FOXK2 facilitates the airway remodeling during chronic asthma by promoting glycolysis in a SIRT2-dependent manner.

Asthma is a chronic pulmonary disease with the worldwide prevalence. The structural alterations of airway walls, termed as "airway remodeling", are documented as the core contributor to the airway dysfunction during chronic asthma. Forkhead box transcription factor FOXK2 is a critical regulator of glycolysis, a metabolic reprogramming pathway linked to pulmonary fibrosis. However, the role of FOXK2 in asthma waits further explored. In this study, the chronic asthmatic mice were induced via ovalbumin (OVA) sensitization and repetitive OVA challenge. FOXK2 was upregulated in the lungs of OVA mice and downregulated after adenovirus-mediated FOXK2 silencing. The lung inflammation, peribronchial collagen deposition, and glycolysis in OVA mice were obviously attenuated after FOXK2 knockdown. Besides, the expressions of FOXK2 and SIRT2 in human bronchial epithelial cells (BEAS-2B) were increasingly upregulated upon TGF-ß1 stimulation and downregulated after FOXK2 knockdown. Moreover, the functional loss of FOXK2 remarkably suppressed TGF-ß1-induced epithelial-mesenchymal transition (EMT) and glycolysis in BEAS-2B cells, as manifested by the altered expressions of EMT markers and glycolysis enzymes. The glycolysis inhibitor 2-deoxy-d-glucose (2-DG) inhibited the EMT in TGF-ß1-induced cells, making glycolysis a driver of EMT. The binding of FOXK2 to SIRT2 was validated, and SIRT2 overexpression blocked the FOXK2 knockdown-mediated inhibition of EMT and glycolysis in TGF-ß1-treated cells, which suggests that FOXK2 regulates EMT and glycolysis in TGF-ß1-treated cells in a SIRT2-dependnet manner. Collectively, this study highlights the protective effect of FOXK2 knockdown on airway remodeling during chronic asthma.

Management of Chronic Asthma in Adults.

Asthma is characterized by chronic inflammation and respiratory symptoms such as wheezing and coughing. In the United States, it affects 25 million people annually. Chronic smokers, poor adherence to medications, incorrect use of inhalers, and overall poor asthma control are known risk factors that lead to poorly controlled chronic asthmatics. Although asthma is traditionally categorized by severity, treatment by primary care providers is guided by the Global Initiative for Asthma or the National Asthma Education and Prevention Program. As more research is available, shared decision-making between health care providers and patients will lead to improved outcomes in managing chronic asthma.

Role of G-protein-coupled estrogen receptor in the pathogenesis of chronic asthma.

BACKGROUND AND AIM: G protein-coupled estrogen receptor (GPER) is an estrogen receptor located on the plasma membrane. We previously reported that the administration of G-1, a GPER-specific agonist, suppressed development of acute ovalbumin (OVA)-induced asthma in a mouse model. Herein, we evaluate the involvement of GPER in a mouse model of chronic OVA asthma. METHODS: G-1 or saline was administered subcutaneously to BALB/c mice with chronic OVA asthma, and pathological and immunological evaluation was performed. In addition, Foxp3-expressing CD4-positive T-cells in the spleen and ILC2 in the lungs were measured using flow cytometry. RESULTS: We observed a significant decrease in the number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) in the G-1 treated group. In the airways, inflammatory cell accumulation, Th2 cytokines (IL-4, IL-5, IL-13, and eotaxin) and epithelial cytokine TSLP were suppressed, while in the BALF, anti-inflammatory cytokines (IL-10 and TGF-ß) were increased. Furthermore, in splenic mononuclear cells, Foxp3-expressing CD4-positive T-cells were increased in the G-1 group, whereas treatment with G-1 did not change the percentage of ILC2 in the lungs. CONCLUSION: G-1 administration suppressed allergic airway inflammation in mice with chronic OVA asthma. GPER may be a potential therapeutic target for chronic allergic asthma.

Management of Chronic Asthma in Adults.

Asthma is characterized by chronic inflammation and respiratory symptoms such as wheezing and coughing. In the United States, it affects 25 million people annually. Chronic smokers, poor adherence to medications, incorrect use of inhalers, and overall poor asthma control are known risk factors that lead to poorly controlled chronic asthmatics. Although asthma is traditionally categorized by severity, treatment by primary care providers is guided by the Global Initiative for Asthma or the National Asthma Education and Prevention Program. As more research is available, shared decision-making between health care providers and patients will lead to improved outcomes in managing chronic asthma.

CD200Fc limits dendritic cell and B-cell activation during chronic allergen exposures.

Allergic asthma is a chronic inflammatory disease characterized by Th2, conventional dendritic cell, and B-cell activation. In addition to excessive inflammation, asthma pathogenesis includes dysregulation of anti-inflammatory pathways, such as the CD200/CD200R pathway. Thus, we investigated whether a CD200R agonist, CD200Fc, could disrupt the inflammatory cascade in chronic allergic asthma pathogenesis using a mice model of experimental asthma. Mice were exposed to house dust mites for 5 wk, and CD200Fc treatment was initiated after chronic inflammation was established (starting on week 4). We demonstrate that chronic house dust mite exposure altered CD200 and CD200R expression on lung immune cell populations, including upregulation of CD200 on alveolar macrophages and reduced expression of CD200 on conventional dendritic cells. CD200Fc treatment does not change bronchoalveolar cellular infiltration, but it attenuates B-cell activation and skews the circulating immunoglobulin profile toward IgG2a. This is accompanied by reduced activation of conventional dendritic cells, including lower expression of CD40, especially on conventional dendritic cell subset 2 CD200R+. Furthermore, we confirm that CD200Fc can directly modulate conventional dendritic cell activation in vitro using bone marrow-derived dendritic cells. Thus, the CD200/CD200R pathway is dysregulated during chronic asthma pathogenesis, and the CD200R agonist modulates B-cell and dendritic cell activation but, in our chronic model, is not sufficient to alter inflammation measured in bronchoalveolar lavage.

Aerosol inhalation of Mycobacterium vaccae ameliorates airway structural remodeling in chronic asthma mouse model.

Background: Airway remodeling is accepted to be a determining component within the natural history of asthma. Nebulized inhalation of Mycobacterium vaccae (M. vaccae) has a protective effect on asthmatic mice. However, little is known regarding the effect of M. vaccae on airway structural remodeling in asthmatic mice. The purpose of this study was to explore the effect and the underlying mechanism of M. vaccae aerosol inhalation on airway structural remodeling in an asthma mouse model. Methods: Chronic asthma mouse models were established by ovalbumin induction. The number of inflammatory cells in bronchoalveolar lavage fluid (BALF), pathological alterations in lung tissue, and levels of associated cytokines (IL-5, IL-13, TNF-α, and ovalbumin-specific immunoglobulin E [OVA-sIgE]) were all assessed after M. vaccae therapy. The relative expression of interleukin (IL)-1ß, tumor necrosis factor-alpha (TNF-α), nuclear factor kappa B (NF-κB), and Wnt1-induced signaling protein 1 (WISP1) mRNA were detected. Western blotting and immunohistochemistry detected the expression of Wnt/ß-catenin pathway-related proteins in lung tissue. Results: M. vaccae aerosol inhalation relieved airway inflammation, airway hyper-responsiveness, and airway remodeling. M. vaccae reduced the levels of IL-5, IL-13, TNF-α, and OVA-sIgE in and downregulated the expression of IL-1ß, TNF-α, NF-κB, and WISP1 mRNA in the pulmonary. In addition, M. vaccae inhibited the expression of ß-catenin, WISP1, and Wnt1 protein and upregulated the expression of glycogen synthase kinase-3beta (GSK-3ß). Conclusion: Nebulized inhalation of M. vaccae can reduce airway remodeling during asthma.

CD44 is critical for the enhancing effect of hyaluronan in allergen-specific sublingual immunotherapy in a murine model of chronic asthma.

Allergen-specific sublingual immunotherapy (SLIT) is a potentially effective disease-modification treatment for patients with allergic asthma. Because CD44 signaling enhances regulatory T (Treg) cell-induction, administering CD44 ligands such as hyaluronan (HA) with allergen-specific SLIT may enhance the therapeutic effects. We evaluated the role of CD44 in Treg cell-induction in T helper type 2 (Th2)-mediated chronic airway inflammation using CD44-/- mice and the efficacy of HA on SLIT in a Dermatophagoides farinae (Df)-induced murine model of chronic asthma. Th2 responses and Treg cell induction were evaluated in CD44-/- mice. We devised a new SLIT model of Df-induced chronic asthma utilizing HA as an adjuvant. The effects of HA added to the new SLIT model were evaluated by the early asthmatic response (EAR) and airway hyperresponsiveness (AHR), eosinophilic airway inflammation, and serum Df-specific IgE levels. Th2-mediated chronic eosinophilic airway inflammation was worse in CD44-/- mice compared with Df-sensitized wild-type (WT) mice. HA enhanced the effect of Df-induced Treg cells in a CD44-dependent manner. Sublingual Df treatment in combination with HA, but not alone, normalized EAR and AHR, and significantly reduced the serum IgE levels and the bronchoalveolar lavage fluid (BALF) eosinophil number. HA also induced Treg cells in a Df-sensitized spleen cell culture in a CD44-dependent manner. The treatment-enhancing effects of HA in this SLIT model were diminished in CD44-/- mice. CD44 is a key contributor to Treg cell induction and critical for the enhancing effects of HA in a Df-induced murine model of chronic asthma.

Systemic administration of c-Kit+ cells diminished pulmonary and vascular inflammation in rat model of chronic asthma.

BACKGROUND: To circumvent some pitfalls related to acute status, chronic model of asthma is conceived to be more suitable approach to guarantee the conditions which are similar to human pulmonary disease. Here, possible therapeutic mechanisms were monitored by which c-kit+ bone marrow cells can attenuate vascular inflammation in rat model of chronic asthma. RESULTS: Data revealed c-Kit+ cells could significantly reduce pathological injures in asthmatic rats via modulating the expression of IL-4, INF-γ, ICAM-1 and VCAM-1 in lung tissues and TNF-α, IL-1ß and NO levels in BALF (p < 0.001 to p < 0.05). Besides, c-Kit+ cells reduced increased levels of VCAM-1 evaluated by immunohistochemistry staining. In contrast to c-Kit+ cells, c-Kit- cells could not exert beneficial effects in the asthmatic conditions. CONCLUSION: Overall, we found that systemic administration of C-kit positive cells can diminish pulmonary and vascular inflammation of chronic asthmatic changes in a rat model. These cells are eligible to suppress inflammation and nitrosative stress in lung tissue coincides with the reduction of pathological changes. These data indicate that C-kit positive cells be used as an alternative cell source for the amelioration of asthmatic changes.

Consumption of differently processed milk products and the risk of asthma in children.

BACKGROUND: Consumption of unprocessed cow's milk has been associated with a lower risk of childhood asthma and/or atopy. Not much is known about differently processed milk products. We aimed to study the association between the consumption of differently processed milk products and asthma risk in a Finnish birth cohort. METHODS: We included 3053 children from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Nutrition Study. Asthma and its subtypes were assessed at the age of 5 years, and food consumption by food records, at the age of 3 and 6 months and 1, 2, 3, 4, and 5 years. We used conventional and processing (heat treatment and homogenization)-based classifications for milk products. The data were analyzed using a joint model for longitudinal and time-to-event data. RESULTS: At the age of 5 years, 184 (6.0%) children had asthma, of whom 101 (54.9%) were atopic, 75 (40.8%) were nonatopic, and eight (4.3%) could not be categorized. Consumption of infant formulas [adjusted hazard ratio (95% confidence intervals) 1.15 (1.07, 1.23), p < .001] and strongly heat-treated milk products [1.06 (1.01, 1.10), p = .01] was associated with the risk of all asthma. Consumption of all cow's milk products [1.09 (1.03, 1.15), p = .003], nonfermented milk products [1.08 (1.02, 1.14), p = .008], infant formulas [1.23 (1.13, 1.34), p < .001], and strongly heat-treated milk products [1.08 (1.02, 1.15), p = .006] was associated with nonatopic asthma risk. All these associations remained statistically significant after multiple testing correction. CONCLUSIONS: High consumption of infant formula and other strongly heat-treated milk products may be associated with the development of asthma.

The nitroxide/antioxidant 3-carbamoyl proxyl attenuates disease severity in murine models of severe asthma.

Asthma is characterized by airway inflammation, hyper-responsiveness, symptoms of dyspnea, wheezing and coughing. In most patients, asthma is well controlled using inhaled corticosteroids and bronchodilators. A minority of patients with asthma develop severe disease, which is frequently only partially responsive or even resistant to treatment with corticosteroids. Severe refractory asthma is associated with structural changes in the airways, termed "airway remodeling", and/or with neutrophilic rather than eosinophilic airway inflammation. While oxidative stress plays an important role in the pathophysiology of asthma, cyclic nitroxide stable radicals, which are unique and efficient catalytic antioxidants, effectively protect against oxidative injury. We have demonstrated that the nitroxide 3-carbamoyl proxyl (3-CP) attenuates airway inflammation and hyperresponsiveness in allergic asthma as well as bleomycin-induced fibrosis both using murine models, most probably through modulation of oxidative stress. The present study evaluates the effect of 3-CP on airway inflammation and remodeling using two murine models of severe asthma where mice are sensitized and challenged either by ovalbumin (OVA) or by house dust mite (HDM). 3-CP was orally administered during the entire period of the experiment or during the challenge period alone where its effect was compared to that of dexamethasone. The induced increase by OVA and by HDM of BALf cell counts, airway hyperresponsiveness, fibrosis, transforming growth factor-beta (TGF-ß) levels in BALf and protein nitration levels of the lung tissue was significantly reduced by 3-CP. The effect of 3-CP, using two different murine models of severe asthma, is associated at least partially with attenuation of oxidative stress and with TGF-ß expression in the lungs. The results of this study suggest a potential use of 3-CP as a novel therapeutic agent in different forms of severe asthma.

Curcumol Ameliorates Lung Inflammation and Airway Remodeling via Inhibiting the Abnormal Activation of the Wnt/ß-Catenin Pathway in Chronic Asthmatic Mice.

BACKGROUND: Curcumol exhibits anti-inflammatory effect, but its effect on chronic asthma lacked research. Therefore, this study explored the role of curcumol in asthma. METHODS: A chronic asthmatic mice model was established by ovalbumin induction. After treatment with curcumol, airway resistance in mice was detected by forced oscillation technique. The histopathological features of airway tissues, pulmonary inflammation, and inflammation cell recruitment in the bronchoalveolar lavage fluid (BALF) of mice were detected by hematoxylin-eosin staining. Collagen deposition in the airways of mice was examined by Masson staining. The secretion of ovalbumin-IgE, IL-4, IL-5, IL-13 in mouse serum and VEGFA secretion in BALF were analyzed by ELISA. Finally, the expressions of ß-catenin, Wnt5a, VEGFA, TGF-ß1, Fibronectin, and MMP-9 in mice lung tissues were determined by Western blot or immunohistochemical. RESULTS: Curcumol attenuated airway hyperresponsiveness, airway remodeling, and pulmonary inflammation in chronic asthmatic mice. Curcumol relieved collagen deposition in airway tissues, inflammation cell recruitment in BALF, and reduced the up-regulation of serum ovalbumin-IgE, IL-4, IL-5, and IL-13 and BALF VEGFA in chronic asthmatic mice. In addition, curcumol attenuated the up-regulated expressions of ß-catenin, Wnt5a, VEGFA, TGF-ß1, Fibronectin, and MMP-9 in the lung tissues of chronic asthmatic mice, but curcumol treatment did not show such effects on healthy mice. CONCLUSION: Our findings revealed that curcumol could ameliorate lung inflammation and airway remodeling by inhibiting the abnormal activation of the Wnt/ß-catenin pathway in chronic asthmatic mice, indicating that curcumol could be used as a novel anti-asthma drug for basic and clinical research.

[Asthma in adults]. / L'asthme chez l'adulte.

Asthma is a chronic, heterogeneous and frequent pathology of the respiratory tract, which can become disabling and whose socio-economic cost is significant. Therapeutic strategies are multiple and complex. Adherence and compliance with treatment are often poor. The dispensing pharmacist can carry out pharmaceutical interviews to promote therapeutic education and therefore the control of asthma.

Promotor Hypomethylation Mediated Upregulation of miR-23b-3p Targets PTEN to Promote Bronchial Epithelial-Mesenchymal Transition in Chronic Asthma.

Chronic asthma is characterized by airway inflammation and irreversible airway remodeling. Epithelial-mesenchymal transition (EMT) is a typical pathological change of airway remodeling. Our previous research demonstrated miR-23b inhibited airway smooth muscle proliferation while the function of miR-23b-3p has not been reported yet. Besides, miRNA is regulated by many factors, including DNA methylation. The function of miR-23b-3p and whether it is regulated by DNA methylation are worth exploring. Balb/c mice were given OVA sensitization to develop the asthmatic model. Expression of miR-23b-3p and EMT markers were measured by RT-qPCR, WB and immunohistochemistry (IHC). DNA methylation was detected by methylation-specific PCR (MSP) and the MassARRAY System. Asthmatic mice and TGF-ß1-stimulated bronchial epithelial cells (BEAS-2B) showed EMT with increased miR-23b-3p. Overexpression of miR-23b-3p promoted EMT and migration, while inhibition of miR-23b-3p reversed these transitions. DNA methyltransferases were decreased in asthmatic mice. MSP and MassARRAY System detected the promotor of miR-23b showed DNA hypomethylation. DNA methyltransferase inhibitor 5'-AZA-CdZ increased the expression of miR-23b-3p. Meanwhile, PTEN was identified as a target gene of miR-23b-3p. Our results indicated that promotor hypomethylation mediated upregulation of miR-23b-3p targets PTEN to promote EMT in chronic asthma. miR-23b-3p and DNA methylation might be potential therapeutic targets for irreversible airway remodeling.

Herbal decoction Divya-Swasari-Kwath attenuates airway inflammation and remodeling through Nrf-2 mediated antioxidant lung defence in mouse model of allergic asthma.

BACKGROUND AND PURPOSE: Asthma is a chronic respiratory disease orchestrated by immune and structural cells. Identification of novel therapeutic strategies are needed for asthma due to the limitations of existing therapies. We have validated the anti-inflammatory, anti-asthmatic and immunomodulatory therapeutic properties of herbal decoction, Divya-Swasari-Kwath (DSK) using mouse model of ovalbumin (OVA) induced allergic asthma. METHODS AND RESULTS: HPLC analysis identified the presence of Rutin, Glycyrrchzin, Gallic acid, Cinnamic acid, Chlorogenic acid, Caffeic acid and Piperine as bioactive herbal metabolites in DSK. Therapeutic treatment with herbal decoction DSK significantly alleviated the pathological features of allergic asthma including inflammatory cell accumulation in Broncho-Alveolar Lavage (BAL) fluids, specifically lymphocytes and eosinophils, lung inflammation, oxidative stress, airway remodelling, and pro-inflammatory cytokine levels. H&E analysis of lung tissue sections identified attenuated inflammatory cell infiltration and thickening of bronchial epithelium by DSK. PAS staining and MT staining identified decrease in OVA-induced mucus hyper secretion and peri-bronchial collagen deposition respectively, upon DSK treatment. Treatment with DSK increased the mRNA expression of antioxidative defence gene Nrf-2 and its downstream target genes HO-1 and NQO-1. In the same line, biochemical analysis for the markers of oxidative/antioxidant system confirmed the restoration of activity of Catalase, GPx, SOD and EPO and the levels of GSH, GSSG, MDA and Nitrite in whole lungs. In line with PAS staining, DSK treatment decreased the OVA-induced expression of Muc5AC and Muc5B genes. DSK treatment reduced the steady state mRNA expression levels of IL-6, IL-1ß, TNF-α, IL-4, -5, -33, IFN-γ in whole lung; and IL-6, TNF-α and IL-1ß protein levels in BALF. CONCLUSION: Collectively, our results suggest that herbal decoction DSK is effective in protecting against allergic airway inflammation and remodelling by regulating anti-oxidant mechanisms. We postulate that DSK could be the potential therapeutic option for allergic asthma management.

Calcio-herbal formulation, Divya-Swasari-Ras, alleviates chronic inflammation and suppresses airway remodelling in mouse model of allergic asthma by modulating pro-inflammatory cytokine response.

Asthma is a chronic allergic respiratory disease with limited therapeutic options. Here we validated the potential anti-inflammatory, anti-asthmatic and immunomodulatory therapeutic properties of calcio-herbal ayurvedic formulation, Divya-Swasari-Ras (DSR) in-vivo, using mouse model of ovalbumin (OVA) induced allergic asthma. HPLC analysis identified the presence of various bioactive indicating molecules and ICP-OES recognized the presence of Ca mineral in the DSR formulation. Here we show that DSR treatment significantly reduced cardinal features of allergic asthma including inflammatory cell accumulation, specifically lymphocytes and eosinophils in the Broncho-Alveolar Lavage (BAL) fluids, airway inflammation, airway remodelling, and pro-inflammatory molecules expression. Conversely, number of macrophages recoverable by BAL were increased upon DSR treatment. Histology analysis of mice lungs revealed that DSR attenuates inflammatory cell infiltration in lungs and thickening of bronchial epithelium. PAS staining confirmed the decrease in OVA-induced mucus secretion at the mucosal epithelium; and trichrome staining confirmed the decrease in peribronchial collagen deposition upon DSR treatment. DSR reduced the OVA-induced pro-inflammatory cytokines (IL-6, IL-1ß and TNF-α) levels in BALF and whole lung steady state mRNA levels (IL-4, -5, -33, IFN-γ, IL-6 and IL-1ß). Biochemical assays for markers of oxidative stress and antioxidant defence mechanism confirmed that DSR increases the activity of SOD, Catalase, GPx, GSH, GSH/GSSG ratio and decreases the levels of MDA activity, GSSG, EPO and Nitrite levels in whole lungs. Collectively, present study suggests that, DSR effectively protects against allergic airway inflammation and possess potential therapeutic option for allergic asthma management.

Effects of superimposed pressure oscillations on a chronic sensitized airways mouse model.

The hyperconstriction of airway smooth muscle (ASM) is the main driving mechanism during an asthmatic attack. The airway lumen is reduced, resistance to airflow increases, and normal breathing becomes more difficult. The tissue contraction can be temporarily relieved by using bronchodilator drugs, which induce relaxation of the constricted airways. In vitro studies indicate that relaxation of isolated, precontracted ASM is induced by mechanical oscillations in healthy subjects but not in asthmatic subjects. Further, short-term acute asthmatic subjects respond to superimposed pressure oscillations (SIPO) generated in the range of 5-15 Hz with ~50% relaxation of preconstricted sensitized airways. Mechanical oscillations, and specifically SIPO, are not widely characterized in asthmatic models. The objective of this in vivo study is to determine the effects of a range of oscillation patterns similar to our previous acute study differing from normal breathing. Both healthy and sensitized mice were observed, with their responses to SIPO treatments measured during induced bronchoconstriction resulting from acetylcholine (Ach) challenge. SIPO-generated results were compared with data from treatments using the bronchorelaxant isoproterenol (ISO). The study shows that SIPO in the range of 5-20 Hz induces relaxation in chronic sensitized airways, with significant improvements in respiratory parameters at SIPO values near 1.7 cmH2O irrespective of the frequency of generation.

Effects of a structured educational intervention in moderate-to-severe elderly asthmatic subjects.

BACKGROUND: Adherence to inhaled drugs is linked to patients' satisfaction with their device, and an incorrect use can negatively affect the outcomes of asthma treatment. We speculated that this is particularly true in elderly asthmatic subjects. AIM: We performed a national pre-post interventional multicentre study, enrolling moderate-to-severe asthmatic subjects aged ≥65 â€‹years treated with fixed inhaled combination drugs by dry powder inhaler (DPI) or pressurized metered dose inhaler (pMDI). Adherence and critical errors were evaluated by means of validated questionnaires at first visit (V1) and after 3-6 months (V2). At V1, subjects underwent intensive training on the correct use of their device by physical demonstration. RESULTS: A total of 411 asthmatics (F/M: 238/173, mean age±SD: 72 â€‹± â€‹5 â€‹years) participated to the study. At V1, 50% of the study subjects showed an Asthma Control Test (ACT) score ≤19 despite GINA step 3 and 4 treatment, and 40% had experienced at least one severe asthma exacerbation in the previous year. Poor adherence to treatment was recorded in 43% of subjects, and at least one error in using the device was registered in 56% of subjects. At V2, available for 318 patients, both the percentage of individuals with poor adherence and with at least one critical error significantly decreased (from 46% to 25%, and from 49% to 25%, respectively; p â€‹< â€‹0.001 for both comparisons) with a significant increase of the ACT score (from 19 â€‹± â€‹4.9 to 20 â€‹± â€‹4.0, p â€‹< â€‹0.001). CONCLUSIONS: Asthma in the elderly is characterized by low levels of symptom control. Educational interventions are strongly advocated in this age group in order to increase adherence to treatment and inhaler techniques.

PARP inhibition by olaparib alleviates chronic asthma-associated remodeling features via modulating inflammasome signaling in mice.

Despite the reported role of poly(ADP-ribose) polymerase (PARP) in asthma inflammation, its contribution during remodeling is not clearly known. The main aim of the current investigation was to examine the potential of olaparib, a pharmacological inhibitor of PARP against airway remodeling using an ovalbumin (OVA)-based murine model of chronic asthma. The results demonstrated that post-challenge olaparib treatment (5 mg/kg i.p., 30 min after OVA exposure) for six weeks (3 days/week) attenuates inflammation, mucus production, and collagen deposition in lungs. Additionally, olaparib blunted the protein expression of STAT-6 and GATA-3 considerably along with a modest reduction in p65-NF-κB phosphorylation. Furthermore, olaparib normalized the OVA-induced redox imbalance as reflected by data on reactive oxygen species, malondialdehyde, protein carbonyls, and reduced glutathione/oxidized glutathione ratio. Interestingly, the protection offered by olaparib was further linked with the altered level of NLRP3 inflammasome-mediated IL-1ß release and consequent expression of its downstream targets matrix metalloproteinase-9 and transforming growth factor beta. Suppressed collagen deposition in the lungs correlates well with the reduced expression of vimentin upon olaparib treatment. Finally, olaparib restored the expression of histone deacetylase 2, a steroid-responsive element in asthma. Overall, results suggest that olaparib prevents OVA-induced airway inflammation as well as remodeling via modulating inflammasome signaling in mice. © 2019 IUBMB Life, 1-11, 2019.

Human pluripotent stem cell-derived mesenchymal stem cells prevent chronic allergic airway inflammation via TGF-ß1-Smad2/Smad3 signaling pathway in mice.

BACKGROUND: Asthma is a chronic disease involving inflamed airways, which were previously demonstrated, can be modulated by the mesenchymal stem cells derived from induced pluripotent stem cells (iPSC-MSCs). However, the long-term effects of iPSC-MSCs in inflamed airways are still unidentified. This study investigated the long-term effects and potential mechanisms involved in the immunomodulatory effects of iPSC-MSCs in the chronic mouse asthma model. METHODS: Both human iPSC-MSCs and bone marrow (BM)-MSCs were transplanted into the long-term ovalbumin-induced mice before sensitization phase or during the challenge phase. Airway hyper-respnsiveness measurement, immunohistochemistry and ELISA were employed to assess the effects of MSCs. In addition, Smad2/3 levels were assessed by western blot analysis to investigate the possible mechanism involved. RESULTS: The systemic administration of human iPSC-MSCs before the challenge protected the mice from the characters of the chronic allergic airway inflammation, in particular improving the airway remodeling and preventing fibrosis. In addition, the TGF-ß1/Smad pathway was identified involved in the immunomodulatory effects of iPSC-MSCs on chronic allergic airway inflammation. CONCLUSIONS: The study demonstrated that iPSC-MSCs are capable of preventing chronic allergic airway inflammation over a prolonged period, which further proved the iPSC-MSC therapeutic potential for allergic airway inflammation in a clinical scenario.

Two Sides of the Same Coin?-Treatment of Chronic Asthma in Children and Adults.

Globally, asthma is one of the most common chronic conditions that affect individuals of all ages. When poorly controlled, it negatively impacts patient's ability to enjoy life and work. At the population level, effective use of recommended strategies in children and adults can reduce symptom burden, improve quality of life and significantly reduce the risk of exacerbation, decline of lung function and asthma-related death. Inhaled corticosteroid as the initial maintenance therapy, ideally started within 2 years of symptom onset, is highly effective in both children and adults and across various degrees of asthma severity. If asthma is not controlled, the choice of subsequent add-on therapies differs between children and adults. Evidence supporting pharmacological approach to asthma management, especially for those with more severe disease, is more robust in adults compared to children. This is, in part, due to various challenges in the diagnosis of asthma, in the recruitment into clinical trials and in the lack of objective outcomes in children, especially those in the preschool age group. Nevertheless, where evidence is emerging for younger children, it seems to mirror the observations in adults. Clinicians need to develop strategies to implement guideline-based recommendations while taking into consideration individual variations in asthma clinical phenotypes, pathophysiology and treatment responses at different ages.