Small interfering RNA targeting NF-κB attenuates lipopolysaccharide-induced acute lung injury in rats

Li, Ning; Song, Yuanbin; Zhao, Wei; Han, Tingting; Lin, Shu-Hui; Ramirez, Oscar; Li, Liang

doi:10.1186/s12899-016-0027-y

Cited by 38 publications

(19 citation statements)

References 20 publications

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“…TNF-α is known to activate two major signaling pathways, namely the NFκB and MAPK pathways. Both these pathways are widely recognized to mediate inflammation in various cell types and pathological conditions [ 21 , 54 ], and are also common putative targets for the treatment of conditions involving pulmonary inflammation including ALI/ARDS [ 55 , 56 , 57 , 58 ]. A similar mechanism of action has also been reported in tHGA-treated activated mast cells, which is associated with its anti-allergic effect via suppression of inflammatory mediators production [ 15 , 16 ].…”

Section: Discussionmentioning

confidence: 99%

The Protective Effects of a Synthetic Geranyl Acetophenone in a Cellular Model of TNF-α-Induced Pulmonary Epithelial Barrier Dysfunction

et al. 2018

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Alveolar epithelial barrier dysfunction contributes to lung edema and can lead to acute lung injury (ALI). The features include increased epithelial permeability, upregulation of inflammatory mediators and downregulation of junctional complex molecules; these changes are often induced by inflammation. tHGA is an acetophenone analogue with therapeutic potential in asthma. Its therapeutic potential in ALI is presently unknown. Herein, the effects of tHGA on epithelial barrier dysfunction were determined in TNF-α-induced human alveolar epithelial cells. The anti-inflammatory properties of tHGA were assessed by monocyte adhesion assay and analysis of MCP-1 and ICAM-1 expression. The epithelial barrier function was assessed by paracellular permeability and transepithelial electrical resistance (TEER) assays, and analysis of junctional complex molecules expression. To elucidate the mechanism of action, the effects of tHGA on the NF-κB and MAPK pathways were determined. Gene and protein expression were analyzed by RT-PCR and Western blotting or ELISA, respectively. tHGA suppressed leukocyte adhesion to TNF-α-induced epithelium and reduced MCP-1 and ICAM-1 gene expression and secretion. tHGA also increased TEER readings, reduced epithelial permeability and enhanced expression of junctional complex molecules (zona occludens-1, occludin and E-cadherin) in TNF-α-induced cells. Correspondingly, the NF-κB, ERK and p38 MAPK pathways were also inhibited by tHGA. These findings suggest that tHGA is able to preserve alveolar epithelial barrier function in response to acute inflammation, via its anti-inflammatory activity and stabilization of epithelial barrier integrity, mediated by NF-κB, ERK and p38 MAPK signaling.

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Section: Discussionmentioning

confidence: 99%

The Protective Effects of a Synthetic Geranyl Acetophenone in a Cellular Model of TNF-α-Induced Pulmonary Epithelial Barrier Dysfunction

et al. 2018

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“…NF-κB is a family of DNA binding proteins involved in the expression of pro-inflammatory factors and thus the development of ARDS. Depletion of NF-κB by specific siRNA targeted NF-κB p65 in lipopolysaccharide (LPS)-induced ALI rat models effectively reduced levels of the pro-inflammatory cytokines and ameliorated symptoms induced by LPS (97). In vivo administration of the siS1PLyase/HMGB1A/R3V6 complex reduced the S1PLyase level and weakened the inflammatory response and apoptosis in an LPS-induced ALI model, indicating that siS1PLyase and HMGB1A have a synergistic therapeutic effect for ALI (98).…”

Section: Inflammatory Diseasesmentioning

confidence: 99%

Nucleic Acid-Based Therapeutics for Pulmonary Diseases

et al. 2018

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Nucleic acid-based therapeutics present huge potential in the treatment of pulmonary diseases ranging from lung cancer to asthma and chronic pulmonary diseases, which are often fatal and widely prevalent. The susceptibility of nucleic acids to degradation and the complex structure of lungs retard the effective pulmonary delivery of nucleic acid drug. To overcome these barriers, different strategies have been exploited to increase the delivery efficiency using chemically synthesized nucleic acids, vector encapsulation, proper formulation, and administration route. However, several limitations regarding off-target effects and immune stimulation of nucleic acid drugs hamper their translation into the clinical practice. Therefore, their successful clinical application will ultimately rely on well-developed carriers and methods to ensure safety and efficacy. In this review, we provide a comprehensive overview of the nucleic acid application for pulmonary diseases, covering action mechanism of the nucleic acid drugs, the novel delivery systems, and the current formulation for the administration to lungs. The latest advances of nucleic acid drugs under clinical evaluation to treat pulmonary disorders will also be detailed.KEY WORDS: nucleic acid; antisense oligonucleotide (ASO); short interfering RNA (siRNA); microRNA (miRNA); pulmonary diseases.

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“…In that, it has been demonstrated that the up-regulation of AhR and NF-jB promotes oxidative stress and apoptosis in cancer and non-cancer human lung epithelial cells (Zhang et al 2015;Jaligama et al 2018). Moreover, AhR knockdown protected zebrafish against cardiac toxicity (Van Tiem and Di Giulio 2011), whereas, NF-jB knockdown protects the lung from lipopolysaccharideinduced inflammation in rats (Li et al 2016).…”

Section: Control (B)mentioning

confidence: 99%

The role of NF-κB and AhR transcription factors in lead-induced lung toxicity in human lung cancer A549 cells

Attafi

Bakheet

Korashy

2019

Toxicology Mechanisms and Methods

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Lead (Pb) is recognized as the first heavy metal of the top six toxic air pollutants threatening human health and the second hazardous substance. Pb exposure is associated with lung impairment and high incidences of lung cancer. Nuclear factor kappa B (NF-jB) and aryl hydrocarbon receptor (AhR) signaling pathways are known to be expressed and play an important role in the lung. However, the link between Pb lung toxicity and NF-jB and/or AhR pathways remains unclear. This study was established to explore the role of NF-jB and AhR modulation in Pb-induced lung toxicity in human lung cancer A549 cells. In the current study, treatment of A549 cells with Pb significantly induced cell apoptosis as evidenced by increasing a) the percentage of cells underwent apoptosis determined by flow cytometry and b) p53 mRNA level. Pb treatment induced oxidative stress by a) increasing the formation of reactive oxygen species and b) decreasing GSTA1 mRNA levels. The toxic effects of Pb on the lung was associated with significant increases in NF-jB and AhR levels which was accompanied with increases in downstream targets genes, iNOS and CYP1A1, respectively. Inhibition of NF-jB or AhR either chemically using resveratrol or genetically using small interfering RNA (siRNA) significantly rescued A549 cells from Pb-mediated lung toxicity. The results clearly indicate that Pb-mediated lung toxicities are NF-jB and AhR-dependent mechanism.

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Small interfering RNA targeting NF-κB attenuates lipopolysaccharide-induced acute lung injury in rats

Cited by 38 publications

References 20 publications

The Protective Effects of a Synthetic Geranyl Acetophenone in a Cellular Model of TNF-α-Induced Pulmonary Epithelial Barrier Dysfunction

The Protective Effects of a Synthetic Geranyl Acetophenone in a Cellular Model of TNF-α-Induced Pulmonary Epithelial Barrier Dysfunction

Nucleic Acid-Based Therapeutics for Pulmonary Diseases

The role of NF-κB and AhR transcription factors in lead-induced lung toxicity in human lung cancer A549 cells

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