Treatment Of Airway Inflammation Research Articles

Icariin attenuates asthmatic airway inflammation via modulating alveolar macrophage activation based on network pharmacology and in vivo experiments.

Icariin (ICA) inhibits inflammatory response in various diseases, but the mechanism underlying ICA treating airway inflammation in asthma needs further understood. We aimed to predict and validate the potential targets of ICA against asthma-associated airway inflammation using network pharmacology and experiments. The ovalbumin-induced asthma-associated airway inflammation mice model was established. The effects of ICA were evaluated by behavioral, airway hyperresponsiveness, lung pathological changes, inflammatory cell and cytokines counts. Next, the corresponding targets of ICA were mined via the SEA, CTD, HERB, PharmMapper, Symmap database and the literature. Pubmed-Gene and GeneCards databases were used to screen asthma and airway inflammation-related targets. The overlapping targets were used to build an interaction network, analyze gene ontology and enrich pathways. Subsequently, flow cytometry, quantitative real-time PCR and western blotting were employed for validation. ICA alleviated the airway inflammation of asthma; 402 targets of ICA, 5136 targets of asthma and 4531 targets of airway inflammation were screened; 216 overlapping targets were matched and predicted ICA possesses the potential to modulate asthmatic airway inflammation by macrophage activation/polarization. Additionally, ICA decreased M1 but elevated M2. Potential targets that were disrupted by asthma inflammation were restored by ICA treatment. ICA alleviates airway inflammation in asthma by inhibiting the M1 polarization of alveolar macrophages, which is related to metabolic reprogramming. Jun, Jak2, Syk, Tnf, Aldh2, Aldh9a1, Nos1, Nos2 and Nos3 represent potential targets of therapeutic intervention. The present study enhances understanding of the anti-airway inflammation effects of ICA, especially in asthma.

Some reflections on immunosuppressants and their delivery to the lungs by aerosol in the treatment of COVID-19

Disorders of immune homeostasis represent the key pathogenetic link of COVID-19, which often manifests as a hyperimmune response to the pathogen, leading to severe uncontrolled inflammation in lungs, followed by complications and death. Accordingly, a certain therapeutic potential is provided by different pharmacological drugs with distinct mechanisms of action, This class of drugs should, however, act in common direction by suppressing the immune response, thus being often classified as immunosuppressants (IS). Of them, the most promising are immunobiological preparations, which include monoclonal antibodies, as well as purinergic regulatory agents. There are several attempts to use the “classical” IS by a certain way, e.g., cytostatics and calcineurin inhibitors which found clinical application in transplantology and oncology. However, their usage for treatment of uncontrolled inflammation of respiratory tract was abandoned by the end of XX century. Meanwhile, the aerosol route of drug administration optimizes treatment, both in terms of their effectiveness, and the reduction of side effects thus promoting usage of IS for treatment of uncontrolled airway inflammation. Previously, the analysis of therapeutic opportunities for some IS delivered as aerosols to the lungs in COVID-19 therapy was not carried out, thus bein the purpose of our work. Methodological analysis was carried out using various databases of biomedical scientific information, including Index Medicus, PubMed, Embase, Cohrane Clinical Trials gov registry and patent databases.The efficiency of the impact of various IS subgroups in COVID-19, including their administration by inhalations into the respiratory ways, was assessed. The role of regulatory T cells considered the central regulator of immune response, in pathogenesis of COVID-19 was considered, and their therapeutic potential was characterized, dependent on phase and severity of the disease as well as drug dose dependence. Methods and approaches to the use of IP, advantages and disadvantages are discussed. The expediency and future prospects of their application are considered.One may conclude that the effectiveness of cytostatics and calcineurin inhibitors in the treatment of airway inflammation in COVID-19 remains unconfirmed and seems to be unpromising. Meanwhile, biological preparations, including monoclonal antibodies and purinergic regulatory agents, offer great promise in this respect.

Curcumin nanocrystals self-stabilized Pickering emulsion freeze-dried powder: Development, characterization, and suppression of airway inflammation

Curcumin, a diketone compound extracted from turmeric's rhizome, is an effective anti-inflammatory drug with multiple pharmacological activities. However, its low oral bioavailability due to its low water solubility and permeability severely limits its clinical applications. Therefore, to enhance the oral bioavailability of curcumin, further enhance its anti-inflammatory effects, and improve its potential in the treatment of airway inflammation, a curcumin nanocrystalline self-stabilizing Pickering emulsion (Cur-NSSPE) was prepared through high-pressure homogenization. Next, Cur-NSSPE was dried using a freeze-drying method to produce Cur-NSSPE-FDP. The prepared Cur-NSSPE and Cur-NSSPE-FDP were physically characterized. The release behavior and transmembrane transport capability of Cur-NSSPE-FDP in vitro were evaluated. Pharmacokinetic study was performed to evaluate its oral bioavailability. The anti-inflammatory effects of Cur-NSSPE-FDP in vivo and in vitro were investigated using RAW 264.7 macrophage inflammation model induced by LPS and IFN-γ and asthma model in BALB/c mice induced by OVA. The average particle size of Cur-NSSPE was (163.66 ± 6.78) nm, and the average drug content was (2.78 ± 0.01) mg/mL. The transmission electron microscopy results showed that the droplets were spherical in shape with a relatively uniform size, and the curcumin nanocrystals formed a spherical core-shell structure wrapped at the interface of the droplets. The scanning electron microscopy showed that Cur-NSSPE-FDP was a neatly arranged, having loose and porous network structure. Furthermore, it can significantly improve the cumulative release of curcumin in vitro and improve oral bioavailability in rats, increase the uptake of RAW264.7 and Caco-2 cells, promote the transport of curcumin across Caco-2 cells, significantly inhibit the expression of inflammatory factors NO, IL-6, TNF-a, MDA, IgE and ICAM-1, and improve the expression of IL-10 and SOD. These results indicated that the curcumin nanocrystalline self-stabilizing Pickering emulsion-freeze dried powder improved the oral bioavailability of curcumin and enhanced its therapeutic effect in airway inflammation.

Fabrication of chitosan-based redox-responsive polymeric nanoparticles: In-vitro and in-vivo evaluation for treating airway inflammation in asthma

Fabrication of chitosan-based redox-responsive polymeric nanoparticles: In-vitro and in-vivo evaluation for treating airway inflammation in asthma

The inhibitory effects of Bakuchicin on ovalbumin-induced allergic airway inflammation via regulating M2 macrophage polarization

Abstract Asthma is an airway inflammatory disease caused by the activation of many immune cells, including macrophages. Bakuchicin (BKC), a furanocoumarin, has anti-inflammatory properties. This study aimed to evaluate the effects of BKC on allergic airway inflammation and demonstrate the mechanisms of macrophage activation and differentiation. We assessed the effects of BKC by evaluating inflammatory markers in an ovalbumin (OVA)-induced airway inflammation mouse model and macrophage cells. BKC treatment alleviated histological changes, mast cell infiltration, and collagen deposition, and reduced the levels of myeloperoxidase, eosinophil peroxidase, β-hexosaminidase, and transforming growth factor-β in the bronchoalveolar fluid (BALF) and the level of immunoglobulins in serum. BKC ameliorated inflammatory symptoms, including the level of inducible nitric oxide synthase (iNOS) in the lung and the expression and secretion of pro-inflammatory cytokines in serum. BKC treatment reduced not only the level of Th2 cytokines but M2 macrophage marker expression and population in the BALF. In vitro, BKC inhibited LPS-stimulated production of nitric oxide and expression of pro-inflammatory cytokines through inhibition of iNOS, COX-2, Akt, MAPKs, IκBα, and NF-κB in J774 A.1 mouse macrophages. Moreover, BKC suppressed IL-4-induced M2 macrophage polarization by inhibiting arginase-1, YM-1, and Fizz-1 and regulating sirtuin 2 levels in bone marrow derived macrophages. Collectively, BKC may help in the prevention and treatment of airway inflammation by regulating macrophage activation and polarization.

ROS induced the Rab26 promoter hypermethylation to promote cigarette smoking-induced airway epithelial inflammation of COPD through activation of MAPK signaling.

Cigarette smoking (CS) exposure-induced airway inflammatory responses drive the occurrence and development of emphysema and chronic obstructive pulmonary disease (COPD). However, its precise mechanisms have not been fully elucidated. In this study, we explore the role of Rab26 in CS exposure modulating the inflammatory response of airway epithelium and the novel mechanism of CS exposure regulation Rab26. These data showed that CS exposure and H2O2 (a type of ROS) suppressed the expression of Rab26 and increased the expression of DNMT3b in vivo and in vitro. GEO data analysis found the level of Rab26 was decreased in the lung tissue of COPD patients. CSE-induced ROS promoted DNA methylation of the Rab26 promoter and inhibited its promoter activity by elevating the DNMT3b level. Antioxidants N-Acetyl-l-cysteine (NAC), 5-Aza-2'-deoxycytidine (5-AZA) (DNA methylation inhibitor) and DNMT3B siRNA alleviated CSE's inhibitory effect on Rab26 expression in vitro. Importantly, NAC alleviated the improved expression of Rab26 and reduced DNMT3B expression, in the airway of smoking exposure as well as attenuated the inflammatory response in vivo. Overexpression of Rab26 attenuated CSE-induced production of inflammatory mediators through part inactivation of p38 and JNK MAPK. On the contrary, silencing Rab26 enhanced p38 and JNK activation and aggravated inflammatory response. These findings suggest that ROS-mediated Rab26 promoter hypermethylation is a critical step in cigarette smoking-induced airway epithelial inflammatory response. Restoring Rab26 in the airway epithelium might be a potential strategy for treating airway inflammation and COPD.

Immunosuppressive drugs and their aerosol delivery for COVID-19 treatment

Despite numerous efforts of healthcare, the incidence of COVID-19 and its fatal complications remains unacceptably high. As COVID-19 pathophysiology is notable for an uncurbed immune response, its treatment protocols routinely include immunosuppressive drugs such as corticosteroids, cytostatic drugs, calcineurin inhibitors, and monoclonal antibodies. Here we review the efficacy of the latter 3 drug classes, in particular inhalation preparations, in COVID-19 treatment and SARSCoV-2 elimination as well as their potential advantages and drawbacks. Efficacy of cytostatic drugs and calcineurin inhibitors in the treatment of airway inflammation in COVID-19 remains unconfirmed. Promising agents in this regard are biologics, including monoclonal antibodies and purinergic agents.

Opuntia ficus-indica Alleviates Particulate Matter 10 Plus Diesel Exhaust Particles (PM10D)—Induced Airway Inflammation by Suppressing the Expression of Inflammatory Cytokines and Chemokines

Particulate matter (PM) exposure may cause adverse health effects such as respiratory disorders. We evaluated the protective effects of various Opuntia ficus-indica (OFI) extracts on airway inflammation associated with exposure to PM10D with an aerodynamic diameter <10 μm (PM10) and diesel exhaust particles (DEP). BALB/c mice were exposed to PM10D via intranasal tracheal injection three times over a period of 12 days and various OFI extracts (water, 30% ethanolic, or 50% ethanolic extracts) were administered orally for 12 days. All OFI extracts suppressed neutrophil infiltration and the number of immune cells (CD3+/CD4+, CD3+/CD8+, and Gr-1+/CD11b) in bronchoalveolar lavage fluid (BALF) and lungs. OFI extracts decreased the expression of cytokines and chemokines, including chemokine (C-X-C motif) ligand (CXCL)-1, interleukin (IL)-17, macrophage inflammatory protein-2, tumor necrosis factor (TNF)-α, cyclooxygenase-2, IL-1α, IL-1β, IL-5, IL-6, transient receptor potential cation channel subfamily V member 1, and mucin 5AC, and inhibited IRAK-1, TNF-α, and CXCL-1 localization in BALF and lungs of mice with PM10D-induced airway inflammation. Serum asymmetric and symmetric dimethyl arginine levels were also decreased by OFI extracts treatment. Moreover, all OFI extracts restored histopathological damage in the trachea and lungs of mice with PM10D-induced airway inflammation. These results indicate that OFI extracts may be used to prevent and treat airway inflammation and respiratory diseases.

Effect of different parts of Pinelliae Rhizoma Decoction against airway inflammation and analysis of effective components

This study investigated the material basis and mechanism of Pinelliae Rhizoma Decoction in the treatment of airway inflammation. The cigarette smoke combined with lipopolysaccharide(LPS) was used to induce an airway inflammation model in mice. The expression levels of IL-6 and IL-8 in the bronchoalveolar lavage fluid(BALF) and the phosphorylation levels of p38 and IκB in the lungs of mice were taken as indexes to screen the effective extracts by system solvent extraction from Pinelliae Rhizoma Decoction(dichloromethane extract, ethyl acetate extract, n-butanol extract, etc.). Meanwhile, the human bronchial epithelial(16-HBE) cell model of cigarette smoke extract(CSE)-induced injury was established, and the mRNA expression levels of IL-6 and IL-8 and the phosphorylation levels of p38 and IκB proteins were also taken as indexes to evaluate the anti-inflammatory effect of different extracts of Pinelliae Rhizoma Decoction. The results showed that Pinelliae Rhizoma Decoction significantly antagonized airway inflammation in mice by down-regulating the expression levels of IL-6 and IL-8 in mice with airway inflammation and 16-HBE cells with CSE-induced injury and inhibiting the phosphorylation levels of p38 and IκB. The dichloromethane and ethyl acetate extracts of Pinelliae Rhizoma Decoction showed significant anti-inflammatory effects, while such effects of other extracts were not prominent. Furthermore, the database of Pinelliae Rhizoma composition was constructed, and the components in effective extracts were analyzed by HPLC-TOF-MS and Nano-LC-MS/MS. As revealed by the results, the compositions of the two effective extracts were similar with 36 common components. They were combined and then divided into Pinelliae Rhizoma alkaloids(PTAs) and Pinelliae Rhizoma non-alkaloids(PTNAs) by 732 cation-exchange resin. Further in vitro investigation confirmed the significant anti-inflammatory effect of PTNAs, while such effect of PTAs was not manifest. The MS analysis showed 172 peptides and 7 organic acids in PTNAs. The peptide content in PTNAs was 63.5% measured by quantitative analysis of BCA assay, and the organic acid content was 9.92% by potentiometric titration method. The findings of this study suggested that Pinelliae Rhizoma Decoction could antagonize airway inflammation in mice by inhibiting phosphorylation of p38 and IκB and blocking the activation of MAPK and NF-κB signaling pathways, and the effective components were related to the peptides and organic acids in PTNAs. The above results lay a foundation for the research on the mechanism and material basis of Pinelliae Rhizoma in antagonizing airway inflammation.

Diallyl disulfide prevents cigarette smoke-induced emphysema in mice

IntroductionCigarette smoke (CS) is the main risk factor for the development of chronic obstructive pulmonary disease (COPD) and pulmonary emphysema. The use of antioxidants has emerged as a potential therapeutic strategy to treat airway inflammation and lung diseases. In the current study, we investigated the potential therapeutic impact of diallyl disulfide (Dads) treatment in a murine model of CS-induced emphysema. MethodsC57BL/6 mice were exposed to CS for 60 consecutive days and treated with vehicle or Dads (30, 60 or 90 mg/kg) by oral gavage for the last 30 days, three times/week. The control group was sham-smoked and received vehicle treatment. All mice were euthanized 24 h after day 60; bronchoalveolar lavage (BAL) was performed and lungs were processed for further experimentation. Histological (HE stained sections, assessment of mean linear intercept (Lm)), biochemical (nitrite, superoxide dismutase (SOD), glutathione transferase (GST), and malondialdehyde (MDA) equivalents), and molecular biology (metalloproteinase (MMP) 12, SOD2, carbonyl reductase 1 (CBR1), nitrotyrosine (PNK), 4-hydroxynonenal (4-HNE), and CYP2E1) analyses were performed. ResultsTreatment with Dads dose-dependently reduced CS-induced leukocyte infiltration into the airways (based on BAL fluid counts) and improved lung histology (indicated by a reduction of Lm). Furthermore, CS exposure dramatically reduced the activity of the antioxidant enzymes SOD and GST in lung tissue and increased nitrite and MDA levels in BAL; these effects were all effectively counteracted by Dads treatment. Western blot analysis further confirmed the antioxidant potential of Dads, showing that treatment prevented the CS-induced decrease in SOD2 expression and increase in lung damage markers, such as CBR1, PNK, and 4-HNE. Furthermore, increased MMP12 (an important hallmark of CS-induced emphysema) and CYP2E1 lung protein levels were significantly reduced in mice receiving Dads treatment. ConclusionOur findings demonstrate that treatment with Dads is effective in preventing multiple pathological features of CS-induced emphysema in an in vivo mouse model. In addition, we have identified several proteins/enzymes, including 4-HNE, CBR1, and CYP2E1, that are modifiable by Dads and could represent specific therapeutic targets for the treatment of COPD and emphysema.

The Potential for Phospholipids in the Treatment of Airway Inflammation: An Unexplored Solution

Asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) are major inflammatory respiratory diseases. Current mainstay therapy for asthma, and chronic obstructive pulmonary disease are corticosteroids, which have well-established side effect profiles. Phospholipids (PLs) are ubiquitous, diverse compounds with varying functions such as their structural role in the cell membrane, energy storage, and cell signaling. Recent advances in understanding PLs role as inflammatory mediators in the body as well as their widespread long-standing use as carrier molecules in drug delivery demonstrate the potential application of PLs in modulating inflammatory conditions. This review briefly explains the main mechanisms of inflammation in chronic respiratory diseases, current anti-inflammatory treatments and areas of unmet need. The structural features, roles of endogenous and exogenous phospholipids, including their use as pharmaceutical excipients, are reviewed. Current research on the immunomodulatory properties of PLs and their potential application in inflammatory diseases is the major section of this review. Considering the roles of PLs as inflammatory mediators and their safety profile established in pharmaceutical formulations, these small molecules demonstrate great potential as candidates in respiratory inflammation. Future studies need to focus on the immunomodulatory properties and the underlying mechanisms of PLs in respiratory inflammatory diseases.

Lipid-Droplet Formation Drives Pathogenic Group 2 Innate Lymphoid Cells in Airway Inflammation

Innate lymphoid cells (ILCs) play an important role in the control and maintenance of barrier immunity. However, chronic activation of ILCs results in immune-mediated pathology. Here, we show that tissue-resident type 2 ILCs (ILC2s) display a distinct metabolic signature upon chronic activation. In the context of allergen-driven airway inflammation, ILC2s increase their uptake of both external lipids and glucose. Externally acquired fatty acids are transiently stored in lipid droplets and converted into phospholipids to promote the proliferation of ILC2s. This metabolic program is imprinted by interleukin-33 (IL-33) and regulated by the genes Pparg and Dgat1, which are both controlled by glucose availability and mTOR signaling. Restricting dietary glucose by feeding mice a ketogenic diet largely ablated ILC2-mediated airway inflammation by impairing fatty acid metabolism and the formation of lipid droplets. Together, these results reveal that pathogenic ILC2 responses require lipid metabolism and identify ketogenic diet as a potent intervention strategy to treat airway inflammation.

Diagnostic Value of Serum Long-Chain Noncoding RNA KCNQ1OT1 in Airway Remodeling in Children with Bronchial Asthma.

The current study aims to investigate the clinical value of serum long non-coding RNA (lncRNA) KCNQ1OT1 in airway remodeling in children with bronchial asthma. Serum and clinical data of 58 children with bronchial asthma were collected and divided into remodeling group and non-remodeling group. Twenty children with respiratory inflammatory diseases were selected as a control group. Real-time fluorescence quantitative PCR (RT-PCR) was used to detect the expression of serum lnc-RNA KCNQ1OT1. The relationship between serum lncRNA KCNQ1OT1 and asthma remodeling was also analyzed. The expression level of serum lncRNA KCNQ1OT1 in the remodeling group was higher than that in the non-remodeling group and the control group, and the difference was statistically significant. In the remodeling group, serum lncRNA KCNQ1OT1 was significantly correlated with the thickness of bronchial mucosal reticular basement membrane and the number of fibroblasts. Receiver operating characteristic curve (ROC) analysis showed that serum lncRNA KCNQ1OT1 could differentiate non-remodeling group from remodeling group. Serum lncRNA KCNQ1OT1 can predict the occurrence of airway remodeling in children with bronchial asthma, thereby initiating early intervention and treatment of airway inflammation.

Preventive and therapeutic effects of Trichinella spiralis adult extracts on allergic inflammation in an experimental asthma mouse model

BackgroundHelminths immunomodulate the host immune system by secreting proteins to create an inhibitory environment as a strategy for survival in the host. As a bystander effect, this balances the host immune system to reduce hypersensitivity to allergens or autoantigens. Based on this, helminth therapy has been used to treat some allergic or autoimmune diseases. As a tissue-dwelling helminth, Trichinella spiralis infection has been identified to have strong immunomodulatory effects; the effective components in the worm have not yet been identified.MethodsThe soluble extracts of T. spiralis adult worms and muscle larvae were used to treat airway inflammation before and after an ovalbumin (OVA)-sensitization/challenge in an OVA-induced asthma mouse model. The therapeutic effects were observed by measuring the level of inflammation in the lungs.ResultsThe soluble products derived from T. spiralis parasites, especially from adult worms, were able to ameliorate OVA-induced airway inflammatory responses which were associated with reduced eosinophil infiltration, OVA-specific IgE, Th2 cytokine IL-4, and increased IL-10 and TGF-β. The stimulation of the Treg response may contribute to the alleviated allergic inflammation.ConclusionsTrichinella spiralis worm extracts stimulate regulatory cytokines that are associated with reduced allergic airway inflammation. The identification of effective components in the adult worm extracts will be a crucial approach for developing a novel therapeutic for allergic and autoimmune diseases.

Tamoxifen in horses: pharmacokinetics and safety study

BackgroundTamoxifen (TAM), a selective modulator of estrogen receptors (SERMs) has been recently explored as a therapeutic option for the oral treatment of airway inflammation in the horse. The objective of this work was to establish pharmacokinetic parameters of TAM and its main metabolites in equines, as well as to determine its clinical safety in short-term treatments.ResultsWe determined TAM and its three main metabolites (4-OH tamoxifen, endoxifen, and N-desmethyl tamoxifen) in plasma after single administration of 0.25 mg/kg in healthy adult horses (n = 12). A maximum concentration of TAM was achieved 3 h after the oral administration (4.65 pg/mL ± 1.69); 4-OH tamoxifen was the metabolite that reached the highest concentration (78 pg/mL ± 70), followed by N-desmethyl tamoxifen (0.43 pg / mL ± 0.48), and finally endoxifen (0.17 pg/mL ± 0.17). All metabolites showed peak concentration 2 h after oral administration of the drug. Oral TAM bioavailability was 13,15% ± 4,18, with a steady state volume of distribution of 7831 ± 2922 (L/kg). Elimination half-life was 15.40 ± 5.80 h, and clearance was 5876 ± 699 (mL/kg/min). Clinical safety of TAM was determined over a 7-day course of treatment (0.25 mg/kg, orally q 24 h, n = 20). No adverse effects were observed through clinical examination, blood hematology, serum biochemistry, ophthalmological and reproductive examinations. Endometrial edema observed in some mares was attributed to normal cyclic activity.ConclusionsTamoxifen has moderate oral bioavailability and a large volume of distribution, with three main metabolites in horses. Additionally, oral TAM administration over a 7-day treatment period demonstrated to be clinically safe, without adverse effects on clinical, hematological or serum biochemical parameters. These data could contribute to the continued research into this drug’s potential for the treatment of different inflammatory conditions in equine species.

Feasibility Study of Mesoporous Silica Particles for Pulmonary Drug Delivery: Therapeutic Treatment with Dexamethasone in a Mouse Model of Airway Inflammation.

Diseases in the respiratory tract rank among the leading causes of death in the world, and thus novel and optimized treatments are needed. The lungs offer a large surface for drug absorption, and the inhalation of aerosolized drugs are a well-established therapeutic modality for local treatment of lung conditions. Nanoparticle-based drug delivery platforms are gaining importance for use through the pulmonary route. By using porous carrier matrices, higher doses of especially poorly soluble drugs can be administered locally, reducing their side effects and improving their biodistribution. In this study, the feasibility of mesoporous silica particles (MSPs) as carriers for anti-inflammatory drugs in the treatment of airway inflammation was investigated. Two different sizes of particles on the micron and nanoscale (1 µm and 200 nm) were produced, and were loaded with dexamethasone (DEX) to a loading degree of 1:1 DEX:MSP. These particles were further surface-functionalized with a polyethylene glycol–polyethylene imine (PEG–PEI) copolymer for optimal aqueous dispersibility. The drug-loaded particles were administered as an aerosol, through inhalation to two different mice models of neutrophil-induced (by melphalan or lipopolysaccharide) airway inflammation. The mice received treatment with either DEX-loaded MSPs or, as controls, empty MSPs or DEX only; and were evaluated for treatment effects 24 h after exposure. The results show that the MEL-induced airway inflammation could be treated by the DEX-loaded MSPs to the same extent as free DEX. Interestingly, in the case of LPS-induced inflammation, even the empty MSPs significantly down-modulated the inflammatory response. This study highlights the potential of MSPs as drug carriers for the treatment of diseases in the airways.

A Pilot Randomized Placebo Controlled Trial of Inhaled Beclomethasone after Community-Acquired Respiratory Viral (CARV) Infection in Lung Transplant Recipients (LTR)

Purpose CARV infections are associated with an increased risk of CLAD development and progression. Inhaled corticosteroids are used to treat airway inflammation , but there is a dearth of data regarding their use in lung transplantation . This study aimed to examine the effect of inhaled beclomethasone on the development and progression of CLAD after CARV. Methods Single-center, double blind, pilot, randomized, placebo controlled trial of inhaled beclomethasone in adult LTR diagnosed with a CARV between Jan 2017 and Dec 2017. Patients were randomized in a 1:1 ratio stratified by BOS stage (BOS 0/0p vs 1/2) within 7 days of CARV. Study drug was continued for 6 months. The primary endpoint was freedom from new or progressive CLAD (defined as a 15% decline in pre CARV FEV1). Secondary endpoints included all-cause mortality and development of new DSA post-CARV. Results 7 patients were randomized to inhaled beclomethasone and 8 to placebo. Baseline demographics were well matched between groups including gender, age at LTR, time from LTR to CARV, upper vs lower CARV, BOS stage, and DSA at the time of study enrollment (Table 1). There was no difference in freedom from CLAD or CLAD progression between the 2 groups (Figure 1). No patients died or developed new DSA during the study period. Conclusion Inhaled beclomethasone was not associated with a lower incidence of new or progressive CLAD after CARV when compared to placebo. However, this study had limited power and sample size. Additional studies are necessary to assess the potential benefit of inhaled corticosteroids in LTR after CARV.

Potential Anti-inflammatory Effects of the Fruits of Paulownia tomentosa.

As part of an ongoing search for new natural products from medicinal plants to treat respiratory disease, six new compounds, a dihydroflavonol (1) and five C-geranylated flavanones (3, 6, 8, 13, and 14), and 13 known compounds were isolated from mature fruits of Paulownia tomentosa. The structures of the new compounds were determined via interpretation of their spectroscopic data (1D and 2D NMR, UV, IR, ECD, and MS). In biological activity assays with human alveolar basal epithelial cells, the expression of TNF-α-induced proinflammatory cytokines (IL-8 and IL-6) was reduced significantly by the EtOAc fraction of a P. tomentosa extract as well as by the new compounds isolated from this fraction. Furthermore, the majority of the isolates (1-19 except 5-7) were found to inhibit human neutrophil elastase (HNE) activity, with IC50 values ranging from 2.4 ± 1.0 to 74.7 ± 8.5 μM. In kinetic enzymatic assays with the HNE substrate MeOSuc-AAPV-pNA, compound 17 exhibited the highest inhibitory activity (Ki = 3.2 μM) via noncompetitive inhibition. These findings suggest that the flavanone constituents of P. tomentosa fruits may be valuable for the development of new drug candidates to treat airway inflammation.

β-Catenin Directs Nuclear Factor-κB p65 Output via CREB-Binding Protein/p300 in Human Airway Smooth Muscle.

β-Catenin is a multifunctional protein that apart from its role in proliferative and differentiation events, also acts upon inflammatory processes, mainly via interaction with nuclear factor-κB (NF-κB). However, there is still controversy as to whether β-catenin facilitates or represses NF-κB output. Insights into the molecular mechanisms underlying the interaction between β-catenin and NF-κB have highlighted the cofactors CREB-binding protein (CBP) and p300 as important candidates. Here, we hypothesized that the interaction of β-catenin with CBP/p300 directs NF-κB output. Using human airway smooth muscle (ASM) cells, we found that β-catenin is essential in interleukin -1β (IL-1β)-mediated expression of interleukin-6 (IL-6) by promoting nuclear translocation of the p65 subunit of NF-κB. These effects were independent from WNT pathway activation or other factors that promote β-catenin signaling. In the nucleus, inhibition of either the CBP- or p300-β-catenin interaction could regulate NF-κB output, by enhancing (CBP inhibition) or inhibiting (p300 inhibition) IL-1β-induced expression of IL-6, respectively. Acetylation of p65 by p300 likely underlies these events, as inhibition of the p300-β-catenin interaction diminished levels of acetylated p65 at lysine 310, thereby reducing p65 transcriptional activity. In conclusion, β-catenin is a critical component of NF-κB-mediated inflammation in human ASM, affecting transcriptional output by interacting with the nuclear cofactors CBP and p300. Targeting β-catenin may be an alternative strategy to treat airway inflammation in patients with airway disease, such as asthma.

The endogenous cannabinoid anandamide increases human airway epithelial cell permeability through an arachidonic acid metabolite

Injury to the bronchial epithelium in respiratory diseases such as asthma and COPD results in the loss of barrier function and an elevated sensitivity to environmental insults. An increased release of the endogenous cannabinoid, anandamide in response to inhalation of allergen in asthmatic patients has been reported. The aim of this study was, therefore, to determine the effects of endocannabinoids on bronchial epithelial cell permeability and to investigate the mechanisms involved.Calu-3 human bronchial epithelial cells were cultured at air–liquid interface to allow development of tight junctions. Changes in Transepithelial Electrical Resistance (TEER), a reflection of epithelial permeability, were measured at various time points post-treatment, and expression of the tight junction proteins, occludin and ZO-1, were determined using Western immunoblotting.Anandamide produced a significant reduction in TEER, which was unaffected by cannabinoid receptor antagonists, but attenuated by URB597, an inhibitor of fatty acid amide hydrolase, and by a combination of cyclooxygenase (COX) and lipoxygenase (LOX) blockade. The anandamide metabolite, arachidonic acid, showed similar TEER decrease that was also prevented in the presence of COX and LOX inhibitor. Expression of occludin and ZO-1 were also reduced by anandamide.These findings indicate a pro-inflammatory-like effect of anandamide on bronchial epithelial permeability, mediated by cyclooxygenase and lipoxygenase metabolites, and suggest that inhibition of anandamide degradation might provide a novel approach to treat airway inflammation.