Anti-inflammatory gene therapy directed at the airway epithelium

Griesenbach, Uta; Scheid, P.; Hillery, Elizabeth; Martin, Rainer de; Huang, Leaf; Geddes, Duncan M.; Alton, Eric W.F.W.

doi:10.1038/sj.gt.3301078

Cited by 58 publications

(45 citation statements)

References 41 publications

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“…It is unknown which type of nuclear signal is more biologically relevant, although in vitro studies have shown that a diffuse pattern of nuclear localization results in downregulation of interleukin-8. 30 Similar to previously published studies, we detected ODNs in the red pulp of the spleen, whereas the white pulp was less efficiently transfected. 31 The red pulp is a highly vascular tissue and allows the passage of blood through the parenchyma, where phagocytic cells remove particulate matter and aged/ abnormal red blood cells.…”

Section: IV Delivery Of Lpdsupporting

confidence: 80%

“…Nuclear factor (NF)-kB is a transcription factor involved in the regulation of many proinflammatory mediators and NF-kB decoys have been shown to downregulate interleukin-8 secretion in CF epithelial cell lines. 30 We used NF-kB decoys as a prototype to assess i.v. delivery of small DNA molecules to the airway epithelial cells via the bronchial circulation.…”

Section: IV Delivery Of Lpdmentioning

confidence: 99%

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Intravenously administered oligonucleotides can be delivered to conducting airway epithelium via the bronchial circulation

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Griesenbach

et al. 2006

Gene Ther

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Section: IV Delivery Of Lpdsupporting

confidence: 80%

Section: IV Delivery Of Lpdmentioning

confidence: 99%

Intravenously administered oligonucleotides can be delivered to conducting airway epithelium via the bronchial circulation

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Griesenbach

et al. 2006

Gene Ther

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“…Transcriptional factor NFjB is a well recognized mediator of inflammatory processes in laboratory animals, patients and in vitro studies (Baeza-Squiban et al 1999;Griesenbach et al 2000;Aldonyte et al 2004Aldonyte et al , 2008. Studies targeting NFjB for treatment purposes are ongoing (Griesenbach et al 2000;Aikawa et al 2002). As our data suggest, MCSsecreted products might be considered as one of the treatment options protecting epithelial cells from injuries.…”

Section: Discussionmentioning

confidence: 68%

“…Other authors have also shown that cytokine release from A549 cells under the stimulation with bacterial irritants is dependent on NFjB (Sachse et al 2006). Transcriptional factor NFjB is a well recognized mediator of inflammatory processes in laboratory animals, patients and in vitro studies (Baeza-Squiban et al 1999;Griesenbach et al 2000;Aldonyte et al 2004Aldonyte et al , 2008. Studies targeting NFjB for treatment purposes are ongoing (Griesenbach et al 2000;Aikawa et al 2002).…”

Section: Discussionmentioning

confidence: 99%

Native matrix-based human lung alveolar tissue model in vitro: studies of the reparatory actions of mesenchymal stem cells

et al. 2016

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Studies of lung diseases in vitro often rely on flat, plastic-based monocultures, due to short lifespan of primary cells, complicated anatomy, lack of explants, etc. We hereby present a native 3D model with cues for repopulating epithelial cells. Abilities of mesenchymal stem cells (MSC) to modulate bacterial lipopolysaccharide (LPS) and cigarette smoke-induced injury to pulmonary epithelium were tested in our model. Post-mortem human lung tissue was sliced, cut and decellularized. Resulting matrix pads were reseeded with pulmonary epithelium (A549 line). Markers of the layer integrity and certain secreted proteins in the presence of cigarette smoke extract (CSE) and LPS were assessed via Western blot, ELISA and RT-PCR assays. In parallel, the effects of MSC paracrine factors on exposed epithelial cells were also investigated at gene and protein levels. When cultured on native 3D matrix, A549 cells obtain dual, type I-and II-like morphology. Exposure to CSE and LPS leads to downregulation of several epithelial proteins and suppressed proliferation rate. MSC medium added to the model restores proliferation rate and some of the epithelial proteins, i.e. e-cadherin and beta-catenin. CSE also increases secretion of proinflammatory cytokines by epithelial cells and upregulates transcription factor NFjB. Some of these effects might be counteracted by MSC in our model. We introduce repopulated decellularized lung matrix that highly resembles in vivo situation and is convenient for studies of disease pathogenesis, cytotoxicology and for exploring therapeutic strategies in the human lung context in vitro. MSC paracrine products have produced protecting effects in our model.

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“…NF B decoy oligonucleotides, which resemble consensus binding sites for NF B, and therefore inactivate the transcription factor have been used successfully in several inflammatory disease animal models. [13][14][15] We have previously demonstrated that NF B decoy oligonucleotides (ODN) reduced basal and LPS-stimulated IL-8 secretion in a CF airway epithelial cell line, 16 but their effect in models of pulmonary inflammation in vivo has not yet been investigated. We have, therefore, assessed the effect of NF B decoy ODN administration during the acute phase of bleomycininduced pulmonary inflammation in C57Bl/6 mice in vivo.…”

Section: Nuclear Transfection Significantly We Determined the Effectmentioning

confidence: 99%

Cytoplasmic deposition of NFκB decoy oligonucleotides is insufficient to inhibit bleomycin-induced pulmonary inflammation

et al. 2002

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Lung inflammation leads to severe tissue destruction and ultimately organ failure in a number of diseases, including cystic fibrosis (CF). The transcription factor nuclear factor kappa B (NF B) regulates expression of many pro-inflammatory mediators. We have assessed the effect of topical administration of NF B decoys in a bleomycin model of acute lung inflammation. Using fluorescein-labelled decoy oligonucleotides (ODN) (80 g/mouse) we have shown that lipid-complexed and 'naked' ODN transfect conducting airway epithelium in a comparable manner (approximately 65% of cells). However, the ODN were detectable in the cytoplasm, but not in the nucleus of transfected cells. An increase of ODN dose to 500 g/mouse did not increase

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Anti-inflammatory gene therapy directed at the airway epithelium

Cited by 58 publications

References 41 publications

Intravenously administered oligonucleotides can be delivered to conducting airway epithelium via the bronchial circulation

Intravenously administered oligonucleotides can be delivered to conducting airway epithelium via the bronchial circulation

Native matrix-based human lung alveolar tissue model in vitro: studies of the reparatory actions of mesenchymal stem cells

Cytoplasmic deposition of NFκB decoy oligonucleotides is insufficient to inhibit bleomycin-induced pulmonary inflammation

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