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Nanoparticle Delivery of Anti-inflammatory LNA Oligonucleotides Prevents Airway Inflammation in a HDM Model of Asthma.

ABSTRACT: To address the problem of poor asthma control due to drug resistance, an antisense oligonucleotide complementary to mmu-miR-145a-5p (antimiR-145) was tested in a house dust mite mouse model of mild/moderate asthma. miR-145 was targeted to reduce inflammation, regulate epithelial-mesenchymal transitions, and promote differentiation of structural cells. In addition, several chemical variations of a nontargeting oligonucleotide were tested to define sequence-dependent effects of the miRNA antagonist. After intravenous administration, oligonucleotides complexed with a pegylated cationic lipid nanoparticle distributed to most cells in the lung parenchyma but were not present in smooth muscle or the mucosal epithelium of the upper airways. Treatment with antimiR-145 and a nontargeting oligonucleotide both reduced eosinophilia, reduced obstructive airway remodeling, reduced mucosal metaplasia, and reduced CD68 immunoreactivity. Poly(A) RNA-seq verified that antimiR-145 increased levels of many miR-145 target transcripts. Genes upregulated in human asthma and the mouse model of asthma were downregulated by oligonucleotide treatments. However, both oligonucleotides significantly upregulated many genes of interferon signaling pathways. These results establish effective lung delivery and efficacy of locked nucleic acid/DNA oligonucleotides administered intravenously, and suggest that some of the beneficial effects of oligonucleotide therapy of lung inflammation may be due to normalization of interferon response pathways.

SUBMITTER: Ramelli SC

PROVIDER: S-EPMC7013130 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Nanoparticle Delivery of Anti-inflammatory LNA Oligonucleotides Prevents Airway Inflammation in a HDM Model of Asthma.

Ramelli Sabrina C SC Comer Brian S BS McLendon Jared M JM Sandy Lydia L LL Ferretti Andrew P AP Barrington Robert R Sparks Jeff J Matar Majed M Fewell Jason J Gerthoffer William T WT

Molecular therapy. Nucleic acids 20200114

To address the problem of poor asthma control due to drug resistance, an antisense oligonucleotide complementary to mmu-miR-145a-5p (antimiR-145) was tested in a house dust mite mouse model of mild/moderate asthma. miR-145 was targeted to reduce inflammation, regulate epithelial-mesenchymal transitions, and promote differentiation of structural cells. In addition, several chemical variations of a nontargeting oligonucleotide were tested to define sequence-dependent effects of the miRNA antagonis ...[more]

PMID: 32044723

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Project description:Allergic airway inflammation (AAI) is a chronic respiratory disease that is considered a severe restriction in daily life and is accompanied by a constant risk of acute aggravation. It is characterized by IgE-dependent activation of mast cells, infiltration of eosinophils, and activated T-helper cell type 2 (Th2) lymphocytes into airway mucosa. Purinergic receptor signaling is known to play a crucial role in inducing and maintaining allergic airway inflammation. Previous studies in an ovalbumin (OVA)-alum mouse model demonstrated a contribution of the P2Y2 purinergic receptor subtype (P2RY2) in allergic airway inflammation. However, conflicting data concerning the mechanism by which P2RY2 triggers AAI has been reported. Thus, we aimed at elucidating the cell-type-specific role of P2RY2 signaling in house dust mite (HDM)-driven model of allergic airway inflammation. Thereupon, HDM-driven AAI was induced in conditional knockout mice, deficient or intact for P2ry2 in either alveolar epithelial cells, hematopoietic cells, myeloid cells, helper T cells, or dendritic cells. To analyze the functional role of P2RY2 in these mice models, flow cytometry of bronchoalveolar lavage fluid (BALF), cytokine measurement of BALF, invasive lung function measurement, HDM re-stimulation of mediastinal lymph node (MLN) cells, and lung histology were performed. Mice that were subjected to an HDM-based model of allergic airway inflammation resulted in reduced signs of acute airway inflammation including eosinophilia in BALF, peribronchial inflammation, Th2 cytokine production, and bronchial hyperresponsiveness in mice deficient for P2ry2 in alveolar epithelial cells, hematopoietic cells, myeloid cells, or dendritic cells. Furthermore, the migration of bone-marrow-derived dendritic cells and bone-marrow-derived monocytes, both deficient in P2ry2, towards ATP was impaired. Additionally, we found reduced levels of MCP-1/CCL2 and IL-8 homologues in the BALF of mice deficient in P2ry2 in myeloid cells and lower concentrations of IL-33 in the lung tissue of mice deficient in P2ry2 in alveolar epithelial cells. In summary, our results show that P2RY2 contributes to HDM-induced airway inflammation by mediating proinflammatory cytokine production in airway epithelial cells, monocytes, and dendritic cells and drives the recruitment of lung dendritic cells and monocytes.

Project description:BACKGROUND:Chronic respiratory diseases, whose one of the hallmarks is oxidative stress, are still incurable and need novel therapeutic tools and pharmaceutical agents. The phenolic compounds contained in grape are endowed with well-recognized anti-oxidant, anti-inflammatory, anti-cancer, and anti-aging activities. Considering that natural anti-oxidants, such as proanthocyanidins, have poor water solubility and oral bioavailability, we have developed a drug delivery system based on solid lipid nanoparticles (SLN), apt to encapsulate grape seed extract (GSE), containing proanthocyanidins. METHODS:Plain, 6-coumarin (6-Coum), DiR- and GSE-loaded SLN were produced with the melt-emulsion method. Physicochemical characterization of all prepared SLN was determined by photon correlation spectroscopy and laser Doppler anemometry. MTT assay (spectrophotometry) and propidium iodide (PI) assay (cytofluorimetry) were used to assess cell viability. Flow cytometry coupled with cell imaging was performed for assessing apoptosis and necrosis by Annexin V/7-AAD staining (plain SLE), cell internalization (6-Coum-SLN) and reactive oxygen species (ROS) production (SLN-GSE). NF-κB nuclear translocation was studied by immunofluorescence. In vivo bio-imaging was used to assess lung deposition and persistence of aerosolized DiR-loaded SLN. RESULTS:Plain SLN were not cytotoxic when incubated with H441 airway epithelial cells, as judged by both PI and MTT assays as well as by apoptosis/necrosis evaluation. 6-Coum-loaded SLN were taken up by H441 cells in a dose-dependent fashion and persisted into cells at detectable levels up to 16 days. SLN were detected in mice lungs up to 6 days. SLN-GSE possessed 243 nm as mean diameter, were negatively charged, and stable in size at 37 °C in Simulated Lung Fluid up to 48 h and at 4 °C in double distilled water up to 2 months. The content of SLN in proanthocyanidins remained unvaried up to 2 months. GSE-loaded SLN determined a significant reduction in ROS production when added 24-72 h before the stimulation with hydrogen peroxide. Interestingly, while at 24 h free GSE determined a higher decrease of ROS production than SLN-GSE, the contrary was seen at 48 and 72 h. Similar results were observed for NF-κB nuclear translocation. CONCLUSIONS:SLN are a biocompatible drug delivery system for natural anti-oxidants obtained from grape seed in a model of oxidative stress in airway epithelial cells. They feature stability and long-term persistence inside cells where they release proanthocyanidins. These results could pave the way to novel anti-oxidant and anti-inflammatory therapies for chronic respiratory diseases.

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Nanoparticle Delivery of Anti-inflammatory LNA Oligonucleotides Prevents Airway Inflammation in a HDM Model of Asthma.

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Nanoparticle Delivery of Anti-inflammatory LNA Oligonucleotides Prevents Airway Inflammation in a HDM Model of Asthma.

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