Sting Pathway ◽  
Abscopal Effects ◽  
Target Effects

Irradiation of tumors generates danger signals and inflammatory cytokines that promote the off-target bystander and abscopal effects, evident especially when radiotherapy is administered in combination with the immune checkpoint inhibitors (ICI). The underlying mechanisms are not fully understood; however, cGAS-STING pathway was recognized as the main mediator. In our study, we demonstrate by immunofluorescent staining that tumor cells as well as macrophages, cell types abundant in the tumor microenvironmeent (TME) accumulate DNA in their cytosol soon after irradiation. This accumulation activated several distinct DNA sensing pathways, most prominently activated DNA sensors being DDX60, DAI, and p204 in tumor cells and DDX60, DAI, p204, and RIG-I in macrophages as determined by PCR and immunofluorescence imaging studies. This was accompanied by increased expression of cytokines evaluated by flow cytometry, TNFα, and IFNβ in tumor cells and IL1β and IFNβ in macrophages, which can alter the TME and mediate off-target effects (bystander or abscopal effects). These results give insight into the mechanisms involved in the stimulation of antitumor immunity by radiation.

scholarly journals Identification and integrated analysis of CircRNA and miRNA of Radiation-Induced lung injury in a mice model

2020 ◽  
Author(s):  
Xi Yang ◽  
Yida Li ◽  
Liqing Zou ◽  
Li Chu ◽  
Luxi Ye ◽  
...  
Keyword(s):  
Lung Injury ◽  
Signaling Pathway ◽  
Cell Receptor ◽  
Differentially Expressed ◽  
Normal Lung ◽  
Future Research ◽  
Circular Rnas ◽  
Integrated Analysis ◽  
Mice Model ◽  
Radiation Induced

Abstract Radiation-induced lung injury (RILI) is a main threat to patients received thoracic radiotherapy, it is of great importance to understand the molecular mechanism of RILI. Circular RNAs (CircRNAs) have been found to act as the regulator of multiple biological processes and circRNA-miRNA-mRNA axis could play an important role in signaling pathway of many human diseases including radiation injury, here, we first investigate the circRNA and miRNA of radiation-induced lung injury in a mice model. The mice received 12 Gy thoracic irradiation and the irradiated lung tissues at 48 hours after irradiation were analyzed by RNA Sequencing (RNA-seq) technique compared with normal lung tissues. We identified 21 significantly up-regulated while significantly 33 down-regulated miRNAs. Among 27 differentially expressed circRNAs, 10 were down-regulated and 17 were up-regulated. We then performed circRNAs GO analysis of the target mRNAs of these significantly differently expressed circRNAs. These differentially expressed miRNAs took part in series of cellular processes such as positive regulation of alpha-beta T cell proliferation, interstitial matrix, collagen fibril organization, chemokine receptor activity, cellular defense response, and B cell receptor signaling pathway. Through this study, we found that immune-related molecular pathways play an important role in the early response after radiotherapy. In the future, research on the target mechanism and early intervention of circRNAs with associated miRNAs will benefit the treatment of RILI.

Prevention and treatment of radiation-induced lung injury

2020 ◽  
Vol 12 (23) ◽  
pp. 2161-2173
Author(s):  
Chengcheng Xia ◽  
Weiyan Shi ◽  
Yuyu Zhang ◽  
Lijuan Ding ◽  
Ling Gao ◽  
...  
Keyword(s):  
Lung Injury ◽  
Cancer Patients ◽  
Radiation Pneumonitis ◽  
Early Stage ◽  
Treatment Options ◽  
Treatment And Prevention ◽  
Thoracic Radiation ◽  
Radiation Induced ◽  
Transplantation Conditioning

Radiation-induced lung injury (RILI) is a common complication in cancer patients receiving local thoracic radiation and bone marrow transplantation conditioning. It is divided into early-stage radiation pneumonitis and advanced radiation fibrosis of the lung. This severely hampers the quality of life and survival of cancer patients. Meanwhile, RILI is a major factor limiting radiation doses in clinical practice, which affects the local control of cancer. Unfortunately, the mechanism of RILI is still not well defined, and there are no treatment options available for these patients. In this review we summarize the methods and agents used for the treatment and prevention of RILI, with the aim of increasing understanding of RILI.

scholarly journals Protection Against Radiation-induced Duox1 and Duox2 Upregulation in Rat’s Lung Tissues by a Combination of Curcumin and L-Selenomethionine

2021 ◽  
Vol In Press (In Press) ◽  
Author(s):  
Masoud Najafi ◽  
Peyman Amini ◽  
Hana Saffar ◽  
Sedighe Kolivand ◽  
Elahe Motevaseli ◽  
...  
Keyword(s):  
Experimental Study ◽  
Free Radicals ◽  
Lung Injury ◽  
Male Rats ◽  
Interleukin 4 ◽  
Injury Treatment ◽  
Radiation Induced ◽  
Lung Irradiation ◽  
Stimulation Of

Background: It has been proposed that increased levels of pro-inflammatory and pro-fibrotic cytokines play a key role in radiation-induced lung injury. Interleukin-4 (IL-4) and IL-13 are two pro-fibrotic cytokines that promote the production of free radicals through stimulation of Duox1 and Duox2. In this experimental study, we aimed to evaluate the expression of IL4Ra1, Duox1, IL13Ra2, and Duox2 genes following rat’s lung irradiation. Objectives: Also, we detected the modulatory effect of a combination of curcumin and L-selenomethionine on the expression of these genes. Methods: Twenty male rats were divided into four groups as G1: control (no treatment or radiation); G2: treatment with a combination of curcumin and L-selenomethionine; G3: radiation; G4: radiation plus a combination of curcumin and L-selenomethionine. sixty-seven days after irradiation, rats were killed for detecting the expression of IL4Ra1, IL13Ra2, Duox1, and Duox2. Results: The results showed no detectable expression for IL13Ra2, while the expression of IL4Ra1, Duox1, and Duox2 was increased. Treatment with a combination of curcumin and L-selenomethionine could attenuate the expression of these genes. Conclusions: This study proposes that upregulation of Duox1 and Duox2 may be involved in radiation-induced lung injury. Treatment with a combination of curcumin and L-selenomethionine may be useful for the mitigation of lung injury through modulation of these genes.

scholarly journals A Network Pharmacology Approach to Investigate the Underlying Mechanisms of Alpinia Katsumadai Hayata on Acne Vulgaris

2021 ◽  
Vol 251 ◽  
pp. 02060
Author(s):  
Li Wang ◽  
Yang Nie ◽  
Huifang Chen ◽  
Jun Sun ◽  
Mingyue Hu ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Acne Vulgaris ◽  
Therapeutic Targets ◽  
Network Pharmacology ◽  
Stress Regulation ◽  
Pathway Network ◽  
Vegf Signaling ◽  
Anti Inflammatory ◽  
Underlying Mechanisms ◽  
Key Pathways

The Alpinia katsumadai Hayata Doukou, DK, is a traditional Chinese medicine that has shown superior anti-inflammatory property, which is widely used in the food and commodity industry. A network pharmacology analysis was performed to identify the potential anti-acne compounds, hub therapeutic targets, and the key pathways via TCMSP, BATMAN, CTD, PDB and PubChem databases. Finally, the “compoundtarget- pathway” network was constructed. The study found total 7 active compounds, including quercetin, (2R)-5,7-dihydroxy-2-phenylchroman-4-one, dehydrodiisoeugenol, (2R)-7-hydroxy-5-methoxy-2- phenylchroman-4-one, Pinocembrin, and 1,7-diphenyl-5-hydroxy-6-hepten-3-one alpinolide peroxide. In addition, 30 therapeutic targets, and 4 hub therapeutic targets of the DK were identified. The biological processes were primarily related to inflammatory response, response to oxidative stress, regulation of insulin secretion, etc. Which was significantly associated with ten pathways including the PI3K-Akt signaling pathways, VEGF signaling pathways, etc. Furtherly, the 4 hub targets AKT1, F2, AR, and PTGS2 with higher connectivity in PPI network were verificated though molecular docking, which once again proved that these targets are potential targets of their corresponding chemical molecules. Therefore, DK might have a synergistic effect on the anti-inflammatory effects via the various active compositions, targets and signaling pathways.

Apoptosis Signaling Pathways as Therapeutic Targets in Lung Injury

2004 ◽  
Vol 1 (3) ◽  
pp. 263-268 ◽  
Author(s):  
Kazuyoshi Kuwano ◽  
Naoki Hagimoto ◽  
Michihiro Yoshimi ◽  
Takashige Maeyama ◽  
Yoichi Nakanishi
Keyword(s):  
Lung Injury ◽  
Signaling Pathways ◽  
Therapeutic Targets

scholarly journals Damage-Associated Molecular Patterns and Their Signaling Pathways in Primary Blast Lung Injury: New Research Progress and Future Directions

2020 ◽  
Vol 21 (17) ◽  
pp. 6303
Author(s):  
Ning Li ◽  
Chenhao Geng ◽  
Shike Hou ◽  
Haojun Fan ◽  
Yanhua Gong
Keyword(s):  
Lung Injury ◽  
Signaling Pathways ◽  
Degradation Products ◽  
Therapeutic Targets ◽  
The Body ◽  
Research Progress ◽  
Future Research ◽  
Primary Blast ◽  
Extracellular Matrix Components ◽  
Blast Lung Injury

Primary blast lung injury (PBLI) is a common cause of casualties in wars, terrorist attacks, and explosions. It can exist in the absence of any other outward signs of trauma, and further develop into acute lung injury (ALI) or a more severe acute respiratory distress syndrome (ARDS). The pathogenesis of PBLI at the cellular and molecular level has not been clear. Damage-associated molecular pattern (DAMP) is a general term for endogenous danger signals released by the body after injury, including intracellular protein molecules (HMGB1, histones, s100s, heat shock proteins, eCIRP, etc.), secretory protein factors (IL-1β, IL-6, IL-10, TNF-α, VEGF, complements, etc.), purines and pyrimidines and their derived degradation products (nucleic acids, ATP, ADP, UDPG, uric acid, etc.), and extracellular matrix components (hyaluronic acid, fibronectin, heparin sulfate, biglycan, etc.). DAMPs can be detected by multiple receptors including pattern recognition receptors (PRRs). The study of DAMPs and their related signaling pathways, such as the mtDNA-triggered cGAS-YAP pathway, contributes to revealing the molecular mechanism of PBLI, and provides new therapeutic targets for controlling inflammatory diseases and alleviating their symptoms. In this review, we focus on the recent progress of research on DAMPs and their signaling pathways, as well as the potential therapeutic targets and future research directions in PBLI.

scholarly journals High-dose thoracic radiation therapy for non-small cell lung cancer: a novel grading scale of radiation-induced lung injury for symptomatic radiation pneumonitis

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Weronika Maria Szejniuk ◽  
Martin Skovmos Nielsen ◽  
Zsuzsanna Takács-Szabó ◽  
Jacek Pawlowski ◽  
Sahar Sulaiman Al-Saadi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Radiation Therapy ◽  
Lung Injury ◽  
Radiation Pneumonitis ◽  
Small Cell ◽  
Ct Scans ◽  
Small Cell Lung ◽  
Thoracic Radiation ◽  
Radiation Induced ◽  
Grading Scale

Abstract Background Symptomatic radiation pneumonitis (RP) may be a serious complication after thoracic radiation therapy (RT) for non-small cell lung cancer (NSCLC). This prospective observational study sought to evaluate the utility of a novel radiation-induced lung injury (RILI) grading scale (RGS) for the prediction of RP. Materials and methods Data of 41 patients with NSCLC treated with thoracic RT of 60–66 Gy were analysed. CT scans were scheduled before RT, one month post-RT, and every three months thereafter for one year. Symptomatic RP was defined as Common Terminology Criteria for Adverse Events grade ≥ 2. RGS grading ranged from 0 to 3. The inter-observer variability of the RGS was assessed by four senior radiologists. CT scans performed 28 ± 10 days after RT were used to analyse the predictive value of the RGS. The change in the RGS severity was correlated to dosimetric parameters. Results The CT obtained one month post-RT showed RILI in 36 (88%) of patients (RGS grade 0 [5 patients], 1 [25 patients], 2 [6 patients], and 3 [5 patients]). The inter-observer agreement of the RGS grading was high (Kendall’s W coefficient of concordance = 0.80, p < 0.01). Patients with RGS grades 2–3 had a significantly higher risk for development of RP (relative risk (RR): 2.4, 95% CI 1.6–3.7, p < 0.01) and RP symptoms within 8 weeks after RT (RR: 4.8, 95% CI 1.3–17.6, p < 0.01) compared to RGS grades 0–1. The specificity and sensitivity of the RGS grades 2–3 in predicting symptomatic RP was 100% (95% CI 80.5–100%) and 45.4% (95% CI 24.4–67.8%), respectively. Increase in RGS severity correlated to mean lung dose and the percentage of the total lung volume receiving 5 Gy. Conclusions The RGS is a simple radiologic tool associated with symptomatic RP. A validation study is warranted.

scholarly journals Cryptotanshinone Ameliorates Radiation-Induced Lung Injury in Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Yifang Jiang ◽  
Fengming You ◽  
Jie Zhu ◽  
Chuan Zheng ◽  
Ran Yan ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Injury ◽  
Pulmonary Function ◽  
Cardiac Fibrosis ◽  
Pulmonary Inflammation ◽  
Collagen Deposition ◽  
Radiation Induced ◽  
Cox 2 ◽  
Underlying Mechanisms ◽  
Marked Drop

Cryptotanshinone (CTS) was reported to repress a variety of systemic inflammation and alleviate cardiac fibrosis, but it is still unclear whether CTS could prevent radiation-induced lung injury (RILI). Here, we investigated the effects and underlying mechanisms of CTS on a RILI rat model. Our data revealed that CTS could efficiently preserve pulmonary function in RILI rats and reduce early pulmonary inflammation infiltration elicited, along with marked decreased levels of IL-6 and IL-10. Moreover, we found that CTS is superior to prednisone in attenuating collagen deposition and pulmonary fibrosis, in parallel with a marked drop of HYP (a collagen indicator) and α-SMA (a myofibroblast marker). Mechanistically, CTS inhibited profibrotic signals TGF-β1 and NOX-4 expressions, while enhancing the levels of antifibrotic enzyme MMP-1 in lung tissues. It is noteworthy that CTS treatment, in consistent with trichrome staining analysis, exhibited a clear advantage over PND in enhancing MMP-1 levels. However, CTS exhibited little effect on CTGF activation and on COX-2 suppression. Finally, CTS treatment significantly mitigated the radiation-induced activation of CCL3 and its receptor CCR1. In summary, CTS treatment could attenuate RILI, especially pulmonary fibrosis, in rats. The regulation on production and release of inflammatory or fibrotic factors IL-6, IL-10, TGF-β1, NOX-4, and MMP-1, especially MMP-1 and inhibition on CCL3/CCR1 activation, may partly attribute to its attenuating RILI effect.

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