Long Non-coding RNAs Are Central Regulators of the IL-1β-Induced Inflammatory Response in Normal and Idiopathic Pulmonary Lung Fibroblasts

AbstractmicroRNAs are non-coding RNAs that negatively regulate gene networks. Previously, we reported a systemically delivered miR-29 mimic MRG-201 that reduced fibrosis in animal models, but at doses prohibiting clinical translation. Here, we generated MRG-229, a next-gen miR-29 mimic with improved chemical stability, conjugated with the internalization moiety BiPPB (PDGFbetaR-specific bicyclic peptide). In TGF-b-treated human lung fibroblasts and precision cut lung slices, MRG-229 decreased COL1A1 and ACTA2 gene expression and reduced collagen production. In bleomycin-treated mice, intravenous or subcutaneous delivery of MRG-229 downregulated profibrotic gene programs at doses more than ten-fold lower than the original compound. In rats and non-human primates, and at clinically relevant doses, MRG-229 was well tolerated, with no adverse findings observed. In human peripheral blood decreased mir-29 concentrations were associated with increased mortality in two cohorts potentially identified as a target population for treatment. Collectively, our results provide support for the development of MRG-229 as a potential therapy in humans with IPF.One Sentence SummaryOne Sentence Summary: A stabilized, next-generation miR-29 mimic has been developed that demonstrates efficacy at commercially viable doses with a robust safety margin in non-human primates.

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Amorphous Silica Nanoparticles Obtained by Laser Ablation Induce Inflammatory Response in Human Lung Fibroblasts

Materials ◽

10.3390/ma12071026 ◽

2019 ◽

Vol 12 (7) ◽

pp. 1026 ◽

Cited By ~ 4

Author(s):

Sorina Voicu ◽

Mihaela Balas ◽

Miruna Stan ◽

Bogdan Trică ◽

Andreea Serban ◽

...

Keyword(s):

Inflammatory Response ◽

Silica Nanoparticles ◽

Human Lung ◽

Lung Fibroblasts ◽

No Production ◽

Dependent Manner ◽

Amorphous Sio2 ◽

Human Lung Fibroblasts ◽

Transmission Electron ◽

Cox 2

Silica nanoparticles (SiO2 NPs) represent environmentally born nanomaterials that are used in multiple biomedical applications. Our aim was to study the amorphous SiO2 NP-induced inflammatory response in MRC-5 human lung fibroblasts up to 72 hours of exposure. The intracellular distribution of SiO2 NPs was measured by transmission electron microscopy (TEM). The lactate dehydrogenase (LDH) test was used for cellular viability evaluation. We have also investigated the lysosomes formation, protein expression of interleukins (IL-1β, IL-2, IL-6, IL-8, and IL-18), COX-2, Nrf2, TNF-α, and nitric oxide (NO) production. Our results showed that the level of lysosomes increased in time after exposure to the SiO2 NPs. The expressions of interleukins and COX-2 were upregulated, whereas the expressions and activities of MMP-2 and MMP-9 decreased in a time-dependent manner. Our findings demonstrated that the exposure of MRC-5 cells to 62.5 µg/mL of SiO2 NPs induced an inflammatory response.

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Regulatory Role of Non-Coding RNAs on Immune Responses During Sepsis

Frontiers in Immunology ◽

10.3389/fimmu.2021.798713 ◽

2021 ◽

Vol 12 ◽

Author(s):

Soudeh Ghafouri-Fard ◽

Tayyebeh Khoshbakht ◽

Bashdar Mahmud Hussen ◽

Mohammad Taheri ◽

Normohammad Arefian

Keyword(s):

Inflammatory Response ◽

Multiple Organ ◽

Organ System ◽

Circular Rnas ◽

System Failure ◽

Multiple Organ System ◽

Organ System Failure ◽

Multiple Organ System Failure ◽

Non Coding Rnas

Sepsis is resulted from a systemic inflammatory response to bacterial, viral, or fungal agents. The induced inflammatory response by these microorganisms can lead to multiple organ system failure with devastating consequences. Recent studies have shown altered expressions of several non-coding RNAs such as long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and circular RNAs (circRNAs) during sepsis. These transcripts have also been found to participate in the pathogenesis of multiple organ system failure through different mechanisms. NEAT1, MALAT1, THRIL, XIST, MIAT and TUG1 are among lncRNAs that participate in the pathoetiology of sepsis-related complications. miR-21, miR-155, miR-15a-5p, miR-494-3p, miR-218, miR-122, miR-208a-5p, miR-328 and miR-218 are examples of miRNAs participating in these complications. Finally, tens of circRNAs such as circC3P1, hsa_circRNA_104484, hsa_circRNA_104670 and circVMA21 and circ-PRKCI have been found to affect pathogenesis of sepsis. In the current review, we describe the role of these three classes of noncoding RNAs in the pathoetiology of sepsis-related complications.

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Inflammatory response to isocyanates and onset of genomic instability in cultured human lung fibroblasts

Genetics and Molecular Research ◽

10.4238/vol8-1gmr544 ◽

2009 ◽

Vol 8 (1) ◽

pp. 129-143 ◽

Cited By ~ 22

Author(s):

P.K. Mishra ◽

A. Bhargava ◽

G.V. Raghuram ◽

S. Gupta ◽

S. Tiwari ◽

...

Keyword(s):

Inflammatory Response ◽

Genomic Instability ◽

Human Lung ◽

Lung Fibroblasts ◽

Human Lung Fibroblasts

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Long Non-coding RNA Rhabdomyosarcoma 2-Associated Transcript Regulates Angiogenesis in Endothelial Cells

Frontiers in Physiology ◽

10.3389/fphys.2021.729157 ◽

2021 ◽

Vol 12 ◽

Author(s):

Maha Alaqeeli ◽

Dominique Mayaki ◽

Sabah N. A. Hussain

Keyword(s):

Endothelial Cells ◽

Umbilical Vein ◽

Lung Fibroblasts ◽

Mrna Levels ◽

Loss Of Function ◽

Cell Counts ◽

Non Coding Rnas ◽

And Migration ◽

Human Aortic Valve ◽

Umbilical Vein Endothelial Cells

Background: Long non-coding RNAs (lncRNAs) are non-coding RNAs that have more than 200 nucleotides. They have recently emerged as important regulators of angiogenesis. To identify novel lncRNAs that may be involved in the regulation of angiogenesis, we detected the mRNA of 84 lncRNAs in human umbilical vein endothelial cells (HUVECs) exposed to hypoxia for 24h. One of these, rhabdomyosarcoma 2-associated transcript (RMST), is significantly upregulated by hypoxia. Little is known about the presence and roles of RMST in EC function.Objective: The main objective of the study was to investigate the regulation of RMST in ECs and to determine its role in EC survival, proliferation, migration, and differentiation.Methods: Using qPCR, basal mRNA levels of 10 RMST isoforms in HUVECs were measured. Levels were then measured in response to 24h of hypoxia, 7days of differentiation in a co-culture assay, and exposure to four different angiogenesis factors. Functional roles of RMST in EC survival, migration, and differentiation were quantified by using a loss-of-function approach (transfection with single-stranded antisense LNA GapmeRs). EC survival was measured using cell counts and crystal violet assays. Cell migration and differentiation were measured using scratch wound healing and Matrigel® differentiation assays, respectively.Results: Five RMST isoforms (RMST-202, -203, -204, -206, and -207) were detected in HUVECs and human microvascular endothelial cells (HMEC-1s). Other types of vascular cells, including human aortic valve interstitial cells and human aortic smooth muscle cells, did not display this expression profile. RMST was significantly upregulated in response to 24h of hypoxia and in response to 7days of HUVEC co-culture with human lung fibroblasts. RMST was significantly downregulated by angiopoietin-2 (Ang-2), but not by VEGF, FGF-2, or angiopoietin-1 (Ang-1). Selective knockdown of RMST demonstrated that it promotes EC survival in response to serum deprivation. It is also required for VEGF- and Ang-1-induced EC survival and migration, but not for differentiation.Conclusion: We conclude that RMST is expressed in human ECs and that this expression is upregulated in response to hypoxia and during differentiation into capillary-like structures. We also conclude that RMST plays important roles in EC survival and migration.

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LncRNA Small nucleolar RNA host gene 16 (SNHG16) silencing protects lipopolysaccharide (LPS)-induced cell injury in human lung fibroblasts WI-38 through acting as miR-141-3p sponge

Bioscience Biotechnology and Biochemistry ◽

10.1093/bbb/zbab016 ◽

2021 ◽

Author(s):

Lei Xia ◽

Guoqing Zhu ◽

Haiyun Huang ◽

Yishui He ◽

Xingguang Liu

Keyword(s):

Inflammatory Response ◽

Target Genes ◽

Human Lung ◽

Host Gene ◽

Lung Fibroblasts ◽

Luciferase Reporter ◽

Small Nucleolar Rna ◽

Human Lung Fibroblasts ◽

Induced Apoptosis ◽

Nucleolar Rna

Abstract LncRNA small nucleolar RNA host gene 16 is correlated with cell injuries, including pneumonia. However, the role and mechanism of SNHG16 remain vague in pneumonia. The interplay among genes was confirmed by dual-luciferase reporter assay, RNA immunoprecipitation and RNA pull-down assay. SNHG16 and SUSD2 were upregulated, and miR-141-3p was downregulated in the serum of acute pneumonia patients and lipopolysaccharide-challenged human lung fibroblasts WI-38. LPS induced apoptosis, autophagy and inflammatory response in WI-38 cells, which was significantly attenuated by SNHG16 knockdown and/or miR-141-3p overexpression. Notably, both SNHG16 and SUSD2 were identified as target genes of miR-141-3p. Besides, the suppressive role of SNHG16 knockdown in LPS-induced apoptosis, autophagy and inflammatory response in WI-38 cells was partially abolished by miR-141-3p silencing, the similar inhibition of miR-141-3p overexpression in LPS-treated WI-38 cells was further blocked by SUSD2 restoration. Knockdown of SNHG16 could alleviate LPS-induced apoptosis, autophagy and inflammation in WI-38 cells partially though SNHG16/miR-141-3p/SUSD2 pathway.

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Brucella-Induced Downregulation of lncRNA Gm28309 Triggers Macrophages Inflammatory Response Through the miR-3068-5p/NF-κB Pathway

Frontiers in Immunology ◽

10.3389/fimmu.2020.581517 ◽

2020 ◽

Vol 11 ◽

Author(s):

Xingmei Deng ◽

Jia Guo ◽

Zhihua Sun ◽

Laizhen Liu ◽

Tianyi Zhao ◽

...

Keyword(s):

Inflammatory Response ◽

Immune Responses ◽

Nlrp3 Inflammasome ◽

Inflammatory Responses ◽

Underlying Mechanism ◽

Bioinformatic Analysis ◽

Luciferase Reporter ◽

Non Coding Rnas ◽

First Time

ObjectivesThe underlying mechanism of the inflammatory response against Brucellosis caused by Brucella remains poorly understood. This study aimed to determine the role of long non-coding RNAs (lncRNAs) in regulating of inflammatory and anti-Brucella responses.Materials and methodsMicroarray analysis was performed to detect differentially expressed lncRNAs in THP-1 cells infected with an S2308 Brucella strain. The candidate lncRNAs were screened using bioinformatic analysis and siRNAs; bioinformatic prediction and luciferase reporter assay were also conducted, while inflammatory responses was assessed using RT‐qPCR, western blot, immunofluorescence, ELISA, HE, and immunohistochemistry.ResultsThe lncRNA Gm28309 was identified to be involved in regulating inflammation induced by Brucella. Gm28309, localized in the cytoplasm, was down-expressed in RAW264.7 cells infected with S2308. Overexpression of Gm28309 or inhibition of miR-3068-5p repressed p65 phosphorylation and reduced NLRP3 inflammasome and IL-1β and IL-18 secretion. Mechanistically, Gm28309 acted as a ceRNA of miR-3068-5p to activate NF-κB pathway by targeting κB-Ras2, an inhibitor of NF-κB signaling. Moreover, the number of intracellular Brucella was higher when Gm28309 was overexpressed or when miR-3068-5p or p65 was inhibited. However, these effects were reversed by the miR-3068-5p mimic.ConclusionsOur study demonstrates, for the first time, that LncRNAs are involved in regulating immune responses during Brucella infection, and Gm28309, an lncRNA, plays a crucial role in activating NF-κB/NLRP3 inflammasome signaling pathway.

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