Glycyrrhetinic acid alleviates radiation-induced lung injury in mice

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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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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Sulodexide Prevents Peritoneal Fibrosis by Downregulating the Expression of TGF-β1 and Its Signaling Pathway Molecules

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/2052787 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Zhiqiang Duan ◽

Jia Yao ◽

Nan Duan ◽

Min Wang ◽

Shiwei Wang

Keyword(s):

Peritoneal Dialysis ◽

Signaling Pathway ◽

Transforming Growth Factor ◽

Vascular Endothelial Cells ◽

Inflammatory Factors ◽

Control Group ◽

Peritoneal Fibrosis ◽

Blank Control Group ◽

Peritoneal Tissue ◽

Tgf Β1

Peritoneal dialysis is one of the main renal replacement treatments. However, long-term peritoneal dialysis keeps the peritoneum in contact with the sugar-containing nonphysiological peritoneal fluid, which leads to recurrent peritonitis, peritoneal fibrosis, and failure of ultrafiltration. Transforming growth factor-β1 (TGF-β1), related cytokines, and inflammatory factors are closely related to peritoneal fibrosis. Sulodexide (SLX) is a new type of glycosaminoglycan preparation, which is involved in the formation of an anionic charge barrier and can maintain the selective permeability of vascular endothelial cells. In this study, the innovative analysis of SLX specifically prevents the process of peritoneal dialysis peritoneal fibrosis by downregulating the expression of TGF-β1 and its signaling pathway molecules. We randomly divided 30 rats into three groups. The blank control group received no treatment. The peritoneal dialysis model group was injected with 4.25% peritoneal dialysate (PDF) 20 ml daily, and the SLX group was injected with 4.25% PDF 20 ml + sulodexide (SLX) 20 mg/kg daily. After 8 weeks of dialysis, the rats were sacrificed, and the peritoneal function test was performed to determine the amount of glucose transport and ultrafiltration. The thickness of peritoneal per unit area was observed under high magnification. The level of inflammation in peritoneal tissue and the expression of TGF-β1/Smad were detected. The results showed that SLX can significantly improve peritoneal tissue thickening and inflammation, can downregulate the expression of TGF-β1, Smad2, Smad3, and Smad7 in peritoneal tissue, and improve the progression of peritoneal fibrosis.

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Identification of lncRNA, MicroRNA, and mRNA-Associated CeRNA Network of Radiation-Induced Lung Injury in a Mice Model

Dose-Response ◽

10.1177/1559325819891012 ◽

2019 ◽

Vol 17 (4) ◽

pp. 155932581989101

Author(s):

Yida Li ◽

Liqing Zou ◽

Xi Yang ◽

Li Chu ◽

Jianjiao Ni ◽

...

Keyword(s):

Cell Differentiation ◽

Lung Injury ◽

Early Stage ◽

Cell Lineage ◽

Late Complications ◽

Control Group ◽

Messenger Rnas ◽

Mice Model ◽

Target Mrnas ◽

Radiation Induced

Radiation-induced lung injury (RILI) can be challenging for thoracic radiotherapy, thus investigating its mechanisms of related pathophysiological process is needed. Long noncoding RNAs (lncRNAs) was found to participate in normal tissue damage induced by ionizing irradiation. Here, we first profiled the dysregulation of lncRNAs, microRNAs (miRNAs), and messenger RNAs (mRNAs) of RILI in mice model receiving 12 Gy thoracic irradiation. The lung tissue was collected 48 hours after irradiation, after which an RNA library was built by RNA sequencing. Compared with the control group, 461 mRNAs and 401 lncRNAs were significantly upregulated, while 936 mRNAs and 501 lncRNAs were significantly downregulated. Then we predicted target miRNAs of the dysregulated lncRNAs and the target mRNAs of these miRNAs. Next, functional annotations of these target mRNAs were performed. Results showed some pathways apparently dysregulated, such as Th1 and Th2 cell differentiation, Th17 cell differentiation, and hematopoietic cell lineage. Through this study, we also highlighted that T helpers could be vital in RILI through lncRNA-miRNA-mRNA network, therefore causing fibrosis, indicating that RNA dysregulation in early stage of RILI may cause severe late complications. Thus, research on the target mechanism and early intervention of lncRNAs with associated competing endogenous RNA network will benefit the treatment of RILI.

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Protective effect of trimetazidine in radiation-induced cardiac fibrosis in mice

Journal of Radiation Research ◽

10.1093/jrr/rraa043 ◽

2020 ◽

Vol 61 (5) ◽

pp. 657-665

Author(s):

Jinmeng Zhang ◽

Xinjia He ◽

Xinya Bai ◽

Yang Sun ◽

Peng Jiang ◽

...

Keyword(s):

Gene Expression ◽

Growth Factor ◽

Molecular Mechanism ◽

Cardiac Fibrosis ◽

Tissue Growth ◽

Control Group ◽

High Dose ◽

X Rays ◽

Radiation Induced ◽

Tgf Β1

Abstract Radiation-induced heart damage is a serious side effect caused by radiotherapy, especially during the treatment of cancer near the chest. Trimetazidine is effective at reducing inflammation in the heart, but how it affects radiation-induced cardiac fibrosis (RICF) is unknown. To investigate the potential effect and molecular mechanism, we designed this project with a C57BL6 male mouse model supposing trimetazidine could inhibit RICF in mice. During the experiment, mice were randomly divided into six groups including a control group (Con), radiation-damaged model group (Mod) and four experimental groups receiving low-dose (10 mg/kg/day) or high-dose (20 mg/kg/day) trimetazidine before or after radiation treatment. Apart from the control group, all mice chests were exposed to 6 MV X-rays at a single dose of 20 Gy to induce RICF, and tissue analysis was done at 8 weeks after irradiation. Fibroblast or interstitial tissues and cardiac fibrosis-like characteristics were determined using haematoxylin and eosin and Masson staining, which can be used to assess myocardial fibrosis. Immunohistochemical analysis and RT-PCR were used to determine gene expression and study the molecular mechanism. As a result, this study suggests that trimetazidine inhibits RICF by reducing gene expression related to myocyte apoptosis and fibrosis formation, i.e. connective tissue growth factor (CTGF), transforming growth factor (TGF)-β1, smad2 and smad3. In conclusion, by regulating the CTGF/TGF-β1/Smad pathway, trimetazidine could be a prospective drug for clinical treatment of RICF.

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Dendrobium Mixture Improved Diabetic Nephropathy in db/db Mice by Regulating TGF-β1/Smads Signal Transduction

10.21203/rs.3.rs-177708/v1 ◽

2021 ◽

Author(s):

Yong Chen ◽

Xiaohui Lin ◽

Yanfang Zheng ◽

Wenzhen Yu ◽

Fan Lin ◽

...

Keyword(s):

Signal Transduction ◽

Diabetic Nephropathy ◽

Mrna Expression ◽

Signaling Pathway ◽

Transforming Growth Factor ◽

Interstitial Fibrosis ◽

Fasting Blood Glucose ◽

Blood Lipid ◽

Control Group ◽

Tgf Β1

Abstract BackgroundDendrobium mixture (DMix) is an effective treatment for diabetic nephropathy (DN), but the underlying molecular mechanism remains unclear. In this study, we investigated whether DMix regulates the transforming growth factor-β1 (TGF-β1)/Smads signal transduction pathway. MethodsTwenty-four db/db mice were randomly divided into three groups: the model, DMix, and gliquidone groups, while eight db/m mice were selected as the normal control group. The drug was administered by continuous gavage for 8 weeks. Body weight (BW), kidney weight (KW), kidney index, fasting blood glucose (FBG), blood lipid, 24-hour urinary albumin excretion rate, blood urea nitrogen, and serum creatinine levels were measured. Pathological changes in the renal tissue were observed using a light microscope. Real-time quantitative PCR and immunohistochemical staining were used to detect mRNA expression of TGF-β1 and alpha-smooth muscle actin (α-SMA) genes and proteins, respectively, in renal tissues. TGF-β1, Smad2, p-Smad2, Smad3, p-Smad3, and α-SMA expression levels were measured using western blotting. ResultsDMix significantly reduced FBG level, BW, KW, and blood lipid level, and improved renal function in db/db mice. Histopathology showed that DMix alleviated glomerular mesangial cell proliferation and renal interstitial fibrosis in db/db mice. Additionally, DMix reduced protein and mRNA expression of TGF-β1 and α-SMA, and inhibited Smad2 and Smad3 phosphorylation. ConclusionsThe findings suggest that DMix may inhibit renal fibrosis and delay the progression of DN by regulating the TGF-β1/Smads signaling pathway. Key words: Diabetic nephropathy, Dendrobium mixture, TGF-β1/Smads signaling pathway

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Huangqi Shengmai Yin Protects against Radiation-Induced Cardiac Fibrosis Injury by Regulating the TGF-β1/Smads and MMPs

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/1358469 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Jing Gu ◽

Yongqi Liu ◽

Hongyan Wu ◽

Hailong Li ◽

Kai Liu

Keyword(s):

Signaling Pathway ◽

Rat Model ◽

Cardiac Fibrosis ◽

Volume Fraction ◽

X Rays ◽

Rat Hearts ◽

Radiation Induced ◽

First Time ◽

Myocardial Pathology ◽

Tgf Β1

Background. Radiation-induced heart damage is considered to be a progressive process of fibrosis. Emerging evidence has indicated that the Smads and matrix metalloproteinases (MMPs)/tissue inhibitors of MMPs (TIMP) may be involved in radiation-induced cardiac fibrosis (RICF) by regulating the activation of TGF-β1 signaling pathway. Based on this, the present study was undertaken to characterize the effect of Huangqi Shengmai Yin (HSY) on RICF in a rat model. Methods. Precardiac region of rats was irradiated with 25 Gy X-rays, and their myocardial pathology scores in terms of injury and collagen volume fraction (CVF) and the expression levels of fibrotic molecules were detected. Results. The pathology scores and CVF in myocardial tissue increased after irradiation, and the expression of TGF-β1, Col1, and Col3 increased. This change indicated that such irradiation promoted the fibrosis damage in rat hearts. The damage was accompanied by an increase in the expression of Smad 2, Smad3, Smad4, and MMP14 and a decrease in the expression of Smad 7 and TIMP1. Administration of HSY weakened the RICF by decreasing pathology score and CVF and decreased the expression of TGF-β1, Col1, and Col3 in irradiated rat hearts. In addition, Smad2, Smad3, Smad4, and MMP14 were downregulated, while Smad 7 and TIMP1 were upregulated during intervention with HSY. Conclusions. The involvement of the TGF-β1/Smads and MMPs/TIMP system in RICF was confirmed. This study demonstrated, for the first time, that HSY attenuates the effects of RICF in a rat model. The effect HSY was found to be closely related to the TGF-β1/Smads signaling pathway and MMPs system. These results suggest that HSY is a prospective drug for clinical treatment of RICF.

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Keratinocyte Growth Factor-2 Reduces Inflammatory Response to Acute Lung Injury Induced by Oleic Acid in Rats by Regulating Key Proteins of the Wnt/β-Catenin Signaling Pathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/8350579 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Shao Tenghao ◽

Chen Ning ◽

Wang Shenghai ◽

Sun Qinlong ◽

Wu Jiaqian ◽

...

Keyword(s):

Acute Lung Injury ◽

Oleic Acid ◽

Lung Injury ◽

Signaling Pathway ◽

Lung Tissue ◽

Blood Cells ◽

Keratinocyte Growth Factor ◽

White Blood Cells ◽

Inflammatory Factors ◽

Control Group

Reducing inflammation can effectively relieve acute lung injury (ALI). Objective. To test whether keratinocyte growth factor-2 (KGF-2) can reduce oleic acid-induced inflammation in ALI of rats and explore its possible mechanism. Methods. 45 Sprague-Dawley rats were randomly divided into control group, ALI group, and ALI + KGF-2 group. The animal model of acute lung injury was established by injecting 0.1 mL/kg oleic acid into the tail vein of rats. Rats in the control group were injected with equal volume of normal saline (NS). Each group needs pretreatment 72 hours before the preparation of the acute lung injury model. The control group and ALI group were instilled with 5 ml/kg NS through the airway, and the same amount of KGF-2 was instilled in the ALI + KGF-2 group. It takes 8 hours to successfully prepare the ALI model. Observe the pathological changes of lung tissue through light microscopy, ultrastructural changes through electron microscopy, and the lung wettability/dry weight (w/d) ratio and lung permeability index (LPI). By detecting changes in inflammatory factors in lung tissue and changes in the number of BALF cells, the changes in inflammation in each group were observed. The expressions of Wnt5a, β-catenin, and APC in lung tissue were detected by immunohistochemistry and Western blot. The changes of key proteins in Wnt/β-catenin signaling pathway in the lung tissue of each group were observed. Result. Compared with the ALI group, after KGF-2 pretreatment, the degree of lung injury was reduced, the expression of inflammatory factors was reduced, and the number of red blood cells and white blood cells in BALF was reduced. It can also be observed that the expression of Wnt5a, β-catenin, and APC, a key protein in the Wnt/β-catenin signaling pathway, is reduced. The analysis showed that the number of inflammatory factors, red blood cells, and white blood cells in BALF was positively correlated with the expression of Wnt5a, β-catenin, and APC. Conclusion. KGF-2 may reduce the inflammatory response in ALI induced by oleic acid by regulating key proteins in the Wnt/β-catenin signaling pathway.

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Nebulized Heparin Attenuates Pulmonary Coagulopathy and Inflammation through Alveolar Macrophages in a Rat Model of Acute Lung Injury

Thrombosis and Haemostasis ◽

10.1160/th17-05-0347 ◽

2017 ◽

Vol 117 (11) ◽

pp. 2125-2134 ◽

Cited By ~ 20

Author(s):

Laura Chimenti ◽

Marta Camprubí-Rimblas ◽

Raquel Guillamat-Prats ◽

Maria Gomez ◽

Jessica Tijero ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Inflammatory Response ◽

Lung Tissue ◽

Alveolar Macrophages ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Coagulation Cascade ◽

Control Group ◽

Proinflammatory Mediators

Objective Alveolar macrophages play a key role in the development and resolution of acute respiratory distress syndrome (ARDS), modulating the inflammatory response and the coagulation cascade in lungs. Anti-coagulants may be helpful in the treatment of ARDS. This study investigated the effects of nebulized heparin on the role of alveolar macrophages in limiting lung coagulation and inflammatory response in an animal model of acute lung injury (ALI). Methods Rats were randomized to four experimental groups. In three groups, ALI was induced by intratracheal instillation of lipopolysaccharide (LPS) and heparin was nebulized at constant oxygen flow: the LPS/Hep group received nebulized heparin 4 and 8 hours after injury; the Hep/LPS/Hep group received nebulized heparin 30 minutes before and 4 and 8 hours after LPS-induced injury; the LPS/Sal group received nebulized saline 4 and 8 hours after injury. The control group received only saline. Animals were exsanguinated 24 hours after LPS instillation. Lung tissue, bronchoalveolar lavage fluid (BALF) and alveolar macrophages isolated from BALF were analysed. Results LPS increased protein concentration, oedema and neutrophils in BALF as well as procoagulant and proinflammatory mediators in lung tissue and alveolar macrophages. In lung tissue, nebulized heparin attenuated ALI through decreasing procoagulant (tissue factor, thrombin–anti-thrombin complexes, fibrin degradation products) and proinflammatory (interleukin 6, tumour necrosis factor alpha) pathways. In alveolar macrophages, nebulized heparin reduced expression of procoagulant genes and the effectors of transforming growth factor beta (Smad 2, Smad 3) and nuclear factor kappa B (p-selectin, CCL-2). Pre-treatment resulted in more pronounced attenuation. Conclusion Nebulized heparin reduced pulmonary coagulopathy and inflammation without producing systemic bleeding, partly by modulating alveolar macrophages.

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Nickel oxide nanoparticles induced pulmonary fibrosis via TGF-β1 activation in rats

Human & Experimental Toxicology ◽

10.1177/0960327116666650 ◽

2016 ◽

Vol 36 (8) ◽

pp. 802-812 ◽

Cited By ~ 17

Author(s):

XH Chang ◽

A Zhu ◽

FF Liu ◽

LY Zou ◽

L Su ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Nickel Oxide ◽

Lung Tissue ◽

Messenger Rna ◽

Transforming Growth Factor ◽

Quantitative Polymerase Chain Reaction ◽

Tissue Inhibitor Of Metalloproteinase ◽

Enzyme Linked Immunosorbent Assay ◽

Control Group ◽

Tgf Β1

Nano nickel oxide (NiO), widely used in industry, has recently been discovered to have pulmonary toxicity. However, no subchronic exposure studies about nano NiO-induced pulmonary fibrosis have been reported. The objective of this study was to investigate pulmonary fibrosis induced by nano NiO and its potential mechanism in rats. Male Wistar rats ( n = 40, 200–240 g) were randomized into control group, nano NiO groups (0.015, 0.06, and 0.24 mg/kg), and micro NiO group (0.024 mg/kg). All rats were killed to collect lung tissue after intratracheal instillation of NiO particles twice a week for 6 weeks. To identify pulmonary fibrosis, Masson trichrome staining, hydroxyproline content, and collagen protein expression were performed. The results showed widespread lung fibrotic injury in histological examination and increased content of hydroxyproline, collagen types I and III in rat lung tissue exposed to nano NiO. To explore the potential pulmonary fibrosis mechanism, transforming growth factor beta 1 (TGF- β1) content was measured by enzyme-linked immunosorbent assay, and the messenger RNA expression of key indicators was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The TGF- β1 content was increased in nano NiO exposure groups, as well as the upregulated gene expression of TGF- β1, Smad2, Smad4, matrix metalloproteinase, and tissue inhibitor of metalloproteinase. The findings indicated that nano NiO could induce pulmonary fibrosis, which may be related to TGF- β1 activation.

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Dendrobium Mixture Ameliorates Diabetic Nephropathy in db/db Mice by Regulating the TGF-β1/Smads Signaling Pathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/9931983 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Yong Chen ◽

Xiaohui Lin ◽

Yanfang Zheng ◽

Wenzhen Yu ◽

Fan Lin ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Signaling Pathway ◽

Transforming Growth Factor ◽

Interstitial Fibrosis ◽

Lipid Level ◽

Fasting Blood Glucose ◽

Blood Lipid ◽

Control Group ◽

Expression Levels ◽

Tgf Β1

Dendrobium mixture (DMix) is an effective treatment for diabetic nephropathy (DN), but the molecular mechanism underlying its action remains unclear. In this study, we investigated whether DMix regulates the transforming growth factor-β1 (TGF-β1)/Smads signal transduction pathway. Twenty-four db/db mice were randomly divided into three groups: the model, DMix, and gliquidone groups, while eight db/m mice were selected as the normal control group. The drug was administered by continuous gavage for 8 weeks. Body weight (BW), kidney weight (KW), kidney index, fasting blood glucose (FBG), blood lipid, 24-hour urinary albumin excretion rate, blood urea nitrogen, and serum creatinine levels were measured. Pathological changes in the renal tissue were observed under a light microscope. Real-time quantitative PCR and immunohistochemical staining were used to detect the mRNA and protein expression levels of TGF-β1 and alpha-smooth muscle actin (α-SMA), respectively, in renal tissues. TGF-β1, Smad2, p-Smad2, Smad3, p-Smad3, and α-SMA expression levels were measured using western blotting. The results showed that DMix significantly reduced the FBG level, BW, KW, and blood lipid level and improved renal function in db/db mice. Histopathology showed that DMix alleviated glomerular mesangial cell proliferation and renal interstitial fibrosis in db/db mice. Additionally, DMix reduced the protein and mRNA expression levels of TGF-β1 and α-SMA and inhibited Smad2 and Smad3 phosphorylation. We conclude that DMix may inhibit renal fibrosis and delay the progression of DN by regulating the TGF-β1/Smads signaling pathway.

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