Paradoxical eosinophilic and cytokine responses to oral corticosteroid treatment in patients with asthma exacerbations.

Background: Thymic stromal lymphopoietin (TSLP) orchestrates eosinophilic inflammation, which may increase during asthma exacerbations. In contrast, microRNA-1 (miR-1) inhibits TSLP-mediated eosinophil trafficking in lung endothelium. Whether the balance of TSLP and miR-1 levels determines the response to oral corticosteroids (OCSs) during the treatment of asthma exacerbations remains unknown. Objective: Our aim was to investigate the involvement of TSLP/miR-1 axis in inflammatory response to OCS treatment for asthma exacerbations. Methods: We measured the concentrations of TSLP and other inflammatory cytokines and miR-1 expression during acute asthma exacerbations treated with standard OCSs in a real-life setting. A total of 28 consecutive patients with acute asthma exacerbations treated with OCS (prednisolone 30 mg/d) for 1 week at the emergency department were studied prospectively. Steroid responders were identified by a significant reduction in blood eosinophil counts, whereas paradoxical responders (PRs) showed no markedly decreased or even increased absolute blood eosinophil counts after OCS treatment. Differential white blood cell counts, blood cytokine levels, and miR-1 expression within and between groups were compared before and after OCS treatment. The baseline cytokine concentrations in both groups were compared with those of patients with stable asthma. Results: OCS treatment significantly reduced TSLP levels in steroid responders, whereas this effect did not occur in PRs (P = .006 and P = .742, respectively). In contrast, miR-1 expression was unchanged in steroid responders in response to OCS, whereas it was markedly reduced in the PRs, despite higher expression at baseline than in patients with stable asthma, which may account for slower resolution of the exacerbation. Conclusions: In some asthmatic patients with acute exacerbations who do not suppress eosinophils after a course of OCS, there is a paradoxical decrease in plasma miR-1 level and increase in TSLP level versus in steroid responders, which may result in slower clinical recovery.

Expert panel consensus recommendations on the utilization of nebulized budesonide for managing asthma and COPD in both stable and exacerbation stages in Thailand.

OBJECTIVE: This study investigated the utilization of nebulized budesonide for acute asthma and COPD exacerbations as well as for maintenance therapy in adults. DATA SOURCES: We conducted a search on PubMed for nebulized budesonide treatment. SELECTED STUDIES: Selecting all English-language papers that utilize Mesh phrases "asthma," "COPD," "budesonide," "nebulized," "adult," "exacerbation," and "maintenance" without temporal restrictions, and narrowing down to clinical research such as RCTs, observational studies, and real-world studies. RESULTS: Analysis of 25 studies was conducted to assess the effectiveness of nebulized budesonide in asthma (n = 10) and COPD (n = 15). The panel in Thailand recommended incorporating nebulized budesonide as an additional or alternative treatment option to the standard of care and systemic corticosteroids (SCS) based on the findings. CONCLUSION: Nebulized budesonide is effective and well-tolerated in treating asthma and COPD, with less systemic adverse effects compared to systemic corticosteroids. High-dose nebulized budesonide can enhance clinical outcomes for severe and mild exacerbations with slow systemic corticosteroid response. Nebulized budesonide can substitute systemic corticosteroids in some situations.

Noninvasive ventilation in patients with acute hypoxemic respiratory failure: a systematic review and meta-analysis of randomized controlled trials.

The clinical benefits of noninvasive ventilation (NIV) for patients with acute hypoxemic respiratory failure (AHRF) is still inconclusive. We aimed to evaluate the effect of NIV compared with conventional oxygen therapy (COT)/high-flow nasal cannula (HFNC) in this patient population. We searched for relevant studies from PubMed, Embase, Cochrane Library, ClinicalTrials.gov, CINHAL, Web of Science up to August 2019 for randomized controlled trials (RCTs) that compared NIV with COT/HFNC in AHRF. The primary outcome was the tracheal intubation rate. Secondary outcomes were intensive care unit (ICU) mortality, and hospital mortality. We applied the GRADE approach to grade the strength of the evidence. Seventeen RCTs that recruited 1738 patients were included in our meta-analysis. When comparing NIV versus COT/HFNC, the pooled risk ratio (RR) for the tracheal intubation rate was 0.68, 95% confidence interval (CI) 0.52-0.89, p = 0.005, I2 = 72.4%, low certainty of evidence. There were no significant differences in ICU mortality (pooled RR = 0.87, 95% CI 0.60-1.26), p = 0.45, I2 = 64.6%) and hospital mortality (pooled RR = 0.71, 95% CI 0.51-1.00, p = 0.05, I2 = 27.4%). Subgroup analysis revealed that NIV application with helmet was significantly associated with a lower intubation rate than NIV with face mask. NIV did not show a significant reduction in intubation rate compared to HFNC. In conclusion, NIV application in patients with medical illness and AHRF was associated with a lower risk of tracheal intubation compared to COT. NIV with helmet and HFNC are promising strategies to avoid tracheal intubation in this patient population and warrant further studies. NIV application had no effect on mortality.The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42018087342).

Involvement of Transforming Growth Factor-ß-Associated Kinase 1 in Fixed Airway Obstruction in Asthmatic Patients with Longer Disease Duration Independent on Airway Eosinophilia.

Objective: Transforming growth factor-ß-associated kinase 1 (TAK1) mediates non-canonical TGF-ß signalling by promoting adhesive, migratory, proliferative and contractile responses of fibroblasts to TGF-ß1. However, TAK1 expression status in asthmatic patients with or without fixed airway obstruction (FAO) is unknown. Patients and Methods: A total of 60 adult asthmatics with FAO were recruited and compared to 43 those without FAO (nFAO). TGF-ß1 concentrations, and total TAK1 and phosphorylated TAK1 (p-TAK1) levels were determined in sputum supernatants, cytospin, and whole cell lysate by ELISA, immunocytochemistry, and Western blot analysis, respectively, in asthmatics with and without FAO. Results: Asthmatic patients with FAO had much greater sputum TGF-ß1 concentrations than those without FAO. This was independent of airway eosinophilia as there was no significant difference in TGF-ß1 levels between high and low eosinophil counts within FAO and nFAO groups. In contrast, patients with FAO in the presence of sputum eosinophilia had greater expression of TAK1 and p-TAK1 than those without sputum eosinophilia (P=0.0032 and P=0.0061, respectively). The Western Blot data of total TAK1 and p-TAK1 were consistent with the immunocytochemistry, showing upregulation in all sputum cell types (neutrophils, eosinophils, macrophages, lymphocytes and airway epithelial cells). In addition, total TAK1 expression negatively correlated with pre- and post-bronchodilator FEV1/FVC ratio. Conclusion: TAK1 may play a key role in asthmatic patients with fixed airway obstruction, which was independent of eosinophilic airway inflammation. The interruption of TAK1 might have favourable clinical impact.

Impact of inhaled fluticasone propionate/salmeterol on health-related quality of life in asthma: A network meta-analysis.

OBJECTIVE: This network meta-analysis (NMA) compared fixed-dose, twice daily fluticasone propionate/salmeterol (FP/Sal) vs. inhaled corticosteroid (ICS) and other ICS/long-acting beta-agonists (LABA) treatments, including when administered using maintenance and reliever therapy (MART) regimens, in terms of improvements in health-related quality of life (HRQoL). The relationship between changes in asthma control and HRQoL was assessed. METHODS: Articles published between 2001 and 2021, reporting change from baseline (CFB) in Asthma Quality of Life Questionnaire (AQLQ) in patients with moderate-to-severe asthma, were identified by a systematic review. Random effects Bayesian NMAs derived estimates of the mean difference in CFB in AQLQ vs. other interventions connected to the network (included 15 studies). Sensitivity analyses explored the impacts of differences in follow-up duration, baseline asthma control, the inclusion of observational studies, adjusting for baseline FEV1, and low-medium ICS dose arms only. Linear regression analysis compared CFBs in AQLQ and Asthma Control Questionnaire (ACQ) score. RESULTS: Mean CFB in AQLQ with FP/Sal vs. comparators demonstrated expected ranked effects: mean difference 0.65 [95% credible interval: 0.54, 0.78] versus placebo, 0.58 [ 0.33, 0.84] versus LABA, 0.21 [ 0.13, 0.31] versus ICS alone, 0.06 [-0.04, 0.19] versus other ICS/LABA, and 0.00 [-0.13, 0.14] versus ICS/formoterol MART. Sensitivity analyses largely showed consistent results. Improvements in AQLQ and ACQ were strongly correlated (R = 0.94). CONCLUSIONS: This NMA demonstrates that HRQoL is responsive to treatment, is strongly related to asthma control and that it can be well-managed in patients with moderate-to-severe asthma using regular treatment with inhaled FP/Sal.

New Versus Old: The Impact of Changing Patterns of Inhaled Corticosteroid Prescribing and Dosing Regimens in Asthma Management.

Inhaled corticosteroid (ICS)-containing therapies are the mainstay of pharmacological management of asthma. They can be administered alone or in combination with a long-acting bronchodilator, depending on asthma severity, and may also be supplemented with short-acting bronchodilators for as-needed rescue medication. Adherence to asthma therapies is generally poor and characterized by underuse of ICS therapies and over-reliance on short-acting bronchodilators, which leads to poor clinical outcomes. This article reviews efficacy versus systemic activity profiles for various dosing regimens of budesonide (BUD) and fluticasone propionate (FP). We performed a structured literature review of BUD and FP regular daily dosing, and BUD/formoterol (FOR) as-needed dosing, to explore the relationship between various dosing patterns of ICS regimens and the risk-benefit profile in terms of the extent of bronchoprotection and cortisol suppression. In addition, we explored how adherence could potentially affect the risk-benefit profile, in patients with mild, moderate, and moderate-to-severe asthma. With a specific focus on BUD or FP-containing treatments, we found that regular daily ICS and ICS/long-acting ß2-agonist (LABA) dosing had a greater degree of bronchoprotection than as-needed BUD/FOR dosing or BUD/FOR maintenance and reliever therapy (MART) dosing, and still maintained low systemic activity. We also found that the benefits of regular daily ICS dosing regimens were diminished when adherence was low (50%); the shorter duration of bronchoprotection observed was similar to that seen with typical as-needed BUD/FOR usage. These findings have implications for aiding clinicians with selecting the most suitable treatment option for asthma management, and subsequent implications for the advice clinicians give their patients.

Inhaled corticosteroid (ICS)-containing therapies can be administered in a variety of ways depending on a patient's asthma severity. Patients with mild asthma tend to experience symptom relief with as-needed or regular daily use of an ICS alone, whereas patients with more severe asthma may require regular daily use of an ICS plus a long-acting ß₂-agonist (LABA) to experience sufficient asthma control. However, failure to correctly adhere to ICS-containing therapies or an over-reliance on short-acting bronchodilators for symptom relief hinders optimal asthma management, thus negatively affecting overall patient health and wellbeing. Understanding how different dosing regimens affect the degree of bronchoprotection (efficacy) and cortisol suppression (systemic activity) of ICS treatments would benefit physicians by helping them to prescribe the most appropriate treatment for their patient's asthma. We performed a structured literature review of two ICS molecules­budesonide (BUD) (alone and combined with formoterol [FOR]) and fluticasone propionate (FP)­to explore the relationship between various ICS dosing regimens, and then used these findings to construct models for ICS risk­benefit profiles. Our models factored in different ICS dosing regimens­as-needed, regular daily dosing, and maintenance and reliever therapy (MART)­and various degrees of treatment adherence. We found that regular daily ICS and ICS/LABA dosing provided better bronchoprotection than as-needed BUD/FOR dosing or BUD/FOR MART dosing, but this benefit was diminished with low adherence. Regular daily dosing maintained low cortisol suppression, which indicated a fairly low risk of negative side effects. Our findings have subsequent implications for optimizing treatment in patients with asthma.

Indoleamine 2,3 dioxygenase (IDO) level as a marker for significant coronary artery disease.

BACKGROUND: Indoleamine 2,3 dioxygenase (IDO), the rate-limiting enzyme in the kynurenine (Kyn) pathway of tryptophan (Trp) degradation, is modulated by inflammation, and is regarded as a key molecule driving immunotolerance and immunosuppressive mechanisms. Little is known about IDO activity in patients with active coronary artery disease (CAD). METHODS: We prospectively enrolled patients who were scheduled to undergo coronary angiography. Measurement of IDO, high-sensitivity troponin T (hs-TnT), and high-sensitivity C-reactive protein (hs-CRP) levels was performed at baseline, and IDO activity was monitored at the 6-month follow-up. RESULTS: Three hundred and five patients were enrolled. Ninety-eight patients (32.1%) presented with recent acute coronary syndrome (ACS). Significant difference in IDO, kynurenine, and hs-TnT between patients with and without significant CAD was observed. Baseline IDO activity, kynurenine level, and hs-TnT level were all significantly higher in significant CAD patients with 3-vessel, 2-vessel, and 1-vessel involvement than in those with insignificant CAD [(0.17, 0.13, and 0.16 vs. 0.03, respectively; p = 0.003), (5.89, 4.58, and 5.24 vs. 2.74 µM/g, respectively; p = 0.011), and (18.27, 12.22, and 12.86 vs. 10.89 mg/dL, respectively; p < 0.001)]. One-year mortality was 3.9%. When we compared between patients who survived and patients who died, we found a significantly lower prevalence of left main (LM) disease by coronary angiogram (6.1% vs. 33.3%, p = 0.007), and also a trend toward higher baseline kynurenine (5.07 vs. 0.79 µM/g, p = 0.082) and higher IDO (0.15 vs. 0.02, p = 0.081) in patients who survived. CONCLUSION: Immunometabolic response mediated via IDO function was enhanced in patients with CAD, and correlated with the extent and severity of disease. Patients with LM disease had higher 1-year mortality. Lower level of IDO, as suggested by inadequate IDO response, demonstrated a trend toward predicting 1-year mortality. Trial registration TCTR Trial registration number TCTR20200626001. Date of registration 26 June 2020. "Retrospectively registered".

Microparticles from human the lower airway show inhibitory activity against respiratory syncytial virus.

Airway microparticles (MPs) have been shown previously to inhibit influenza virus by trapping virions on their surface through their surface viral receptor. It was hypothesized that airway MPs may carry most of the epithelial cell surface molecules, including receptors for respiratory viruses, and may be able to inhibit various respiratory viruses. We show here that MPs from human bronchoalveolar lavage (BAL) can inhibit respiratory syncytial virus (RSV). Those MPs stained positive for the RSV receptor, CX3CR1. Furthermore, incubating the MPs with a monoclonal antibody against CX3CR1 reduced the anti-RSV activity. These data indicate that MPs can contribute to respiratory innate antiviral defense.

Role of autophagy in regulating interleukin-10 and the responses to corticosteroids and statins in asthma.

BACKGROUND: Interleukin (IL)-10 is a key anti-inflammatory cytokine that may be reduced in asthma but is enhanced by corticosteroids, especially when combined with a statin, although the mechanisms of these effects are uncertain. OBJECTIVE: To study the role of autophagy in macrophages in promoting inflammation in asthma through reducing IL-10 secretion and how corticosteroids and statins may reverse this process. METHODS: We conducted a randomised double-blind placebo-controlled study in moderate to severe asthmatic patients (n = 44) to investigate the effect of an inhaled corticosteroid (budesonide 400 µg/day) and the combination of budesonide with an oral statin (simvastatin 10 mg/day) given for 8 weeks on autophagy protein expression in sputum cells by using immunocytochemistry and measurement of IL-10 release. In in vitro experiments, we studied cross-regulation between autophagy and IL-10 release by measuring the expression of autophagy proteins in M2-like macrophages and the effects of budesonide and simvastatin on these mechanisms. RESULTS: In asthmatic patients, inhaled budesonide inhibited airway macrophage autophagy (beclin-1, LC3) as well as autophagic flux (p62), which was enhanced by simvastatin and was correlated with increased sputum IL-10 and reduced IL-4 concentrations. In macrophages in vitro, budesonide and simvastatin inhibited rapamycin-induced autophagy as well as autophagic flux, with reduced expression of beclin-1 and LC3, but enhanced the accumulation of p62 and increased expression of IL-10, which itself further inhibited autophagy in macrophages. With siRNA-mediated silencing, LC3-deficient macrophages also showed a maximal induction of IL-10 transcription. Neutralisation of IL-10 with recombinant specific blocking antibody and silencing IL-10 transcription reversed the inhibitory effects of budesonide and simvastatin on macrophage autophagy. CONCLUSION AND CLINICAL RELEVANCE: Inhibition by corticosteroids and a statin of macrophage autophagy enhances IL-10 production, resulting in the control of asthmatic inflammation.

Role of microRNA in severe asthma.

The various roles of microRNAs (miRNAs) in the epigenetic regulation of human disease are gaining importance as areas of research, and a better understanding of these roles may identify targets for development of novel therapies for severe asthma. MiRNAs, a class of small non-coding RNAs that serve as post-transcriptional gene repressors, are recognized as critical components in regulating tissue homeostasis. Alteration in miRNA expression disrupts homeostasis and is an underlying mechanism for development of chronic respiratory diseases, including asthma. Differential profiles of miRNA expression are involved in inflammation and remodeling pathogenicity via activating airway structural cells and immune cells and inducing cytokine releases. miRNA action leads to asthma progression from mild to severe stages. Here, current knowledge of the heterogeneous roles of miRNAs in severe asthma, including biological mechanisms underlying Th2 and macrophage polarization, type 2 innate lymphoid cell (ILC2) biology regulation, steroid-resistant asthma phenotype, airway smooth muscle (ASM) dysfunction, and impaired anti-viral innate immune, are reviewed.

Assessment of proximal and peripheral airway dysfunction by computed tomography and respiratory impedance in asthma and COPD patients with fixed airflow obstruction.

OBJECTIVE: To ascertain: (i) if elderly patients with fixed airflow obstruction (FAO) due to asthma and chronic obstructive pulmonary disease (COPD) have distinct airway morphologic and physiologic changes; (ii) the correlation between the morphology of proximal/peripheral airways and respiratory impedance. METHODS: Twenty-five asthma cases with FAO and 22 COPD patients were enrolled. High-resolution computed tomography was used to measure the wall area (WA) and lumen area (LA) of the proximal airway at the apical segmental bronchus of the right upper lobe (RB1) adjusted by body surface area (BSA) and bronchial wall thickening (BWT r ) of the peripheral airways and extent of expiratory air trapping (AT exp ). Respiratory impedance included resistance at 5 Hz (R5) and 20 Hz (R20) and resonant frequency (Fres). Total lung capacity (TLC) and residual volume (RV) were measured. RESULTS: Asthma patients had smaller RB1-LA/BSA than COPD patients (10.5 ± 3.4 vs. 13.3 ± 5.0 mm2/m2, P = 0.037). R5(5.5 ± 2.0 vs. 3.4 ± 1.0 cmH2O/L/s, P = 0.02) and R20(4.2 ± 1.7 vs. 2.6 ± 0.7 cmH2O/L/s, P = 0.001) were higher in asthma cases. AT exp and BWT r were similar in both groups. Regression analysis in asthma showed that forced expiratory volume in one second (FEV1) and Fres were associated with RB1-WA/BSA (R2= 0.34, P = 0.005) and BWT r (0.5, 0.012), whereas RV/TLC was associated with AT exp (0.38, 0.001). CONCLUSIONS: Asthma patients with FAO had a smaller LA and higher resistance of the proximal airways than COPD patients. FEV1 and respiratory impedance correlated with airway morphology.

Correction: Suppression of GATA-3 Nuclear Import and Phosphorylation: A Novel Mechanism of Corticosteroid Action in Allergic Disease.

[This corrects the article DOI: 10.1371/journal.pmed.1000076.].

Long-term effectiveness of omalizumab treatment in Thai severe asthmatic patients: A real-life experience.

BACKGROUND: To evaluate long-term effectiveness of omalizumab in 'real-life' setting of Thai asthmatic patients. METHODS: We conducted multi-center, observational study in severe asthma patients who received omalizumab in Thailand. Outcomes were asthma exacerbation (hospitalization and ER visit), asthma control test (ACT), and daily ICS dose. Data were evaluated at baseline, 16 Week, and 52 Week. RESULTS: A total of 78 patients received omalizumab treatment (average duration 16.9 months with range 16 weeks-2 years). The mean annualized rate of exacerbations was reduced from baseline (3.79) at Week 16 (3.54) and Week 52 (1.16), (p<0.05), respectively. The mean hospitalization rate was reduced from 0.49 in previous year to 0.15 at Week 16 and 0.19 at Week 52. A reduction in ER visit rates was observed at Week 16 (0.15) and Week 52 (0.97) respectively from baseline (1.44) (p<0.05). The ACT score increased from 15.4 at baseline to 20.6 at Week 16 (p<0.001) and increased to 21.5 at Week 52 (p<0.001). The number of patients with controlled asthma (ACT≥20) increased from 16 of 51 at baseline to 32 of 45 at Week 16 and 25 of 32 at week 52, respectively. The median daily dose of ICS equivalent to fluticasone was reduced from baseline 680 mcg to 500 mcg at Week 52. In all, 22 patients discontinued omalizumab after 1 year. Six patients who discontinued omalizumab were restarted due to relapse of symptoms. CONCLUSIONS: These data confirms the effectiveness of one-year duration of omalizumab treatment in Thai severe asthmatic patients. Furthermore, 27% of patients who discontinued treatment required restarting due to relapse of symptoms.

Microparticle and anti-influenza activity in human respiratory secretion.

Respiratory secretions, such as saliva and bronchoalveolar fluid, contain anti-influenza activity. Multiple soluble factors have been described that exert anti-influenza activity and are believed to be responsible for the anti-influenza activity in respiratory secretions. It was previously shown that a bronchial epithelial cell culture could produce exosome-like particles with anti-influenza activity. Whether such extracellular vesicles in respiratory secretions have anti-influenza activity is unknown. Therefore, we characterized bronchoalveolar lavage fluid and found microparticles, which mostly stained positive for epithelial cell markers and both α2,3- and α2,6-linked sialic acid. Microparticles were purified from bronchoalveolar lavage fluid and shown to exhibit anti-influenza activity by a hemagglutination inhibition (HI) assay and a neutralization (NT) assay. In addition, physical binding between influenza virions and microparticles was demonstrated by electron microscopy. These findings indicate that respiratory microparticles containing viral receptors can exert anti-viral activity by probably trapping viral particles. This innate mechanism may play an important role in the defense against respiratory viruses.

Association between levels of fractional exhaled nitric oxide and asthma exacerbations in Thai children.

BACKGROUND AND OBJECTIVE: Fractional exhaled nitric oxide (FeNO) has been used as a marker for airway inflammation. We evaluated the association between FeNO levels and asthma exacerbations (AEs) in Thai children and young adults. METHODS: This was a prospective cohort study in patients with atopic asthma aged 7-20 years. Asthma control level and management were evaluated every 3 months for 1 year. Spirometry and FeNO measurements were performed at baseline, and 6 and 12 months. RESULTS: In all, 70 patients (median age: 12.6 (7.2-19.8) years) were enrolled, of whom 18% had an AE during the study period. Median FeNO levels were significantly higher in patients with an AE than in those without an AE (35.6 ppb vs 16.5 ppb; P = 0.012). FeNO of 31 ppb provided optimal sensitivity (92.3%) and specificity (75.4%) for AE prediction. Sensitivity and specificity of FeNO levels were higher than those of forced expiratory volume in 1 s and forced expiratory flow at 25-75% of forced vital capacity bronchodilator reversibility for the prediction of an AE, but the difference was not significant (P = 0.121). None of the patients with FeNO level of 0-20 ppb had an AE within 12 months. Percentage of patients with FeNO of 21-40 ppb who suffered an AE was 20% and 30% at 6 and 12 months, respectively. CONCLUSION: The optimal cut-off point of FeNO level for the prediction of AE is 31 ppb. AE within the next 12 months was significantly more common in patients with higher FeNO levels and in patients with a higher rate of previous 12-month exacerbations.

Effects of the Ayurved Siriraj Wattana recipe on functional and phenotypic characterization of cytokine-induced killer cells and dendritic cells in vitro.

BACKGROUND: Ayurved Siriraj Wattana recipe (AVS073), has been prescribed as tonic, to increase appetite, and for pain relief. It also exhibits antioxidant, anti-inflammatory, immunomodulating and anti-cancer activities. However, the immunomodulatory effects on antigen-presenting cells and effector T cells remained elusive. We thus aimed to study the effects of AVS073 on differentiation, maturation, functions and proportions of CIK cells and monocyte-derived DCs. METHODS: CIK cells and monocyte-derived DCs were treated with AVS073, followed by the assessment of T-helper (Th) phenotypes using real-time RT-PCR and flow cytometry. RESULTS: AVS073 promoted Th1 phenotype in CD3+CD56+ subset of CIK cells through increasing STAT4, T-bet, and interferon-γ. AVS073 inhibited Th2 phenotype through decreasing STAT6. AVS073 inhibited Treg phenotype through decreasing STAT5A, STAT5B and IDO. AVS073 promoted Th17 phenotype through increasing STAT3, RORC and IL-17. AVS073 treatment of mDCs resulted in increasing Th1-prone cytokine (IL-12) and Th17-prone cytokines (IL-6 and IL-23). CONCLUSIONS: AVS073 upregulated Th1 and Th17, but downregulated Th2 and Treg phenotypes within CD3+CD56+ cells. The treatment of mDCs drove Th1 and Th17-polarizations.

Simvastatin up-regulates adenosine deaminase and suppresses osteopontin expression in COPD patients through an IL-13-dependent mechanism.

BACKGROUND: Adenosine deaminase (ADA) and osteopontin (OPN) may play opposing roles in the pathogenesis of COPD. Deficiency of ADA results in enhanced adenosine signaling which up-regulates OPN expression. Although statins suppress OPN in cancer cells, little is known about their effects on ADA and OPN in COPD patients. METHODS: We extended a previous randomized double-blind placebo crossover study to investigate the effects of simvastatin (20 mg/day) on sputum ADA and OPN expression and explored the underlying signaling pathways involved by conducting in vitro experiments with cigarette smoke extract (CSE)-treated monocyte-derived macrophages (MDM) from COPD patients and healthy subjects. RESULTS: Simvastatin decreased sputum IL-13, OPN and CD73, while increasing ADA expression, irrespective of inhaled corticosteroid treatment and smoking status in parallel to increased inosine levels. The degree of simvastatin-restored ADA activity was significantly correlated with the magnitude of changes in pre-bronchodilator FEV1. Mechanistic exploration showed that CSE enhanced the expression of IL-13, which induced an increase in OPN and inhibited ADA mRNA accumulation in MDM from COPD patients but not healthy subjects through a STAT6-dependent mechanism. Simvastatin treatment inhibited IL-13 transcription in a dose-dependent manner, and therefore diminished the IL-13-induced increase in OPN and restored IL-13-suppressed ADA. There was no effect of simvastatin on adenosine receptors in CSE-stimulated MDM, indicating that its effects were on the adenosine pathway. CONCLUSION: Simvastatin reversed IL-13-suppressed ADA activity that leads to the down-regulation of adenosine signaling and therefore inhibits OPN expression through the direct inhibition of IL-13-activated STAT6 pathway. Inhibition of IL-13 may reverse the imbalance between ADA and OPN in COPD and therefore may prevent COPD progression.