| 141. |
- Siddhuraj, Premkumar, et al.
(författare)
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Lung Mast Cells Have a High Constitutive Expression of Carboxypeptidase A3 mRNA That Is Independent from Granule-Stored CPA3
- 2021
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 10:2
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Tidskriftsartikel (refereegranskat)abstract
- The mast cell granule metalloprotease CPA3 is proposed to have important tissue homeostatic functions. However, the basal CPA3 mRNA and protein expression among mast cell populations has remained poorly investigated. Using a novel histology-based methodology that yields quantitative data on mRNA and protein expression at a single-cell level, the present study maps CPA3 mRNA and protein throughout the MCT and MCTC populations in healthy skin, gut and lung tissues. MCTC cells had both a higher frequency of CPA3 protein-containing cells and a higher protein-staining intensity than the MCT population. Among the tissues, skin MCs had highest CPA3 protein intensity. The expression pattern at the mRNA level was reversed. Lung mast cells had the highest mean CPA3 mRNA staining. Intriguingly, the large alveolar MCT population, that lack CPA3 protein, had uniquely high CPA3 mRNA intensity. A broader multi-tissue RNA analysis confirmed the uniquely high CPA3 mRNA quantities in the lung and corroborated the dissociation between chymase and CPA3 at the mRNA level. Taken together, our novel data suggest a hitherto underestimated contribution of mucosal-like MCT to baseline CPA3 mRNA production. The functional consequence of this high constitutive expression now reveals an important area for further research.
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| 142. |
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| 143. |
- Skogvall, Staffan, et al.
(författare)
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Oral iodinated activated charcoal improves lung function in patients with COPD.
- 2014
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Ingår i: Respiratory Medicine. - : Elsevier BV. - 1532-3064 .- 0954-6111. ; 108:6, s. 905-909
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Tidskriftsartikel (refereegranskat)abstract
- The effect of 8 weeks treatment with oral iodinated activated charcoal (IAC) on lung function of patients with moderate chronic obstructive pulmonary disease (COPD) was examined in a double blind randomized placebo controlled parallel group study with 40 patients. In the IAC group, patients showed a statistically significant improvement of FEV1 baseline by 130 ml compared to placebo, corresponding to 8.2% improvement (p = 0.031*). Correlation statistics revealed that the improvement of FEV1 baseline was significantly correlated both to FEV1 post-bronchodilator (p = 0.0020**) and FEV1 post-exercise (0.033*) values. This demonstrates that the improved baseline lung function by IAC did not inhibit a further beta2-adrenoceptor relaxation, and thus that patients did not reach a limit for maximal improvement of the lung function after IAC treatment. Eight patients in the IAC group developed abnormal thyroid hormone levels transiently during the treatment. This side effect was not correlated to improvement of lung function (p = 0.82). No serious adverse effects directly related to the treatment were recorded. In summary, this study demonstrates that iodinated activated charcoal surprisingly and significantly improved lung function of patients with moderate COPD. The underlying mechanism of action is unclear, but is likely to be different from the drugs used today. The immediate conclusion is that further studies are now justified in order to determine clinical efficacy of IAC in COPD and explore possible mechanisms of action.
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| 144. |
- Strickson, Sam, et al.
(författare)
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Oxidised IL-33 drives COPD epithelial pathogenesis via ST2-independent RAGE/EGFR signalling complex
- 2023
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Ingår i: European Respiratory Journal. - 0903-1936. ; 62:3
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Tidskriftsartikel (refereegranskat)abstract
- Background Epithelial damage, repair and remodelling are critical features of chronic airway diseases including chronic obstructive pulmonary disease (COPD). Interleukin (IL)-33 released from damaged airway epithelia causes inflammation via its receptor, serum stimulation-2 (ST2). Oxidation of IL-33 to a non-ST2-binding form (IL-33ox) is thought to limit its activity. We investigated whether IL-33ox has functional activities that are independent of ST2 in the airway epithelium. Methods In vitro epithelial damage assays and three-dimensional, air–liquid interface (ALI) cell culture models of healthy and COPD epithelia were used to elucidate the functional role of IL-33ox. Transcriptomic changes occurring in healthy ALI cultures treated with IL-33ox and COPD ALI cultures treated with an IL-33-neutralising antibody were assessed with bulk and single-cell RNA sequencing analysis. Results We demonstrate that IL-33ox forms a complex with receptor for advanced glycation end products (RAGE) and epidermal growth factor receptor (EGFR) expressed on airway epithelium. Activation of this alternative, ST2-independent pathway impaired epithelial wound closure and induced airway epithelial remodelling in vitro. IL-33ox increased the proportion of mucus-producing cells and reduced epithelial defence functions, mimicking pathogenic traits of COPD. Neutralisation of the IL-33ox pathway reversed these deleterious traits in COPD epithelia. Gene signatures defining the pathogenic effects of IL-33ox were enriched in airway epithelia from patients with severe COPD. Conclusions Our study reveals for the first time that IL-33, RAGE and EGFR act together in an ST2-independent pathway in the airway epithelium and govern abnormal epithelial remodelling and mucoobstructive features in COPD.
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| 145. |
- Subramaniyam, Devipriya, et al.
(författare)
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Secretory Leukocyte Protease Inhibitor inhibits neutrophil apoptosis.
- 2011
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Ingår i: Respirology. - : Wiley. - 1440-1843 .- 1323-7799. ; Dec, s. 300-307
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Tidskriftsartikel (refereegranskat)abstract
- SUMMARY AT A GLANCE: Secretory leukocyte proteinase inhibitor (SLPI) is a major anti-elastase barrier at the epithelial surfaces of upper respiratory tract. Our findings indicate clear up-regulation of SLPI in response to endotoxin in nasal secretions. In addition, SLPI shows dose-dependent anti-apoptotic and chemotactic effects on primary human neutrophils. ABSTRACT: Background and objective: The Secretory Leukocyte Protease Inhibitor (SLPI) is a major anti-elastase barrier at the epithelial surfaces of upper respiratory tract. In addition to its anti-protease activity, SLPI has been shown to express anti-bacterial, anti-viral and anti-inflammatory properties. Methods: We measured SLPI concentration in nasal lavage fluid of healthy volunteers after challenge with endotoxin (LPS) and evaluated SLPI effects in vitro on neutrophil chemotaxis, adhesion, cytokine (IL-8) release and apoptosis. Results: SLPI concentration in nasal lavage (n = 9) 2, 6 and 24 hrs after the challenge with LPS (25 µg) increased from 32% to 238% compared to baseline (226 ± 71 ng/ml). In vitro, SLPI (20 to 80µg/ml) induced neutrophil chemotaxis (6-fold, p < 0.001) and decreased neutrophil apoptosis by 73% (p = 0.006), relative to controls. However, SLPI had no affect on IL-8 release or neutrophil adhesion to fibronectin. SLPI-positive immunoreactivity was co-localised with neutrophils in lung specimens from patients with chronic obstructive pulmonary disease. Conclusions: Our findings indicate up-regulation of SLPI in response to LPS in nasal secretions and show anti-apoptotic effects of SLPI in primary human neutrophils suggesting a new role of SLPI during neutrophilic inflammation.
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| 146. |
- Sverrild, Asger, et al.
(författare)
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Airway responsiveness to mannitol in asthma is associated with chymase-positive mast cells and eosinophilic airway inflammation.
- 2016
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Ingår i: Clinical and Experimental Allergy. - : Wiley. - 1365-2222 .- 0954-7894. ; 46:2, s. 288-297
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Tidskriftsartikel (refereegranskat)abstract
- Airway hyperresponsiveness (AHR) to inhaled mannitol is associated with indirect markers of mast cell activation and eosinophilic airway inflammation. It is unknown how AHR to mannitol relates to mast cell phenotype, mast cell function and measures of eosinophilic inflammation in airway tissue. We compared the number and phenotype of mast cells, mRNA expression of mast cell associated genes and number of eosinophils in airway tissue of subjects with asthma and healthy controls in relation to AHR to mannitol.
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| 147. |
- Sverrild, Asger, et al.
(författare)
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Eosinophilic airway inflammation in asthmatic patients is associated with an altered airway microbiome
- 2017
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749. ; 140:2, s. 11-417
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Tidskriftsartikel (refereegranskat)abstract
- Background: Asthmatic patients have higher microbiome diversity and an altered composition, with more Proteobacteria and less Bacteroidetes compared with healthy control subjects. Studies comparing airway inflammation and the airway microbiome are sparse, especially in subjects not receiving anti-inflammatory treatment. Objective: We sought to describe the relationship between the airway microbiome and patterns of airway inflammation in steroid-free patients with asthma and healthy control subjects. Methods: Bronchoalveolar lavage fluid was collected from 23 steroid-free nonsmoking patients with asthma and 10 healthy control subjects. Bacterial DNA was extracted from and subjected to Illumina MiSeq sequencing of the 16S rDNA V4 region. Eosinophils and neutrophils in the submucosa were quantified by means of immunohistochemical identification and computerized image analysis. Induced sputum was obtained, and airway hyperresponsiveness to mannitol and fraction of exhaled nitric oxide values were measured. Relationships between airway microbial diversity and composition and inflammatory profiles were analyzed. Results: In asthmatic patients airway microbial composition was associated with airway eosinophilia and AHR to mannitol but not airway neutrophilia. The overall composition of the airway microbiome of asthmatic patients with the lowest levels of eosinophils but not asthmatic patients with the highest levels of eosinophils deviated significantly from that of healthy subjects. Asthmatic patients with the lowest levels of eosinophils had an altered bacterial abundance profile, with more Neisseria, Bacteroides, and Rothia species and less Sphingomonas, Halomonas, and Aeribacillus species compared with asthmatic patients with more eosinophils and healthy control subjects. Conclusion: The level of eosinophilic airway inflammation correlates with variations in the microbiome across asthmatic patients, whereas neutrophilic airway inflammation does not. This warrants further investigation on molecular pathways involved in both patients with eosinophilic and those with noneosinophilic asthma.
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| 148. |
- Sverrild, Asger, et al.
(författare)
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The effect of tezepelumab on airway hyperresponsiveness to mannitol in asthma (UPSTREAM)
- 2022
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Ingår i: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 59:1
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Tidskriftsartikel (refereegranskat)abstract
- RATIONALE AND OBJECTIVES: Thymic stromal lymphopoietin (TSLP), an epithelial upstream cytokine, initiates production of type-2 (T2) cytokines with eosinophilia and possibly airway hyperresponsiveness (AHR) in asthma.This study aimed to determine whether tezepelumab (a human monoclonal antibody targeting TSLP) decreases AHR and airway inflammation in patients with symptomatic asthma on maintenance treatment with inhaled corticosteroids.METHODS AND MEASUREMENTS: In this double-blind, placebo-controlled randomised trial adult patients with asthma and AHR to mannitol received either 700 mg tezepelumab or placebo intravenously at 4-week intervals for 12 weeks. AHR to mannitol was assessed, and a bronchoscopy was performed at baseline and after 12 weeks. The primary outcome was the change in AHR from baseline to week-12 and secondary outcomes were changes in airway inflammation.RESULTS: Forty patients were randomised to receive either tezepelumab (n=20) or placebo (n=20). The mean change in PD15 with tezepelumab was 1.9 DD (95% CI 1.2 to 2.5) versus 1·0 (95% CI 0.3 to 1.6) with placebo; p=0.06. Nine (45%) tezepelumab and three (16%) placebo patients had a negative PD15 test at week-12, p=0.04. Airway tissue and BAL eosinophils decreased by 74% (95% CI -53 to -86) and 75% (95% CI -53 to -86) respectively with tezepelumab compared with an increase of 28% (95% CI -39 to 270) and a decrease of 7% (95% CI -49 to 72) respectively with placebo, p=0.004 and p=0.01.CONCLUSIONS: Inhibiting TSLP-signalling with tezepelumab reduced the proportion of patients with AHR and decreased eosinophilic inflammation in BAL and airway tissue.
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| 149. |
- Swärd, Karl, et al.
(författare)
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Elevated pulmonary arterial pressure and altered expression of Ddah1 and Arg1 in mice lacking cavin-1/PTRF.
- 2013
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Ingår i: Physiological Reports. - 2051-817X. ; 1:1, s. 00008-00008
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Tidskriftsartikel (refereegranskat)abstract
- Caveolae are invaginations in the plasma membrane that depend on caveolins and cavins for maturation. Here, we investigated the pulmonary phenotype in mice lacking cavin-1. Bright field and electron-microscopy showed that the cavin-1-deficient mice lacked caveolae in the lung, had an increased lung tissue density, and exhibited hypertrophic remodeling of pulmonary arteries. The right ventricle of the heart moreover had an increased mass and the right ventricular pressure was elevated. A microarray analysis revealed upregulation of Arg1 and downregulation of Ddah1, molecules whose altered expression has previously been associated with pulmonary arterial hypertension. Taken together, this work demonstrates vascular remodeling and increased pulmonary blood pressure in cavin-1 deficient mice and associates this phenotype with altered expression of Arg1 and Ddah1.
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| 150. |
- Sönnerfors, Pernilla, et al.
(författare)
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The challenges of recruiting never-smokers with chronic obstructive pulmonary disease from the large population-based Swedish CArdiopulmonary bioImage study (SCAPIS) cohort.
- 2024
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Ingår i: European Clinical Respiratory Journal. - : Taylor & Francis. - 2001-8525. ; 11:1, s. 2372903-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A substantial proportion of individuals with COPD have never smoked, and it is implied to be more common than previously anticipated but poorly studied.AIM: To describe the process of recruitment of never-smokers with COPD from a population-based cohort (n = 30 154).METHODS: We recruited never-smokers with COPD, aged 50-75 years, from six University Hospitals, based on: 1) post broncho-dilator forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) < 0.70 and 2) FEV1 50-100% of predicted value and 3) being never-smokers (self-reported). In total 862 SCAPIS participants were identified, of which 652 were reachable and agreed to a first screening by telephone. Altogether 128 (20%) were excluded due to previous smoking or declined participation. We also applied a lower limit of normal (LLN) of FEV1/FVC (z-score<-1.64) according to the Global Lung Initiative to ensure a stricter definition of airflow obstruction.RESULTS: Data on respiratory symptoms, health status, and medical history were collected from 492 individuals, since 32 were excluded at a second data review (declined or previous smoking), prior to the first visit. Due to not matching the required lung function criteria at a second spirometry, an additional 334 (68%) were excluded. These exclusions were by reason of: FEV1/FVC ≥0.7 (49%), FEV1 > 100% of predicted (26%) or z-score ≥ -1,64 (24%). Finally, 154 never-smokers with COPD were included: 56 (36%) women, (mean) age 60 years, FEV1 84% of predicted, FEV1/FVC: 0.6, z-score: -2.2, Oxygen saturation: 97% and BMI: 26.8 kg/m2.CONCLUSIONS: The challenges of a recruitment process of never-smokers with COPD were shown, including the importance of correct spirometry testing and strict inclusion criteria. Our findings highlight the importance of repeated spirometry assessments for improved accuracy in diagnosing COPD.
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