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

Peter Barnes and colleagues show that corticosteroids have a potent inhibitory effect on GATA-3 via two interacting mechanisms that suppress Th2 cytokine expression. This novel mechanism of corticosteroid action may help explain the efficacy of corticosteroids in allergic diseases

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

Abstract 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, I 2 = 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, I 2 = 64.6%) and hospital mortality (pooled RR = 0.71, 95% CI 0.51–1.00, p = 0.05, I 2 = 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)

Additional file 1: of Simvastatin up-regulates adenosine deaminase and suppresses osteopontin expression in COPD patients through an IL-13-dependent mechanism

Simvastatin up-regulates adenosine deaminase and suppresses osteopontin expression in COPD patients through an IL-13-dependent mechanism. (DOCX 21 kb

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 (BWTr) of the peripheral airways and extent of expiratory air trapping (ATexp). 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. ATexp and BWTr 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 BWTr (0.5, 0.012), whereas RV/TLC was associated with ATexp (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

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

Sunitinib Indirectly Enhanced Anti-Tumor Cytotoxicity of Cytokine-Induced Killer Cells and CD3⁺CD56⁺ Subset through the Co-Culturing Dendritic Cells

<div><p>Cytokine-induced killer (CIK) cells have reached clinical trials for leukemia and solid tumors. Their anti-tumor cytotoxicity had earlier been shown to be intensified after the co-culture with dendritic cells (DCs). We observed markedly enhanced anti-tumor cytotoxicity activity of CIK cells after the co-culture with sunitinib-pretreated DCs over that of untreated DCs. This cytotoxicity was reliant upon DC modulation by sunitinib because the direct exposure of CIK cells to sunitinib had no significant effect. Sunitinib promoted Th1-inducing and pro-inflammatory phenotypes (IL-12, IFN-γ and IL-6) in DCs at the expense of Th2 inducing phenotype (IL-13) and regulatory phenotype (PD-L1, IDO). Sunitinib-treated DCs subsequently induced the upregulation of Th1 phenotypic markers (IFN-γ and T-bet) and the downregulation of the Th2 signature (GATA-3) and the Th17 marker (RORC) on the CD3⁺CD56⁺ subset of CIK cells. It concluded that sunitinib-pretreated DCs drove the CD3⁺CD56⁺ subset toward Th1 phenotype with increased anti-tumor cytotoxicity.</p></div

The cytotoxic activity of all conditions of CD3⁺CD56⁺ cells could be neutralized with αIFN-γ treatment.

<p>The CD3⁺CD56⁺ cells from each condition were incubated with the attached HubCCA1 cells (5,000 cells/well) for 4 h before the PI assay. These conditions included the untreated CD3⁺CD56⁺ cells, αIFN-γ treatment to CD3⁺CD56⁺ cells, CD3⁺CD56⁺ cells primed with mDC, αIFN-γ treatment to CD3⁺CD56⁺ cells primed with mDC, CD3⁺CD56⁺ cells primed with sunitinib-pretreated mDC, and αIFN-γ treatment to CD3⁺CD56⁺ cells primed with sunitinib-pretreated mDC. * designates conditions that provided statistically difference after αIFN-γ treatment at the same E:T ratio with p<0.05.</p

Fluticasone propionate–mediated inhibition of p38 MAP kinase phosphorylation and activation is associated with a marked down-regulation of GATA-3 serine phosphorylation.

<p>(A) Western blot analysis shows that FP (10⁻⁸ M, 30 min) treatment reduced dual phosphorylation (threonine-180 and tyrosine-182) of p38 MAPK in anti-CD3/CD28–co-stimulated HuT-78 cells. (B) Time course of the effect of FP (10⁻⁸ M) on phosphorylation of activated transcription factor 2 (ATF-2), a measure of p38 MAPK activity. (C) FP-induced inhibition of p38 MAPK activity is associated with the decrease of anti-CD3/CD28 co-stimulation–induced serine phosphorylation (P-Ser) of GATA-3. For (A–C), quantification of the densitometry data is also shown. Each bar represents mean±SEM of at least three independent experiments. ^###<i>p</i><0.001 compared to control, ***<i>p</i><0.001 compared to αCD3/CD28-stimulated cells. (D) FP induced MKP-1 mRNA in a concentration-dependent manner. All results are representative of at least three independent experiments and where appropriate expressed as means±SEM, *<i>p</i><0.05. (E) FP induces MKP-1 mRNA in a time-dependent manner. Results are representative of two independent experiments. All data except (E) were analysed by ANOVA followed by Newman-Keuls post-test.</p