Protective effect of melatonin entrapped PLGA nanoparticles on radiation-induced lung injury through the the miR-21/TGF-β1/Smad3 pathway

Background/Aims: As a major complication after thoracic radiotherapy, radiation-induced lung injury (RILI) has great impact on long term quality of life and could result in fatal respiratory insufficiency The present study was aimed to evaluate the effects of Myrtol standardized on RILI, and to investigate the underlying mechanism. Methods: A mouse model of radiation-induced lung injury was generated by using thoracic irradiation with a single dose of 16Gy. Mice were orally administrated with Myrtol (25 mg/kg/day) for 4 weeks after irradiation, while prednisone (5 mg/kg/day) was used as a positive control. After then, the body weight and lung coefficient were calculated. The severity of fibrosis was evaluated by observing pulmonary sections after radiation and collagen content in lung tissues was calculated following the hydroxyproline (HYP) assay. Pathological changes were observed in all the groups by using HE staining and Masson staining. The serum levels of TGF-β1, TNF-α, IL-1β, IL-6, and PGE2 were also measured with an ELISA assay. Western blot assay was used to measure the impact of Myrtol on AKT and its downstream signaling pathway, including MMP-2 and MMP-9. The levels of Vimentin and α-SMA were evaluated with an immunofluorescence assay. Results: Treatment with Myrtol standardized, but not prednisone, reduced lung coefficient and collagen deposition in lung tissues, while attenuated histological damages induced by irradiation. Myrtol standardized also reduced the production of MDA, while increased the level of SOD. It was also observed that Myrtol standardized inhibited TGF-β1 and a series of pro-inflammatory cytokines including TNF-α, IL-1β, IL-6, PGE2. While in prednisone group, even though the early pneumonitis was ameliorated, the collagen disposition remained unchanged in latter times. Immunofluorescence analysis also revealed elevation of vimentin and α-SMA in the alveoli after a single dose of 16Gy. Conclusion: The present results suggest Myrtol standardized as an effective agent for attenuating the lung injury induced by irradiation.

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Protective effects of ulinastatin and methylprednisolone against radiation-induced lung injury in mice

Journal of Radiation Research ◽

10.1093/jrr/rrw036 ◽

2016 ◽

Vol 57 (5) ◽

pp. 505-511 ◽

Cited By ~ 4

Author(s):

Yu Sun ◽

Yu-Jun Du ◽

Hui Zhao ◽

Guo-Xing Zhang ◽

Ni Sun ◽

...

Keyword(s):

Lung Injury ◽

Lung Tissue ◽

Transforming Growth Factor ◽

Lavage Fluid ◽

Protective Effects ◽

Pathological Changes ◽

Tnf Α ◽

Methylprednisolone Treatment ◽

Radiation Induced ◽

Tgf Β1

Abstract The effectiveness of ulinastatin and methylprednisolone in treating pathological changes in mice with radiation-induced lung injury (RILI) was evaluated. Forty C57BL/6 female mice received whole-chest radiation (1.5 Gy/min for 12 min) and were randomly allocated into Group R (single radiation, n = 10), Group U (ulinastatin treatment, n = 10), Group M (methylprednisolone treatment, n = 10), or Group UM (ulinastatin and methylprednisolone treatment, n = 10). Another 10 untreated mice served as controls (Group C). Pathological changes in lung tissue, pulmonary interstitial area density (PIAD) and expression levels of transforming growth factor β1 (TGF-β1) and tumor necrosis factor α (TNF-α) in lung tissue, serum and bronchoalveolar lavage fluid were determined. Alleviation of pathological changes in lung tissue was observed in Groups U, M and UM. Treatment with ulinastatin, methylprednisolone or both effectively delayed the development of fibrosis at 12 weeks after radiation. Ulinastatin, methylprednisolone or both could alleviate the radiation-induced increase in the PIAD ( P < 0.05 or P < 0.01). Treatment with ulinastatin, methylprednisolone or both significantly reduced the expression of TNF-α, but not TGF-β1, at 9 weeks after radiation compared with Group R ( P < 0.01). Ulinastatin and / or methylprednisolone effectively decreased the level of TNF-α in lung tissue after RILI and inhibited both the inflammatory response and the development of fibrosis.

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Glycyrrhetinic acid alleviates radiation-induced lung injury in mice

Journal of Radiation Research ◽

10.1093/jrr/rrw091 ◽

2017 ◽

Vol 58 (1) ◽

pp. 41-47 ◽

Cited By ~ 5

Author(s):

Jinmei Chen ◽

Weijian Zhang ◽

Lurong Zhang ◽

Jiemin Zhang ◽

Xiuying Chen ◽

...

Keyword(s):

Lung Injury ◽

Signaling Pathway ◽

Lung Tissue ◽

Transforming Growth Factor ◽

Early Stage ◽

Glycyrrhetinic Acid ◽

Control Group ◽

X Rays ◽

Radiation Induced ◽

Tgf Β1

Abstract Radiation-induced lung injury (RILI) is a common complication of thoracic radiotherapy, but efficacious therapy for RILI is lacking. This study ascertained whether glycyrrhetinic acid (GA; a functional hydrolyzed product of glycyrrhizic acid, which is extracted from herb licorice) can protect against RILI and investigated its relationship to the transforming growth factor (TGF)-β1/Smads signaling pathway. C57BL/6 mice were divided into four groups: a control group, a GA group and two irradiation (IR) groups. IR groups were exposed to a single fraction of X-rays (12 Gy) to the thorax and administered normal saline (IR + NS group) or GA (IR + GA group). Two days and 17 days after irradiation, histologic analyses were performed to assess the degree of lung injury, and the expression of TGF-β1, Smad2, Smad3 and Smad7 was recorded. GA administration mitigated the histologic changes of lung injury 2 days and 17 days after irradiation. Protein and mRNA expression of TGF-β1, Smad2 and Smad3, and the mRNA level of Smad7, in lung tissue were significantly elevated after irradiation. GA decreased expression of TGF-β1, Smad2 and Smad3 in lung tissue, but did not increase Smad7 expression. GA can protect against early-stage RILI. This protective effect may be associated with inhibition of the TGF-β1/Smads signaling pathway.

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Activation of The P62-Keap1-NRF2 Pathway Protects Against Ferroptosis in Radiation-Induced Lung Injury

10.21203/rs.3.rs-1032461/v1 ◽

2021 ◽

Author(s):

Xuan Li ◽

Jingyao Chen ◽

Sujuan Yuan ◽

Xibing Zhuang ◽

Tiankui Qiao

Keyword(s):

Cell Death ◽

Lung Injury ◽

Protective Effect ◽

Background Radiation ◽

Specific Inhibitor ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Quinone Oxidoreductase ◽

Nrf2 Pathway ◽

Radiation Induced

Abstract Background Radiation-induced lung injury (RILI) is one of the most common, serious and dose-limiting complications of thoracic radiotherapy. A primary reason for this is the radiation-induced cell death. Ferroptosis is a recently recognized form of regulated cell death, characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS). The ROS induced by irradiation might be the original trigger of ferroptosis in RILI. Furthermore, activation of the P62-Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (NRF2) pathway has been shown to exert a protective effect, blunting ferroptosis. Therefore, this study aims to explore the protective effect of the P62-Keap1-NRF2 pathway against radiation-induced ferroptosis in alveolar epithelial cells. Results Firstly, our results demonstrated that radiation induced ferroptosis in vitro RILI cell model, which could be significantly reduced by Ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis. Then, we found that overexpression of P62 interacted with Keap1 to promote NRF2 translocation into the nucleus and upregulation its target proteins quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HO1) and ferritin heavy chain 1 (FTH1). Conclusion Collectively, the activation of the P62-Keap1-NRF2 pathway prevents radiation-induced ferroptosis in RILI cells, providing a theoretical basis for further research to find a potential approach for RILI therapy.

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LncRNA-RP11 Modulates TGF-β1-Activated Radiation-Induced Lung Injury Through Downregulating microRNA-29a

Dose-Response ◽

10.1177/1559325820949071 ◽

2020 ◽

Vol 18 (4) ◽

pp. 155932582094907

Author(s):

Xi Yang ◽

Jianjiao Ni ◽

Yida Li ◽

Liqing Zou ◽

Tiantian Guo ◽

...

Keyword(s):

Lung Injury ◽

Human Lung ◽

Human Fibroblasts ◽

Bioinformatic Analysis ◽

Fine Tuning ◽

Lung Fibroblasts ◽

Human Lung Fibroblasts ◽

Thoracic Radiation ◽

Radiation Induced ◽

Tgf Β1

Radiation-induced lung injury (RILI) is one of the most serious complications of thoracic radiation and TGF-β1 is a central regulator of RILI. However, the molecular mechanism underlying the fine tuning of TGF-β1 signaling in RILI has not been fully understood. In the current study, differentially expressed long non-coding RNAs (LncRNAs) among human lung fibroblasts cell lines HFL-1 and WI-38 treated with TGF-β1, were identified by microarray and validated by real time PCR. LncRNA-RP11 was found to be the most increased LncRNA and it mediated the promotion of fibrogenic activity in human lung fibroblasts after TGF-β1 treatment. Bioinformatic analysis revealed that TGF-β1 may be associated with the component and structure of extracellular matrix in lung fibroblasts cells, and LncRNA-RP11 was predicted and confirmed to be a competing endogenous RNA by directly binding to miR-29a. Functional experiments investigating the biological role of LncRNA-RP11/miR-29a axis in RILI, were then carried out in human fibroblasts. The results showed that radiation promoted the expression of LncRNA-RP11, but regressed the expression of miR-29a. Furthermore, radiation elevated the expression of various common collagenic proteins, which could be abolished by overexpression of miR-29a.

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TGF-β1-based CRISPR/Cas9 gene therapy attenuate Radiation-induced Lung Injury

Current Gene Therapy ◽

10.2174/1566523220666201230100523 ◽

2020 ◽

Vol 20 ◽

Author(s):

Shuai Zhen ◽

Rong Qiang ◽

Jiaojiao Lu ◽

Xiaoqian Tuo ◽

Xiling Yang ◽

...

Keyword(s):

Gene Therapy ◽

Lung Injury ◽

Bronchoalveolar Lavage Fluid ◽

Lavage Fluid ◽

Terminal Deoxynucleotidyl Transferase ◽

Cytokine Levels ◽

Radiation Induced ◽

Mouse Lungs ◽

Tgf Β1 ◽

Masson Staining

Background: Radiation-induced lung injury (RILI) is lacking effective therapeutic strategies. In this study, we conducted TGF-β1-based CRISPR/Cas9 gene therapy for RILI. Objectives: Mouse lungs were irradiated with a single-dose of 20-Gy gamma rays followed by intravenous administration of Ad-CRISPR-TGF-β1 or Ad- CRISPR-Null. Methods: Haematoxylin and eosin staining, as well as Masson staining were performed to observe lung morphology. Albumin and IgM concentrations in bronchoalveolar lavage fluid were measured by ELISA. Cytokine levels were measured using ELISA and/or real-time PCR with terminal deoxynucleotidyl transferase mediated nick-end labelling. Results: Ad-CRISPR-TGFβ1 improved histopathological and biochemical markers of lung injury, reduced secretion and expression of inflammatory cytokines, and inhibited progression of fibrosis. Importantly, the SK1/S1P axis—which is known to play a key role via S1P1 in TGF-β1-dependent S1PR pattern remodelling—is responsible for promoting fibrosis. Conclusion: Our results indicate novel insights for RILI therapy.

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Thymoquinone Ameliorates Lung Inflammation and Pathological Changes Observed in Lipopolysaccharide-Induced Lung Injury

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/6681729 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Mostafa Boskabady ◽

Mohammad Reza Khazdair ◽

Rahimeh Bargi ◽

Saeideh Saadat ◽

Arghavan Memarzia ◽

...

Keyword(s):

Lung Injury ◽

Protective Effect ◽

Lung Inflammation ◽

Therapeutic Potential ◽

Pathological Changes ◽

Immunomodulatory Effects ◽

Bronchoalveolar Fluid ◽

Anti Inflammatory ◽

Wbc Count ◽

Tgf Β1

Anti-inflammatory, antioxidant, and immunomodulatory effects of thymoquinone (TQ) have been shown. The effects of TQ on lipopolysaccharide- (LPS-) induced inflammation and pathological changes in rats’ lung were investigated in this study. Four groups of rats included (1) control (saline treated); (2) LPS (treated with 1 mg/kg/day i.p. for two weeks); and (3 and 4) 5 or 10 mg/kg TQ i.p. 30 min prior to LPS administration. Total and differential WBC counts in the blood and bronchoalveolar fluid (BALF), TGF-β1, INF-γ, PGE2, and IL-4 levels in the BALF and pathological changes of the lung were evaluated. Total WBC count and eosinophil, neutrophil, and monocyte percentage were increased, but the lymphocyte percentage was reduced in the blood and BALF. The BALF levels of PGE2, TGF-β1, and INF-γ were also increased, but IL-4 level was reduced due to LPS administration. LPS also induced pathological insults in the lung of rats ( P < 0.05 to P < 0.001 for all changes in LPS-exposed animals). Treatment with TQ showed a significant improvement in all changes induced by LPS ( P < 0.05 to P < 0.05 ). TQ showed a protective effect on LPS-induced lung inflammation and pathological changes in rats which suggested a therapeutic potential for TQ on lung injury.

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Effect of αvβ3 Blockade Against Acute Lung Injury Induced by Influenza A Virus and Its Mechanism

10.21203/rs.3.rs-545939/v1 ◽

2021 ◽

Author(s):

Wendi Yu ◽

Maoseng Zeng ◽

Jinyuan Liu ◽

Huixian Wang ◽

peiping xu

Keyword(s):

Influenza Virus ◽

Acute Lung Injury ◽

Lung Injury ◽

Protective Effect ◽

Influenza A Virus ◽

Influenza A ◽

Integrin Αvβ3 ◽

Tgf Β1

Abstract Integrin αvβ3 is a heterodimer formed by αv and β3 subunits that is expressed in pulmonary endothelial cells, alveolar epithelial cells, interstitial cells and macrophages. Integrin αvβ3 not only has a common role of integrin family molecules in inflammation and tissue fibrosis, but also mediates the adsorption and penetration of various viruses into susceptible cells. Nevertheless, there are few studies on the effect of αvβ3 on acute lung injury (ALI) induced by influenza virus and its mechanism. Here, the effects of αvβ3 blockade [Cyclo(RGDyK)] against ALI induced by influenza A virus (IAV) in vitro and in vivo and its possible mechanism were studied. A549 cells and mice were infected with influenza virus A/FM/1/47 to induce ALI in vitro and in vivo. The results showed that Cyclo(RGDyK) reduced the ALI induced by IAV, alleviated pulmonary edema, improved lung histopathological changes and alleviated the accumulation of inflammatory cells in the lung. Cyclo(RGDyK) had inhibitory effect on cells and mice infected by IAV. Cyclo(RGDyK) (150 µg/kg) showed effective antiviral activity in vivo. Cyclo(RGDyK) had 70% protective effect against IAV and effectively reduced virus titer and inflammation in lung tissue. Cyclo(RGDyK) exhibited significantly anti-inflammatory and anti-fibrotic effect on improving the pneumonia and degree of pulmonary fibrosis and reducing the levels of pulmonary fibrotic markers (LN, HA, PCIII, IV-C, TGF-β1, and α-SMA). Additionally, Cyclo(RGDyK) inhibited expression of αvβ3,TGF-β1, HIF-1α, NF-κB, and p38 MAPK in the cells and mice lung tissues. The results showed that Cyclo(RGDyK) had a protective effect on ALI in mice infected with IAV and inhibited the progress of lung inflammation and fibrosis, which may be concern with its regulation of αvβ3/TGF-β1/HIF-1α signaling pathway.

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