Respiratory viruses, predominantly rhinoviruses are the major cause of asthma exacerbations. Impaired production of interferon-β in rhinovirus infected bronchial epithelial cells (BECs) and of the ...newly discovered interferon-λs in both BECs and bronchoalveolar lavage cells, is implicated in asthma exacerbation pathogenesis. Thus replacement of deficient interferon is a candidate new therapy for asthma exacerbations. Rhinoviruses and other respiratory viruses infect both BECs and macrophages, but their relative capacities for α-, β- and λ-interferon production are unknown. To provide guidance regarding which interferon type is the best candidate for development for treatment/prevention of asthma exacerbations we investigated respiratory virus induction of α-, β- and λ-interferons in BECs and peripheral blood mononuclear cells (PBMCs) by reverse transferase-polymerase chain reaction and enzyme-linked immunosorbent assay. Rhinovirus infection of BEAS-2B BECs induced interferon-α mRNA expression transiently at 8 h and interferon-β later at 24 h while induction of interferon-λ was strongly induced at both time points. At 24 h, interferon-α protein was not detected, interferon-β was weakly induced while interferon-λ was strongly induced. Similar patterns of mRNA induction were observed in primary BECs, in response to both rhinovirus and influenza A virus infection, though protein levels were below assay detection limits. In PBMCs interferon-α, interferon-β and interferon-λ mRNAs were all strongly induced by rhinovirus at both 8 and 24 h and proteins were induced: interferon-α>-β>-λ. Thus respiratory viruses induced expression of α-, β- and λ-interferons in BECs and PBMCs. In PBMCs interferon-α>-β>-λ while in BECs, interferon-λ>-β>-α. We conclude that interferon-λs are likely the principal interferons produced during innate responses to respiratory viruses in BECs and interferon-αs in PBMCs, while interferon-β is produced by both cell types.
Current pharmacological therapies for COPD improve quality of life and symptoms and reduce exacerbations. Given the progressive nature of COPD, it is arguably more important to understand whether the ...available therapies are able to delay clinical deterioration; the concept of "clinically important deterioration" (CID) has therefore been developed. We evaluated the efficacy of the single-inhaler triple combination beclometasone dipropionate, formoterol fumarate, and glycopyrronium (BDP/FF/G), using data from three large 1-year studies.
The studies compared BDP/FF/G to BDP/FF (TRILOGY), tiotropium (TRINITY), and indacaterol/glycopyrronium (IND/GLY; TRIBUTE). All studies recruited patients with symptomatic COPD, FEV
<50%, and an exacerbation history. We measured the time to first CID and to sustained CID, an endpoint combining FEV
, St George's Respiratory Questionnaire (SGRQ), moderate-to-severe exacerbations, and death. The time to first CID was based on the first occurrence of any of the following: a decrease of ≥100 mL from baseline in FEV
, an increase of ≥4 units from baseline in SGRQ total score, the occurrence of a moderate/severe COPD exacerbation, or death. The time to sustained CID was defined as: a CID in FEV
and/or SGRQ total score maintained at all subsequent visits, an exacerbation, or death.
Extrafine BDP/FF/G significantly extended the time to first CID vs BDP/FF (HR 0.61,
<0.001), tiotropium (0.72,
<0.001), and IND/GLY (0.82,
<0.001), and significantly extended the time to sustained CID vs BDP/FF (HR 0.64,
<0.001) and tiotropium (0.80,
<0.001), with a numerical extension vs IND/GLY.
In patients with symptomatic COPD, FEV
<50%, and an exacerbation history, extrafine BDP/FF/G delayed disease deterioration compared with BDP/FF, tiotropium, and IND/GLY.
The studies are registered in ClinicalTrials.gov: TRILOGY, NCT01917331; TRINITY, NCT01911364; TRIBUTE, NCT02579850.
Oxidants and asthma Caramori, G; Papi, A
Thorax,
02/2004, Letnik:
59, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Many decades of research have produced a significant amount of data showing increased oxidative stress in asthma and indicating a potential role for oxidants in the pathogenesis of the disease, ...particularly during exacerbations. Putatively relevant pro-oxidative mechanisms have also been identified. Currently available asthma drugs are generally effective for the treatment of the disease, but their effects on oxidative stress have still not been completely elucidated. From the data available in the literature one can conclude that antioxidant compounds may have a potential role in the treatment of asthma, especially of asthma exacerbations. More convincing evidence from controlled clinical trials is required.
Chronic obstructive pulmonary disease (COPD) is characterised by oxidative stress and increased risk of lung carcinoma. Oxidative stress causes DNA damage which can be repaired by DNA-dependent ...protein kinase complex.
To investigate DNA damage/repair balance and DNA-dependent protein kinase complex in COPD lung and in an animal model of smoking-induced lung damage and to evaluate the effects of oxidative stress on Ku expression and function in human bronchial epithelial cells.
Protein expression was quantified using immunohistochemistry and/or western blotting. DNA damage/repair was measured using colorimetric assays.
8-OH-dG, a marker of oxidant-induced DNA damage, was statistically significantly increased in the peripheral lung of smokers (with and without COPD) compared with non-smokers, while the number of apurinic/apyrimidinic (AP) sites (DNA damage and repair) was increased in smokers compared with non-smokers (p = 0.0012) and patients with COPD (p < 0.0148). Nuclear expression of Ku86, but not of DNA-PKcs, phospho-DNA-PKcs, Ku70 or γ-H2AFX, was reduced in bronchiolar epithelial cells from patients with COPD compared with normal smokers and non-smokers (p < 0.039). Loss of Ku86 expression was also observed in a smoking mouse model (p < 0.012) and prevented by antioxidants. Oxidants reduced (p < 0.0112) Ku86 expression in human bronchial epithelial cells and Ku86 knock down modified AP sites in response to oxidative stress.
Ineffective DNA repair rather than strand breakage per se accounts for the reduced AP sites observed in COPD and this is correlated with a selective decrease of the expression of Ku86 in the bronchiolar epithelium. DNA damage/repair imbalance may contribute to increased risk of lung carcinoma in COPD.
1-μm-thick self-lubricating CrN–Ag composite coatings containing 16at.% Ag were deposited on Si substrates by reactive co-sputtering at Ts=400°C, and were covered with CrN cap layers with a columnar ...microstructure and a thickness d=0–1000nm. Vacuum annealing at Ta=500 and 600°C for 1h causes Ag transport to the sample surface and the formation of Ag surface grains. Quantitative scanning electron microscopy and energy dispersive spectroscopy analyses show that increasing d from 0 to 10 to 100nm for Ta=500°C leads to a decrease in the areal density of Ag surface grains from 0.86 to 0.45 to 0.04μm−2, while their lateral size remains constant at 360±60nm. However, increasing Ta to 600°C causes a doubling of the Ag grain size, and a 4–30 times larger overall Ag transport. These results are explained by kinetic barriers for Ag diffusion through the porous cap layer with a porosity that decreases with increasing d, resulting in an effective activation barrier for Ag transport that increases from 0.78eV in the absence of a cap layer to 0.89eV for d=10nm and 1.07eV for d=30nm. Auger electron spectroscopy depth profile analyses of annealed layers reveal no detectable Ag within the CrN cap layer and a uniform depletion of the Ag reservoir throughout the composite coating thickness, indicating unhindered Ag transport within the composite. The overall results show that a CrN diffusion barrier cap layer is an effective approach to control Ag lubricant transport to the surface of CrN–Ag composite coatings.
► CrN–Ag composite coatings are capped with CrN diffusion barriers. ► Ag diffuses to the surface during annealing at 500 or 600°C. ► The Ag transport is controlled by the cap thickness d=0–1000nm. ► The activation energy for Ag transport increases with increasing d.
Summary
The role of small airway abnormalities in asthma pathogenesis has been extensively studied and debated for several decades. However, whether or not small airway abnormalities play a relevant ...role in specific phenotypes of asthmatic patients and contribute to clinical presentation is largely unknown. In the present review, we evaluated available data on the role of small airways in severe asthma, with a further focus on asthma in smokers and asthma in the elderly. These phenotypes are characterized by a poor response to treatment and they can represent a model of greater small airway impairment. In severe asthmatics, small airway involvement has been shown through evidence of both distal inflammation and of increased air trapping. The few available data on asthmatics who smoke, and elderly asthmatics, similarly suggests that small airway abnormalities contribute to the pathogenesis of the disease. In this perspective, there could be a rationale for specifically assessing small airway impairment in these patients and for clinical studies evaluating whether pharmacological approaches targeting the more peripheral airways result in clinical benefits beyond conventional therapy.
There are increased numbers of activated T lymphocytes in the bronchial mucosa of stable chronic obstructive pulmonary disease (COPD) patients. T helper type 17 (Th17) cells release interleukin ...(IL)-17 as their effector cytokine under the control of IL-22 and IL-23. Furthermore, Th17 numbers are increased in some chronic inflammatory conditions. To investigate the expression of interleukin (IL)-17A, IL-17F, IL-21, IL-22 and IL-23 and of retinoic orphan receptor RORC2, a marker of Th17 cells, in bronchial biopsies from patients with stable COPD of different severity compared with age-matched control subjects. The expression of IL-17A, IL-17F, IL-21, IL-22, IL-23 and RORC2 was measured in the bronchial mucosa using immunohistochemistry and/or quantitative polymerase chain reaction. The number of IL-22⁺ and IL-23⁺ immunoreactive cells is increased in the bronchial epithelium of stable COPD compared with control groups. In addition, the number of IL-17A⁺ and IL-22⁺ immunoreactive cells is increased in the bronchial submucosa of stable COPD compared with control non-smokers. In all smokers, with and without disease, and in patients with COPD alone, the number of IL-22⁺ cells correlated significantly with the number of both CD4⁺ and CD8⁺ cells in the bronchial mucosa. RORC2 mRNA expression in the bronchial mucosa was not significantly different between smokers with normal lung function and COPD. Further, we report that endothelial cells express high levels of IL-17A and IL-22. Increased expression of the Th17-related cytokines IL-17A, IL-22 and IL-23 in COPD patients may reflect their involvement, and that of specific IL-17-producing cells, in driving the chronic inflammation seen in COPD.
•Vitexin-2-O-xyloside was purified from Beta vulgaris cicla seeds.•Betalains were purified from red beet root by anionic exchange chromatography.•Betalains increase vitexin-2-O-xyloside cytotoxicity ...in CaCo-2 colon cancer cells.•The cytotoxic effect is mediated by activation of an intrinsic apoptotic pathway.
Vitexin-2-O-xyloside (XVX) from Beta vulgaris var. cicla L. (BVc) seeds, betaxanthin (R1) and betacyanin (R2) fractions from Beta vulgaris var. rubra L. (BVr) roots were combined and tested for cytotoxicity in CaCo-2 colon cancer cells. XVX was the most cytotoxic molecule, but the combination of XVX with R1 and R2 significantly prolonged its cytotoxicity. Cytotoxicity was mediated by the intrinsic apoptotic pathway, as shown by an increase in Bcl2-like protein 4, cleaved Poly ADP-Ribosyl Polymerase 1 and cleaved Caspase 3 levels with a parallel decrease in anti-apoptotic protein B-cell leukemia/lymphoma 2 levels. R1 and R2, used alone or in combination, reduced oxidative stress triggered by H2O2 in CaCo-2 cells. Betalains dampened cyclooxygenase-2 and interleukin-8 mRNA expression after lipopolysaccharide induction in CaCo-2, showing an anti-inflammatory action. Our results support the use of a cocktail of R1, R2 and XVX as a chemopreventive tool against colon cancer.
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