Transforming Growth Factor-β1 Promotes M1 Alveolar Macrophage Polarization in Acute Lung Injury by Up-Regulating DNMT1 to Mediate the microRNA-124/PELI1/IRF5 Axis

ObjectiveMacrophages function as key orchestrators in the pathogenesis of acute lung injury (ALI). The current study sets out to investigate the molecular mechanism of transforming growth factor-β (TGFβ1) in the regulation of M1 alveolar macrophage polarization in ALI by modulating DNA methyltransferase 1 (DNMT1), along with the microRNA (miR)-124/Pellino 1 (PELI1)/interferon regulatory factor 5 (IRF5) axis.MethodsFirst, ALI mouse models were established, and the proportion of M1 and M2 macrophages in mouse lung tissues was detected using flow cytometry. The targeting relationship between miR-124 and PELI1 was verified with the help of a dual luciferase gene reporter assay. Following TGFβ1 knockdown, RT-qPCR and Western blot assay were performed to analyze the expression patterns of TGFβ1, DNMT1, miR-124, and PELI1 and M1/M2 polarization markers in the lung tissues of ALI mice. Immunofluorescence was further employed to detect nuclear translocation of IRF5 in macrophages.ResultsThe polarization of M1 macrophages was found to be positively correlated with the severity of lung injury. TGFβ1, DNMT1, PELI1 were highly expressed, while miR-124 was down-regulated in ALI mice, and IRF5 was primarily distributed in the nucleus. TGFβ1 promoted the polarization of M1 alveolar macrophages by up-regulating DNMT1. Furthermore, DNMT1 down-regulated the expression of miR-124, which led to enhancement of M1 alveolar macrophage polarization. Meanwhile, over-expression of miR-124 inhibited the nuclear translocation of IRF5 and suppressed M1 alveolar macrophage polarization. On the other hand, over-expression of PELI1 reversed the above trends.ConclusionCollectively, our findings indicated that TGFβ1 can promote the expression of DNMT1, which down-regulates miR-124 to activate PELI1 and nuclear translocation of IRF5, thereby aggravating ALI in mice.

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Metalloproteinase and growth factor interactions: do they play a role in pulmonary fibrosis?

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00489.2001 ◽

2002 ◽

Vol 283 (1) ◽

pp. L1-L11 ◽

Cited By ~ 26

Author(s):

Margaret K. Winkler ◽

John L. Fowlkes

Keyword(s):

Acute Lung Injury ◽

Growth Factors ◽

Growth Factor ◽

Pulmonary Fibrosis ◽

Lung Injury ◽

Transforming Growth Factor ◽

Interstitial Fibrosis ◽

Inflammatory Cells ◽

Transforming Growth Factor Β ◽

Target Cells

Chronic lung disease due to interstitial fibrosis can be a consequence of acute lung injury and inflammation. The inflammatory response is mediated through the migration of inflammatory cells, actions of proinflammatory cytokines, and the secretion of matrix-degrading proteinases. After the initial inflammatory insult, successful healing of the lung may occur, or alternatively, dysregulated tissue repair can result in scarring and fibrosis. On the basis of recent insights into the mechanisms underlying acute lung injury and its long-term consequences, data suggest that proteinases, such as the matrix metalloproteinases (MMPs), may not only be involved in the breakdown and remodeling that occurs during the injury but may also cause the release of growth factors and cytokines known to influence growth and differentiation of target cells within the lung. Through the release of and activation of fibrosis-promoting cytokines and growth factors such as transforming growth factor-β1, tumor necrosis factor-α, and insulin-like growth factors by MMPs, we propose that these metalloproteinases may be integral to the initiation and progression of pulmonary fibrosis.

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microRNA-145-5p attenuates acute lung injury via targeting ETS2

10.21203/rs.3.rs-698885/v1 ◽

2021 ◽

Author(s):

Liang Qiao ◽

Rongxia Li ◽

Shangang Hu ◽

Yu Liu ◽

Hongqiang Liu ◽

...

Keyword(s):

Acute Lung Injury ◽

Growth Factor ◽

Lung Injury ◽

Inflammatory Response ◽

Transforming Growth Factor ◽

Recombinant Adenovirus ◽

Transforming Growth Factor Β1 ◽

Inflammatory Factors ◽

Smad Pathway ◽

Tgf Β1

Abstract Objective Previously, the protective effect of microRNA (miR)-145-5p has been discovered in acute lung injury (ALI). Thus, this study attempts to further discuss the mechanism of miR-145-5p in ALI through the downstream E26 transformation-specific proto-oncogene 2 (ETS2)/transforming growth factor β1 (TGF-β1)/Smad pathway. Methods A lipopolysaccharide (LPS)-induced rat ALI model was established. Recombinant adenovirus miR-145-5p and/or ETS2 overexpression plasmid was administrated into rats. Afterwards, pathological damage in the lung tissue, wet/dry (W/D) ratio, apoptosis and contents of serum inflammatory factors were observed. miR-145-5p, ETS2, TGF-β1, Smad2/3, phosphorylated Smad2/3 levels were measured in rats. Results miR-145-5p was down-regulated, ETS2 was up-regulated and TGF-β1/Smad pathway was activated in LPS-suffered rats. Overexpression of miR-145-5p inactivated the TGF-β1/Smad pathway and attenuated ALI, as reflected by relived pathological damage, and decreased W/D ratio, apoptosis and inflammatory response. Oppositely, loss of miR-145-5p or enhancement of ETS2 worsened ALI and activated the TGF-β1/Smad pathway. Moreover, elevation of ETS2 decreased miR-145-5p-mediated protection against ALI. Conclusion Evidently, miR-145-5p negatively regulates ETS2 expression and inactivates TGF-β1/Smad pathway to ameliorate ALI in rats.

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Role of growth factors in acute lung injury induced by paraquat in a rat model

Human & Experimental Toxicology ◽

10.1177/0960327110372648 ◽

2010 ◽

Vol 30 (6) ◽

pp. 460-469 ◽

Cited By ~ 13

Author(s):

Xiangdong Jian ◽

Ming Li ◽

Yijing Zhang ◽

Yanjun Ruan ◽

Guangran Guo ◽

...

Keyword(s):

Gene Expression ◽

Acute Lung Injury ◽

Growth Factors ◽

Growth Factor ◽

Lung Injury ◽

Rat Model ◽

Transforming Growth Factor ◽

Pcr Analysis ◽

Circulatory Level

Paraquat (PQ) can cause acute lung injury in humans and experimental animals. However, the role of growth factors in the progression of injury has not been clearly established. We developed an animal model of PQ-induced lung injury using Wistar rats. One milliliter of PQ solution (30, 60, and 120 mg/kg) was applied through the lavage, while the same amount of vehicle was applied to control rats. Based on histopathology, the lungs of some animals exposed to PQ showed acute fulmination, resulting in death, while others showed a more protracted injury, resulting in typical pulmonary fibrosis at 21 days. Using this PQ-poisoned rat model, we examined the intrapulmonary gene expression and circulatory level of cytokines and growth factors at 8 hours, 24 hours, 3 days, 7 days, 14 days, and 21 days after PQ administration. Semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis demonstrated that the gene expression levels of interleukin-1 beta and interleukin-6 were significantly increased at 21 days after PQ challenge compared with the controls. The mRNA expression of tumor necrosis factor-alpha was also significantly increased except on days 14 and 21 after PQ treatment. Moreover, PQ-treated rats showed enhanced gene expression of growth factors such as platelet-derived growth factor-A and insulin-like growth factor-1 at 21 days and transforming growth factor-beta 1 at 14 days. ELISA results showed the circulatory level of cytokines and growth factors coincided with intrapulmonary gene expression. The synergistic effects of these molecules are presumed to cause pulmonary damage due to PQ challenge and may become targets of treatment.

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Soluble Transforming Growth Factor-α Is Present in the Pulmonary Edema Fluid of Patients With Acute Lung Injury

CHEST Journal ◽

10.1378/chest.111.3.652 ◽

1997 ◽

Vol 111 (3) ◽

pp. 652-656 ◽

Cited By ~ 43

Author(s):

Asha N. Chesnutt ◽

Farrah Kheradmand ◽

Hans G. Folkesson ◽

Michael Alberts ◽

Michael A. Matthay

Keyword(s):

Acute Lung Injury ◽

Growth Factor ◽

Lung Injury ◽

Pulmonary Edema ◽

Transforming Growth Factor ◽

Transforming Growth Factor Α ◽

Edema Fluid ◽

Factor Α

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Gene Expression Changes during the Development of Acute Lung Injury Role of Transforming Growth Factor β

American Journal of Respiratory and Critical Care Medicine ◽

10.1164/rccm.200502-286oc ◽

2005 ◽

Vol 172 (11) ◽

pp. 1399-1411 ◽

Cited By ~ 46

Author(s):

Scott C. Wesselkamper ◽

Lisa M. Case ◽

Lisa N. Henning ◽

Michael T. Borchers ◽

Jay W. Tichelaar ◽

...

Keyword(s):

Gene Expression ◽

Acute Lung Injury ◽

Growth Factor ◽

Lung Injury ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β

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Interleukin-1β augments in vitro alveolar epithelial repair

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.2000.279.6.l1184 ◽

2000 ◽

Vol 279 (6) ◽

pp. L1184-L1190 ◽

Cited By ~ 80

Author(s):

Thomas Geiser ◽

Pierre-Henri Jarreau ◽

Kamran Atabai ◽

Michael A. Matthay

Keyword(s):

Acute Lung Injury ◽

Growth Factor ◽

Lung Injury ◽

Wound Repair ◽

Transforming Growth Factor ◽

Epithelial Repair ◽

Transforming Growth Factor Α ◽

Alveolar Epithelial ◽

Factor Α

Biologically active interleukin (IL)-1β is present in the pulmonary edema fluid obtained from patients with acute lung injury and has been implicated as an important early mediator of nonpulmonary epithelial wound repair. Therefore, we tested the hypothesis that IL-1β would enhance wound repair in cultured monolayers from rat alveolar epithelial type II cells. IL-1β (20 ng/ml) increased the rate of in vitro alveolar epithelial repair by 118 ± 11% compared with that in serum-free medium control cells ( P < 0.01). IL-1β induced cell spreading and migration at the edge of the wound but not proliferation. Neutralizing antibodies to epidermal growth factor (EGF) and transforming growth factor-α or inhibition of the EGF receptor by tyrphostin AG-1478 or genistein inhibited IL-1β-induced alveolar epithelial repair, indicating that IL-1β enhances in vitro alveolar epithelial repair by an EGF- or transforming growth factor-α-dependent mechanism. Moreover, the mitogen-activated protein kinase pathway is involved in IL-1β-induced alveolar epithelial repair because inhibition of extracellular signal-regulated kinase activation by PD-98059 inhibited IL-1β-induced alveolar epithelial repair. In conclusion, IL-1β augments in vitro alveolar epithelial repair, indicating a possible novel role for IL-1β in the early repair process of the alveolar epithelium in acute lung injury.

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Canagliflozin alleviates LPS-induced acute lung injury by modulating alveolar macrophage polarization

International Immunopharmacology ◽

10.1016/j.intimp.2020.106969 ◽

2020 ◽

Vol 88 ◽

pp. 106969

Author(s):

Fengyu Lin ◽

Chao Song ◽

Yanjun Zeng ◽

Yi Li ◽

Haitao Li ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Alveolar Macrophage ◽

Macrophage Polarization

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Early Activation of Pulmonary TGF-β1/Smad2 Signaling in Mice with Acute Pancreatitis-Associated Acute Lung Injury

Mediators of Inflammation ◽

10.1155/2014/148029 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 11

Author(s):

Hamid Akbarshahi ◽

Asha Sam ◽

Chaolei Chen ◽

Ann H. Rosendahl ◽

Roland Andersson

Keyword(s):

Acute Pancreatitis ◽

Acute Lung Injury ◽

Lung Injury ◽

Transforming Growth Factor ◽

Nuclear Translocation ◽

Specific Therapy ◽

Smad7 Expression ◽

Alk 5 ◽

Late Stages ◽

Tgf Β1

Acute lung injury is caused by many factors including acute pancreatitis. There is no specific therapy directed at underlying pathophysiological mechanisms for acute lung injury. Transforming growth factor-β(TGF-β) is involved in the resolution of lung injury in later phases of the disease. Some evidence exists demonstrating that TGF-βnot only is involved in the late stages, but also contributes to lung injury early on in the progress of the disease. Acute pancreatitis was induced using ductal ligation in mice. TGF-β1, 2, and 3, TβRII, ALK-5, Smad2, 3, 4, and 7, and P-Smad2 expression in the lungs were analyzed at 9 and 24 h. We demonstrate that TGF-β1 levels in the lungs of mice with acute pancreatitis increase as early as 9 h after induction. We observed an increased expression of ALK-5 in acute pancreatitis at both 9 and 24 h. Inhibitory Smad7 expression was transiently increased at 9 h in acute pancreatitis, but reduced later at 24 h, with a concomitant increased nuclear translocation of phosphorylated Smad2. Our findings demonstrate activation of TGF-βsignaling in the lungs as early as 24 h after acute pancreatitis, suggesting that TGF-βmay represent a potential therapeutic candidate in acute pancreatitis-induced acute lung injury.

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