| 1. |
- Andreasson, Jesper, et al.
(författare)
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Exhaled phospholipid transfer protein and hepatocyte growth factor receptor in lung adenocarcinoma
- 2022
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Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 23:1, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Screening decreases mortality among lung cancer patients but is not widely implemented, thus there is an unmet need for an easily accessible non-invasive method to enable early diagnosis. Particles in exhaled air offer a promising such diagnostic tool. We investigated the validity of a particles in exhaled air device (PExA) to measure the particle flow rate (PFR) and collect exhaled breath particles (EBP) to diagnose primary lung adenocarcinoma (LUAD).METHODS: Seventeen patients listed for resection of LUAD stages IA-IIIA and 18 non-cancer surgical control patients were enrolled. EBP were collected before and after surgery for LUAD, and once for controls. Proteomic analysis was carried out using a proximity extension assay technology. Results were validated in both plasma from the same cohort and with microarray data from healthy lung tissue and LUAD tissue in the GSE10072 dataset.RESULTS: Of the 92 proteins analyzed, levels of five proteins in EBP were significantly higher in the LUAD patients compared to controls. Levels of phospholipid transfer protein (PLTP) and hepatocyte growth factor receptor (MET) decreased in LUAD patients after surgery compared to control patients. PFR was significantly higher in the LUAD cohort at all timepoints compared to the control group. MET in plasma correlated significantly with MET in EBP.CONCLUSION: Collection of EBP and measuring of PFR has never been performed in patients with LUAD. In the present study PFR alone could distinguish between LUAD and patients without LUAD. PLTP and MET were identified as potential biomarkers to evaluate successful tumor excision.
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| 2. |
- Backman, Helena, et al.
(författare)
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Decreased COPD prevalence in Sweden after decades of decrease in smoking
- 2020
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Ingår i: Respiratory Research. - : Springer Nature. - 1465-9921 .- 1465-993X. ; 21
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundCOPD has increased in prevalence worldwide over several decades until the first decade after the millennium shift. Evidence from a few recent population studies indicate that the prevalence may be levelling or even decreasing in some areas in Europe. Since the 1970s, a substantial and ongoing decrease in smoking prevalence has been observed in several European countries including Sweden. The aim of the current study was to estimate the prevalence, characteristics and risk factors for COPD in the Swedish general population. A further aim was to estimate the prevalence trend of COPD in Northern Sweden from 1994 to 2009.MethodsTwo large random population samples were invited to spirometry with bronchodilator testing and structured interviews in 2009–2012, one in south-western and one in northern Sweden, n = 1839 participants in total. The results from northern Sweden were compared to a study performed 15 years earlier in the same area and age-span. The diagnosis of COPD required both chronic airway obstruction (CAO) and the presence of respiratory symptoms, in line with the GOLD documents since 2017. CAO was defined as post-bronchodilator FEV1/FVC < 0.70, with sensitivity analyses based on the FEV1/FVC < lower limit of normal (LLN) criterion.ResultsBased on the fixed ratio definition, the prevalence of COPD was 7.0% (men 8.3%; women 5.8%) in 2009–2012. The prevalence of moderate to severe (GOLD ≥ 2) COPD was 3.5%. The LLN based results were about 30% lower. Smoking, occupational exposures, and older age were risk factors for COPD, whereof smoking was the most dominating risk factor. In northern Sweden the prevalence of COPD, particularly moderate to severe COPD, decreased significantly from 1994 to 2009, and the decrease followed a decrease in smoking.ConclusionsThe prevalence of COPD has decreased in Sweden, and the prevalence of moderate to severe COPD was particularly low. The decrease follows a major decrease in smoking prevalence over several decades, but smoking remained the dominating risk factor for COPD.
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| 3. |
- Bandeira, Elga, et al.
(författare)
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Effects of mesenchymal stem cell-derived nanovesicles in experimental allergic airway inflammation
- 2023
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Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Allergic asthma is associated with airflow obstruction and hyper-responsiveness that arises from airway inflammation and remodeling. Cell therapy with mesenchymal stem cells (MSC) has been shown to attenuate inflammation in asthma models, and similar effects have recently been observed using extracellular vesicles (EV) obtained from these cells. Biologically functional vesicles can also be artificially generated from MSC by extruding cells through membranes to produce EV-mimetic nanovesicles (NV). In this study, we aimed to determine the effects of different MSC-derived vesicles in a murine model of allergic airway inflammation.Methods EV were obtained through sequential centrifugation of serum-free media conditioned by human bone marrow MSC for 24 h. NV were produced through serial extrusion of the whole cells through filters. Both types of vesicles underwent density gradient purification and were quantified through nanoparticle tracking analysis. C57BL/6 mice were sensitized to ovalbumin (OVA, 8 mu g), and then randomly divided into the OVA group (intranasally exposed to 100 mu g OVA for 5 days) and control group (exposed to PBS). The mice were then further divided into groups that received 2 x 10(9) EV or NV (intranasally or intraperitoneally) or PBS immediately following the first OVA exposure.Results Administration of EV and NV reduced cellularity and eosinophilia in bronchoalveolar lavage (BAL) fluid in OVA-sensitized and OVA-exposed mice. In addition, NV treatment resulted in decreased numbers of inflammatory cells within the lung tissue, and this was associated with lower levels of Eotaxin-2 in both BAL fluid and lung tissue. Furthermore, both intranasal and systemic administration of NV were effective in reducing inflammatory cells; however, systemic delivery resulted in a greater reduction of eosinophilia in the lung tissue.Conclusions Taken together, our results indicate that MSC-derived NV significantly reduce OVA-induced allergic airway inflammation to a level comparable to EV. Thus, cell-derived NV may be a novel EV-mimetic therapeutic candidate for treating allergic diseases such as asthma.
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| 4. |
- Bergwik, Jesper, et al.
(författare)
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A novel quinoline with airway relaxant effects and anti-inflammatory properties
- 2024
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Ingår i: Respiratory Research. - 1465-9921 .- 1465-993X. ; 25:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: In chronic pulmonary diseases characterized by inflammation and airway obstruction, such as asthma and COPD, there are unmet needs for improved treatment. Quinolines is a group of small heterocyclic compounds that have a broad range of pharmacological properties. Here, we investigated the airway relaxant and anti-inflammatory properties of a novel quinoline (RCD405). Methods: The airway relaxant effect of RCD405 was examined in isolated airways from humans, dogs, rats and mice. Murine models of ovalbumin (OVA)-induced allergic asthma and LPS-induced airway inflammation were used to study the effects in vivo. RCD405 (10 mg/kg) or, for comparisons in selected studies, budesonide (3 mg/kg), were administered intratracheally 1 h prior to each challenge. Airway responsiveness was determined using methacholine provocation. Immune cell recruitment to bronchi was measured using flow cytometry and histological analyses were applied to investigate cell influx and goblet cell hyperplasia of the airways. Furthermore, production of cytokines and chemokines was measured using a multiplex immunoassay. The expression levels of asthma-related genes in murine lung tissue were determined by PCR. The involvement of NF-κB and metabolic activity was measured in the human monocytic cell line THP-1. Results: RCD405 demonstrated a relaxant effect on carbachol precontracted airways in all four species investigated (potency ranking: human = rat > dog = mouse). The OVA-specific IgE and airway hyperresponsiveness (AHR) were significantly reduced by intratracheal treatment with RCD405, while no significant changes were observed for budesonide. In addition, administration of RCD405 to mice significantly decreased the expression of proinflammatory cytokines and chemokines as well as recruitment of immune cells to the lungs in both OVA- and LPS-induced airway inflammation, with a similar effect as for budesonide (in the OVA-model). However, the effect on gene expression of Il-4, IL-5 and Il-13 was more pronounced for RCD405 as compared to budesonide. Finally, in vitro, RCD405 reduced the LPS-induced NF-κB activation and by itself reduced cellular metabolism. Conclusions: RCD405 has airway relaxant effects, and it reduces AHR as well as airway inflammation in the models used, suggesting that it could be a clinically relevant compound to treat inflammatory airway diseases. Possible targets of this compound are complexes of mitochondrial oxidative phosphorylation, resulting in decreased metabolic activity of targeted cells as well as through pathways associated to NF-κB. However, further studies are needed to elucidate the mode of action.
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| 5. |
- Buschur, Kristina L., et al.
(författare)
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Distinct COPD subtypes in former smokers revealed by gene network perturbation analysis
- 2023
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Ingår i: Respiratory Research. - : Springer Nature. - 1465-9921 .- 1465-993X. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundChronic obstructive pulmonary disease (COPD) varies significantly in symptomatic and physiologic presentation. Identifying disease subtypes from molecular data, collected from easily accessible blood samples, can help stratify patients and guide disease management and treatment.MethodsBlood gene expression measured by RNA-sequencing in the COPDGene Study was analyzed using a network perturbation analysis method. Each COPD sample was compared against a learned reference gene network to determine the part that is deregulated. Gene deregulation values were used to cluster the disease samples.ResultsThe discovery set included 617 former smokers from COPDGene. Four distinct gene network subtypes are identified with significant differences in symptoms, exercise capacity and mortality. These clusters do not necessarily correspond with the levels of lung function impairment and are independently validated in two external cohorts: 769 former smokers from COPDGene and 431 former smokers in the Multi-Ethnic Study of Atherosclerosis (MESA). Additionally, we identify several genes that are significantly deregulated across these subtypes, including DSP and GSTM1, which have been previously associated with COPD through genome-wide association study (GWAS).ConclusionsThe identified subtypes differ in mortality and in their clinical and functional characteristics, underlining the need for multi-dimensional assessment potentially supplemented by selected markers of gene expression. The subtypes were consistent across cohorts and could be used for new patient stratification and disease prognosis.
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| 6. |
- Chen, Wenjia, et al.
(författare)
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Can we predict who will benefit most from biologics in severe asthma? : A post-hoc analysis of two phase 3 trials
- 2023
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Ingår i: Respiratory Research. - : BioMed Central (BMC). - 1465-9921 .- 1465-993X. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundIndividualized prediction of treatment response may improve the value proposition of advanced treatment options in severe asthma. This study aimed to investigate the combined capacity of patient characteristics in predicting treatment response to mepolizumab in patients with severe asthma.MethodsPatient-level data were pooled from two multinational phase 3 trials of mepolizumab in severe eosinophilic asthma. We fitted penalized regression models to quantify reductions in the rate of severe exacerbations and the 5-item Asthma Control Questionnaire (ACQ5) score. The capacity of 15 covariates towards predicting treatment response was quantified by the Gini index (measuring disparities in treatment benefit) as well as observed treatment benefit within the quintiles of predicted treatment benefit.ResultsThere was marked variability in the ability of patient characteristics to predict treatment response; covariates explained greater heterogeneity in predicting treatment response to asthma control than to exacerbation frequency (Gini index 0.35 v. 0.24). Key predictors for treatment benefit for severe exacerbations included exacerbation history, blood eosinophil count, baseline ACQ5 score and age, and those for symptom control included blood eosinophil count and presence of nasal polyps. Overall, the average reduction in exacerbations was 0.90/year (95%CI, 0.87-0.92) and average reduction in ACQ5 score was 0.18 (95% CI, 0.02-0.35). Among the top 20% of patients for predicted treatment benefit, exacerbations were reduced by 2.23/year (95% CI, 2.03-2.43) and ACQ5 score were reduced by 0.59 (95% CI, 0.19-0.98). Among the bottom 20% of patients for predicted treatment benefit, exacerbations were reduced by 0.25/year (95% CI, 0.16-0.34) and ACQ5 by -0.20 (95% CI, -0.51 to 0.11).ConclusionA precision medicine approach based on multiple patient characteristics can guide biologic therapy in severe asthma, especially in identifying patients who will not benefit as much from therapy. Patient characteristics had a greater capacity to predict treatment response to asthma control than to exacerbation.
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| 7. |
- Ekström, Magnus, et al.
(författare)
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Exertional breathlessness related to medical conditions in middle-aged people: the population-based SCAPIS study of more than 25,000 men and women.
- 2024
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Ingår i: Respiratory research. - : BioMed Central (BMC). - 1465-993X .- 1465-9921. ; 25:1
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Tidskriftsartikel (refereegranskat)abstract
- Breathlessness is common in the population and can be related to a range of medical conditions. We aimed to evaluate the burden of breathlessness related to different medical conditions in a middle-aged population.Cross-sectional analysis of the population-based Swedish CArdioPulmonary bioImage Study of adults aged 50-64years. Breathlessness (modified Medical Research Council [mMRC]≥2) was evaluated in relation to self-reported symptoms, stress, depression; physician-diagnosed conditions; measured body mass index (BMI), spirometry, venous haemoglobin concentration, coronary artery calcification and stenosis [computer tomography (CT) angiography], and pulmonary emphysema (high-resolution CT). For each condition, the prevalence and breathlessness population attributable fraction (PAF) were calculated, overall and by sex, smoking history, and presence/absence of self-reported cardiorespiratory disease.We included 25,948 people aged 57.5±[SD] 4.4; 51% women; 37% former and 12% current smokers; 43% overweight (BMI 25.0-29.9), 21% obese (BMI≥30); 25% with respiratory disease, 14% depression, 9% cardiac disease, and 3% anemia. Breathlessness was present in 3.7%. Medical conditions most strongly related to the breathlessness prevalence were (PAF 95%CI): overweight and obesity (59.6-66.0%), stress (31.6-76.8%), respiratory disease (20.1-37.1%), depression (17.1-26.6%), cardiac disease (6.3-12.7%), anemia (0.8-3.3%), and peripheral arterial disease (0.3-0.8%). Stress was the main factor in women and current smokers.Breathlessness mainly relates to overweight/obesity and stress and to a lesser extent to comorbidities like respiratory, depressive, and cardiac disorders among middle-aged people in a high-income setting-supporting the importance of lifestyle interventions to reduce the burden of breathlessness in the population.
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| 8. |
- Ekström, Magnus, et al.
(författare)
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Research race-specific reference values and lung function impairment, breathlessness and prognosis : Analysis of NHANES 2007–2012
- 2022
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Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Spirometry reference values differ by race/ethnicity, which is controversial. We evaluated the effect of race-specific references on prevalence of lung function impairment and its relation to breathlessness and mortality in the US population. Methods: Population-based analysis of the National Health and Nutrition Examination Survey (NHANES) 2007–2012. Race/ethnicity was analyzed as black, white, or other. Reference values for forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were calculated for each person using the Global Lung Initiative (GLI)-2012 equations for (1) white; (2) black; and (3) other/mixed people. Outcomes were prevalence of lung function impairment (< lower limit of normal [LLN]), moderate/severe impairment (< 50%pred); exertional breathlessness; and mortality until 31 December, 2015. Results: We studied 14,123 people (50% female). Compared to those for white, black reference values identified markedly fewer cases of lung function impairment (FEV1) both in black people (9.3% vs. 36.9%) and other non-white (1.5% vs. 9.5%); and prevalence of moderate/severe impairment was approximately halved. Outcomes by impairment differed by reference used: white (best), other/mixed (intermediate), and black (worst outcomes). Black people with FEV1 ≥ LLNblack but < LLNwhite had 48% increased rate of breathlessness and almost doubled mortality, compared to blacks ≥ LLNwhite. White references identified people with good outcomes similarly in black and white people. Findings were similar for FEV1 and FVC. Conclusion: Compared to using a common reference (for white) across the population, race-specific spirometry references did not improve prediction of breathlessness and prognosis, and may misclassify lung function as normal despite worse outcomes in black people.
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| 9. |
- Emilsson, Össur Ingi, et al.
(författare)
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Exhaled biomarkers in adults with non-productive cough
- 2023
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Ingår i: Respiratory Research. - : BioMed Central (BMC). - 1465-9921 .- 1465-993X. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundChronic cough is a common condition but disease mechanisms are not fully understood. Our aim was to study respiratory biomarkers from the small airways in individuals with non-productive cough.MethodsA cohort of 107 participants answered detailed questionnaires, performed spirometry, exhaled NO measurement, impulse oscillometry, gave blood samples and particles in exhaled air (PEx) samples. Current smokers (N = 38) were excluded. A total of 14 participants reported non-productive cough (cases). A total of 55 participants reported no cough (control group). PEx samples, containing exhaled particles derived from small airways, were collected and analysed with the SOMAscan proteomics platform.ResultsParticipants with non-productive cough had similar age, sex, BMI, and inflammation markers in blood tests, as participants without cough. The proteomics analysis found 75 proteins significantly altered among participants with chronic cough compared to controls, after adjusting for sex and investigator performing the PExA measurement (all with p-value < 0.05 and q-value ≤ 0.13, thereof 21 proteins with a q-value < 0.05). These proteins were mostly involved in immune and inflammatory responses, complement and coagulation system, but also tight junction proteins and proteins involved in neuroinflammatory responses.ConclusionsThis exploratory study on proteomics of exhaled particles among individuals with chronic cough found alterations in relative abundance of 75 proteins. The proteins identified are implicated in both pathways known to be implicated in cough, but also potentially new pathways. Further studies are needed to explore the importance of these findings.
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| 10. |
- Eriksson Ström, Jonas, et al.
(författare)
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Airway regulatory T cells are decreased in COPD with a rapid decline in lung function
- 2020
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Ingår i: Respiratory Research. - : BioMed Central. - 1465-9921 .- 1465-993X. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Differences in the expression of regulatory T cells (Tregs) have been suggested to explain why some smokers develop COPD and some do not. Upregulation of Tregs in response to smoking would restrain airway inflammation and thus the development of COPD; while the absense of such upregulation would over time lead to chronic inflammation and COPD. We hypothesized that—among COPD patients—the same mechanism would affect rate of decline in lung function; specifically, that a decreased expression of Tregs would be associated with a more rapid decline in FEV1.Methods: Bronchoscopy with BAL was performed in 52 subjects recruited from the longitudinal OLIN COPD study; 12 with COPD and a rapid decline in lung function (loss of FEV1 ≥ 60 ml/year), 10 with COPD and a non-rapid decline in lung function (loss of FEV1 ≤ 30 ml/year), 15 current and ex-smokers and 15 non-smokers with normal lung function. BAL lymphocyte subsets were determined using flow cytometry.Results: The proportions of Tregs with regulatory function (FoxP3+/CD4+CD25bright) were significantly lower in COPD subjects with a rapid decline in lung function compared to those with a non-rapid decline (p = 0.019). This result was confirmed in a mixed model regression analysis in which adjustments for inhaled corticosteroid usage, smoking, sex and age were evaluated. No significant difference was found between COPD subjects and smokers or non-smokers with normal lung function.Conclusions: COPD subjects with a rapid decline in lung function had lower proportions of T cells with regulatory function in BAL fluid, suggesting that an inability to suppress the inflammatory response following smoking might lead to a more rapid decline in FEV1.
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