| 1. |
- Aidoukovitch, Alexandra, et al.
(författare)
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Antimicrobial peptide LL-37 and its pro-form, hCAP18, in desquamated epithelial cells of human whole saliva
- 2020
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Ingår i: European Journal of Oral Sciences. - : Wiley. - 0909-8836 .- 1600-0722. ; 128:1, s. 1-6
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Tidskriftsartikel (refereegranskat)abstract
- The antimicrobial peptide LL-37 is active against oral bacteria and has been demonstrated to be present in human saliva, but its distribution in different fractions of saliva is not known. LL-37 is formed from its intracellular pro-form, hCAP18, in an extracellular enzymatic reaction catalyzed by proteinase 3 and kallikrein 5. Here, we prepared cell-containing and cell-free fractions of unstimulated human whole saliva by centrifugation after depolymerization of mucins with dithiothreitol, and measured the levels of hCAP18/LL-37 in these fractions using ELISA. Cellular expression of hCAP18/LL-37 was determined by western blotting and immunocytochemistry. The ELISA analyses demonstrated that both cells and cell-free saliva contained hCAP18/LL-37. Western blot analysis of cell-pellet homogenates showed a strong band corresponding to hCAP18 at the correct molecular weight and a weak band corresponding to LL-37. Phase-contrast and light microscopy revealed that the cells consisted of desquamated epithelial cells. These cells expressed cytoplasmic immunoreactivity for hCAP18/LL-37. The peripheral part of the cytoplasm, corresponding to the plasma membrane, was particularly rich in hCAP18/LL-37 immunoreactivity. No immunoreactivity was observed after omission of the primary antibody. We conclude that desquamated epithelial cells of human whole saliva contain antimicrobial hCAP18/LL-37, suggesting that these cells may take part in the innate immune system by harboring and releasing these peptides.
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| 2. |
- Aidoukovitch, Alexandra, et al.
(författare)
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Desquamated Epithelial Cells of Unstimulated Human Whole Saliva Express Both EGF Transcript and Protein
- 2022
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Ingår i: International Journal of Dentistry. - : Hindawi Limited. - 1687-8728 .- 1687-8736. ; 2022, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The aim of this study was to investigate if desquamated oral epithelial cells (DOECs) express the epidermal growth factor (EGF) and if these cells thereby may contribute to salivary EGF contents.BACKGROUND: DOECs have recently been shown to harbor the antimicrobial peptide LL-37, proposing that they may also store other biologically important salivary peptides/proteins. The EGF peptide is a growth factor which plays a critical role to maintain epithelial integrity and promote epithelial healing. The EGF is produced by salivary glands, but it is not known whether DOECs contain the EGF and thereby contribute to salivary EGF levels.MATERIALS AND METHODS: DOECs were isolated from unstimulated whole saliva collected from four healthy volunteers. EGF protein expression was determined in cell lysates by dot blot and ELISA. Cellular distribution of cytokeratin, the proliferation marker Ki67, and EGF immunoreactivity were assessed by immunocytochemistry. EGF gene expression was investigated by qPCR. Expression of EGF transcript and protein in DOECs was compared to that in the human cultured keratinocyte cell line (HaCaT) cells.RESULTS: EGF protein expression was detected in DOEC cell lysates by both dot blot and ELISA. Strong cytoplasmic EGF immunoreactivity was observed in DOECs, although some cells showed only a weak immunoreactive signal for EGF. Moreover, DOECs, besides containing EGF protein, also expressed transcript for EGF. Interestingly, ELISA analysis revealed that EGF protein contents were higher in DOECs than in HaCaT cells. ELISA analysis also disclosed that EGF concentration was about 10 times higher in whole saliva compared to DOECs. EGF transcript expression was about 50% lower in HaCaT cells stimulated with high (10%) compared to low (0.1%) concentration of fetal bovine serum, representing growth-stimulated and growth-restricted conditions, respectively, implying that growth-stimulus exerts negative feedback on EGF gene activity in HaCaT cells.CONCLUSION: Here, we show for the first time that DOECs express the EGF, arguing that these cells contribute to salivary EGF contents and hence may play a role in gingival epithelial repair and wound healing.
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| 3. |
- Andersson, Cecilia, et al.
(författare)
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Alveolar mast cells shift to an FcεRI-expressing phenotype in mild atopic asthma: a novel feature in allergic asthma pathology.
- 2011
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Ingår i: Allergy. - : Wiley. - 1398-9995 .- 0105-4538. ; 66:12, s. 1590-1597
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Tidskriftsartikel (refereegranskat)abstract
- Background: A unique feature of alveolar mast cells is their low high-affinity IgE receptor (FcεRI) expression. Recent discoveries in uncontrolled asthma suggest that the appearance of FcεRI-expressing alveolar mast cells may be a novel disease-specific feature of allergic asthma. This study investigates whether increased FcεRI-expressing alveolar mast cells are present in patients with mild allergic asthma or even in non-asthmatic allergic rhinitis patients (AR) who have developed bronchial hyperactivity (BHR). Methods: Bronchial and alveolar tissues were obtained from healthy controls, AR patients with or without BHR, and AR patients with concurrent asthma. Samples were processed for immunohistochemical identification of MC(T) and MC(TC) and expression of FcεRI and surface-bound IgE. Results: Bronchial mast cell expression of FcεRI was high in all groups. In contrast, in the alveolar tissue, the expression of FcεRI on mast cells was low in healthy controls and in the AR patient groups, whereas a high expression was present in AR patients with concurrent asthma (P = 0.006 compared to controls). The asthmatics had a 29-fold increase in numbers (P = 0.006) and a 19-fold increase in proportion (P = 0.007) of alveolar mast cells that expressed surface-bound IgE. Conclusions: The present data show that alveolar mast cells in patients with mild atopic asthma, but not atopic patients with AR, have turned into a highly FcεRI- and IgE-expressing phenotype. These data support the hypothesis that increased FcεRI expression on alveolar mast cells is a novel disease-specific feature of allergic asthma that is important for understanding asthma phenotypes and designing new therapeutic strategies.
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| 4. |
- Andersson, Cecilia, et al.
(författare)
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Revisiting the role of the mast cell in asthma.
- 2016
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Ingår i: Current Opinion in Pulmonary Medicine. - 1531-6971. ; 22:1, s. 10-17
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Forskningsöversikt (refereegranskat)abstract
- In humans, mast cells are ubiquitously present in tissues adjacent to external environment and consequently have an important sentential role in host defence, homeostasis and repair. Their key role in allergen-mediated conditions has been recognized for many decades already. So far, therapies targeting mast cells offered clinical efficacy in allergic conditions except for asthma. More recently, sophisticated sampling and detection techniques revealed pleiotrophic immunological and functional properties of mast cells in and beyond asthma with potential clinical and management implications. These findings bring back the mast cell as a key player in the field of asthma and warrant a review of the recent literature.
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| 5. |
- Aronsson, David, et al.
(författare)
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Airway resistance and reactance are affected in systemic sclerosis.
- 2015
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Ingår i: European clinical respiratory journal. - : Informa UK Limited. - 2001-8525. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- Interstitial lung disease often occurs as an early complication of systemic sclerosis (SSc). The aim was to investigate whether impulse oscillometry (IOS) could be used to evaluate lung impairment in SSc.
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| 6. |
- Aronsson, David, et al.
(författare)
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Allergic rhinitis with hyper-responsiveness differ from asthma in degree of peripheral obstruction during metacholine challenge test.
- 2008
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Ingår i: Clinical Physiology and Functional Imaging. - 1475-0961. ; 28:2, s. 81-85
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Tidskriftsartikel (refereegranskat)abstract
- Allergic rhinitis (AR) is a risk factor for developing clinical asthma. Moreover, AR is often associated with bronchial hyper-responsiveness (BHR). The aim of this study was to compare the degree of involvement of the peripheral airways during metacholine (MCh) challenge test in asthmatics and patients with AR with or without BHR by using the impulse oscillometry (IOS) technique. Fifty-three patients with seasonal AR were investigated with MCh challenge test and IOS. Thirteen healthy non-reactive subjects served as controls. MCh challenge test was performed, cut-off value FEV1PD20 2000 μg. Linear regression analysis was used to calculate a MCh/FEV1 slope (Slope-FEV1MCh), which was used as an index of BHR. IOS was performed, measuring respiratory resistance and reactance during the MCh challenge test. Twenty-six subjects had both AR and asthma symptoms, 27 patients reported AR only, without asthma symptoms, 17 (63%) manifested BHR by spirometric criteria. Patients with AR and symptoms of asthma manifested greater peripheral airway obstruction compared to those with AR only with BHR. Increased peripheral obstruction in the asthmatic group compared to patients with AR and BHR may explain previous findings that asthmatics perceive greater airway obstruction during MCh challenge tests.
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| 7. |
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| 8. |
- Aronsson, David, et al.
(författare)
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Comparison of central and peripheral airway involvement before and during methacholine, mannitol and eucapnic hyperventilation challenges in mild asthmatics.
- 2011
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Ingår i: Clinical Respiratory Journal. - 1752-6981. ; 5:1, s. 41565-41565
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Testing for airway hyperresponsiveness with indirect stimuli as exercise or mannitol has been proposed to better reflect underlying airway inflammation, as compared with methacholine (MCh), believed to act directly on airway smooth muscle cells. Objective: To investigate whether different direct and indirect stimuli induces different patterns of obstruction, recorded as central and peripheral resistance, and to see whether baseline resistance could predict a positive response to direct or indirect provocation. Methods: Thirty-four mild asthmatics and 15 controls underwent MCh, mannitol and eucapnic voluntary hyperventilation (EVH) challenge tests. The response was evaluated with spirometry and impulse oscillometry (IOS). Results: Twenty-three out of 34 asthmatics were positive to either EVH (22) or mannitol (13). Those positive to mannitol had a significant increased baseline value of IOS parameters such as ΔR5-R20 and AX. Twelve of the asthmatics had a 10% fall or more in forced expiratory volume in 1 s (FEV(1) ) in all three challenge tests. However, the response pattern measured by IOS did not differ between the tests. When the limit for a positive mannitol provocation was set to 10% fall in FEV(1) , 16 out of 19 mannitol-positive patients were also positive to EVH. Conclusion: Even in mild asthmatics, a substantial number had a positive indirect test. Mannitol FEV(1) provocative dose to decrease FEV(1) by 10% from baseline (PD10) was closely associated to EVH10%. No difference in bronchoconstrictive pattern could be seen between the different provocation tests, but those positive to mannitol had more peripheral airway involvement at baseline. This supports the idea that peripheral airway involvement is an important predictor of asthma airway reactivity. Please cite this paper as: Aronsson D, Tufvesson E, Bjermer L. Comparison of central and peripheral airway involvement before and during methacholine, mannitol and eucapnic hyperventilation challenges in mild asthmatics. Clin Respir J 2011; 5: 10-18.
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| 9. |
- Backer, Vibeke, et al.
(författare)
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Clinical characteristics of the BREATHE cohort–a real-life study on patients with asthma and COPD
- 2020
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Ingår i: European clinical respiratory journal. - : Informa UK Limited. - 2001-8525. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The BREATHE study is a cross-sectional study of real-life patients with asthma and/or COPD in Denmark and Sweden aiming to increase the knowledge across severities and combinations of obstructive airway disease. Design: Patients with suspicion of asthma and/or COPD and healthy controls were invited to participate in the study and had a standard evaluation performed consisting of questionnaires, physical examination, FeNO and lung function, mannitol provocation test, allergy test, and collection of sputum and blood samples. A subgroup of patients and healthy controls had a bronchoscopy performed with a collection of airway samples. Results: The study population consisted of 1403 patients with obstructive airway disease (859 with asthma, 271 with COPD, 126 with concurrent asthma and COPD, 147 with other), and 89 healthy controls (smokers and non-smokers). Of patients with asthma, 54% had moderate-to-severe disease and 46% had mild disease. In patients with COPD, 82% had groups A and B, whereas 18% had groups C and D classified disease. Patients with asthma more frequently had childhood asthma, atopic dermatitis, and allergic rhinitis, compared to patients with COPD, asthma + COPD and Other, whereas FeNO levels were higher in patients with asthma and asthma + COPD compared to COPD and Other (18 ppb and 16 ppb vs 12.5 ppb and 14 ppb, p < 0.001). Patients with asthma, asthma + COPD and Other had higher sputum eosinophilia (1.5%, 1.5%, 1.2% vs 0.75%, respectively, p < 0.001) but lower sputum neutrophilia (39.3, 43.5%, 40.8% vs 66.8%, p < 0.001) compared to patients with COPD. Conclusions: The BREATHE study provides a unique database and biobank with clinical information and samples from 1403 real-life patients with asthma, COPD, and overlap representing different severities of the diseases. This research platform is highly relevant for disease phenotype- and biomarker studies aiming to describe a broad spectrum of obstructive airway diseases.
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| 10. |
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| 11. |
- Berggren-Nylund, Rebecca, et al.
(författare)
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Effects of hypoxia on bronchial and alveolar epithelial cells linked to pathogenesis in chronic lung disorders
- 2023
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Ingår i: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 14, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Chronic lung disorders involve pathological alterations in the lung tissue with hypoxia as a consequence. Hypoxia may influence the release of inflammatory mediators and growth factors including vascular endothelial growth factor (VEGF) and prostaglandin (PG)E 2. The aim of this work was to investigate how hypoxia affects human lung epithelial cells in combination with profibrotic stimuli and its correlation to pathogenesis. Methods: Human bronchial (BEAS-2B) and alveolar (hAELVi) epithelial cells were exposed to either hypoxia (1% O 2) or normoxia (21% O 2) during 24 h, with or without transforming growth factor (TGF)-β1. mRNA expression of genes and proteins related to disease pathology were analysed with qPCR, ELISA or immunocytochemistry. Alterations in cell viability and metabolic activity were determined. Results: In BEAS-2B and hAELVi, hypoxia significantly dowregulated genes related to fibrosis, mitochondrial stress, oxidative stress, apoptosis and inflammation whereas VEGF receptor 2 increased. Hypoxia increased the expression of Tenascin-C, whereas both hypoxia and TGF-β1 stimuli increased the release of VEGF, IL-6, IL-8 and MCP-1 in BEAS-2B. In hAELVi, hypoxia reduced the release of fibroblast growth factor, epidermal growth factor, PGE 2, IL-6 and IL-8, whereas TGF-β1 stimulus significantly increased the release of PGE 2 and IL-6. TGF-β1 stimulated BEAS-2B cells showed a decreased release of VEGF-A and IL-8, while TGF-β1 stimulated hAELVi cells showed a decreased release of PGE 2 and IL-8 during hypoxia compared to normoxia. Metabolic activity was significantly increased by hypoxia in both epithelial cell types. Discussion: In conclusion, our data indicate that bronchial and alveolar epithelial cells respond differently to hypoxia and profibrotic stimuli. The bronchial epithelium appears more responsive to changes in oxygen levels and remodelling processes compared to the alveoli, suggesting that hypoxia may be a driver of pathogenesis in chronic lung disorders.
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| 12. |
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| 13. |
- Bolger, C., et al.
(författare)
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Effect of inspired air conditions on exercise-induced bronchoconstriction and urinary CC16 levels in athletes
- 2011
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Ingår i: Journal of Applied Physiology. - : American Physiological Society. - 1522-1601 .- 8750-7587. ; 111:4, s. 1059-1065
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Tidskriftsartikel (refereegranskat)abstract
- Bolger C, Tufvesson E, Anderson SD, Devereux G, Ayres JG, Bjermer L, Sue-Chu M, Kippelen P. Effect of inspired air conditions on exercise-induced bronchoconstriction and urinary CC16 levels in athletes. J Appl Physiol 111: 1059-1065, 2011. First published July 28, 2011; doi:10.1152/japplphysiol.00113.2011.-Injury to the airway epithelium has been proposed as a key susceptibility factor for exercise-induced bronchoconstriction (EIB). Our goals were to establish whether airway epithelial cell injury occurs during EIB in athletes and whether inhalation of warm humid air inhibits this injury. Twenty-one young male athletes (10 with a history of EIB) performed two 8-min exercise tests near maximal aerobic capacity in cold dry (4 degrees C, 37% relative humidity) and warm humid (25 degrees C, 94% relative humidity) air on separate days. Postexercise changes in urinary CC16 were used as a biomarker of airway epithelial cell perturbation and injury. Bronchoconstriction occurred in eight athletes in the cold dry environment and was completely blocked by inhalation of warm humid air [maximal fall in forced expiratory volume in 1 s = 18.1 +/- 2.1% (SD) in cold dry air and 1.7 +/- 0.8% in warm humid air, P < 0.01]. Exercise caused an increase in urinary excretion of CC16 in all subjects (P < 0.001), but this rise in CC16 was blunted following inhalation of warm humid air [median CC16 increase pre- to postchallenge = 1.91 and 0.35 ng/mu mol in cold dry and warm humid air, respectively, in athletes with EIB (P = 0.017) and 1.68 and 0.48 ng/mu mol in cold dry and warm humid air, respectively, in athletes without EIB (P = 0.002)]. The results indicate that exercise hyperpnea transiently disrupts the airway epithelium of all athletes (not only in those with EIB) and that inhalation of warm moist air limits airway epithelial cell perturbation and injury.
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| 14. |
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| 15. |
- Bolger, Claire, et al.
(författare)
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Hyperpnea-Induced Bronchoconstriction and Urinary CC16 Levels in Athletes
- 2011
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Ingår i: Medicine & Science in Sports & Exercise. - 1530-0315. ; 43:7, s. 1207-1213
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Tidskriftsartikel (refereegranskat)abstract
- BOLGER, C., E. TUFVESSON, M. SUE-CHU, G. DEVEREUX, J. G. AYRES, L. BJERMER, and P. KIPPELEN. Hyperpnea-Induced Bronchoconstriction and Urinary CC16 Levels in Athletes. Med. Sci. Sports Exerc., Vol. 43, No. 7, pp. 1207-1213, 2011. Purpose: Exercise-induced bronchoconstriction (EIB) is a common condition in both individuals with asthma and otherwise healthy elite athletes. Although excessive water loss by peripheral airways during hyperpnea is regarded as the initial trigger for EIB, the cascade of events that follows remains unclear. Our goal was to establish whether transient disruption of the airway epithelial barrier occurs after a short period of hyperpnea of dry air in athletes with EIB. Methods: Urinary concentration of the pneumoprotein Clara cell (CC16) was used as an assumed biomarker of lung epithelial cell damage or dysfunction. Samples were collected at baseline and for 90 min after an 8-min eucapnic voluntary hyperpnea (EVH) test in 50 female individuals (28 athletes and 22 untrained). Results: Nineteen subjects (10 athletes) demonstrated a sustained bronchoconstriction after EVH (mean +/- SE forced expiratory volume in the first second (FEV1) fall from baseline = 23.4% +/- 2.6%). The remaining subjects had a negative challenge result with an FEV1 fall of 5.9% +/- 0.6%. An increase (P < 0.001) in urinary CC16 concentration was noticed after EVH in all but one subject, with no group difference (median CC16 increase before to after challenge: athletes EVH- 0.083 ng.mu mol(-1), athletes EVH+ 0.223 ng.mu mol(-1), untrained EVH- 0.074 ng.mu mol(-1), untrained EVH+ 0.571 ng.mu mol(-1); P > 0.05). Conclusions: Urinary levels of CC16 are increased after EVH in all individuals (trained and untrained, with and without EIB) suggestive of dehydration-induced perturbation of the distal respiratory epithelium during episodes of hyperventilation.
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| 16. |
- Bolger, Claire, et al.
(författare)
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Urinary cc16 levels in winter versus summer sport athletes after eucapnic voluntary hyperpnoea
- 2009
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Konferensbidrag (refereegranskat)abstract
- Exercise induced bronchoconstriction (EIB) is highly prevalent in elite athletes, especially in those training in cold dry environments. Dehydration of the airways plays a key role in this process. EIB has recently been linked to airway epithelial injury in asthmatic individuals. The aim of the study is to determine whether a short period of hyperpnoea of dry air causes airway epithelial disruption in winter and/or summer sport athletes. We hypothesise that urinary level of the Clara cell protein (CC16) – an indirect marker of permeability/cellular integrity of the lung epithelial barrier – will be increased after a eucapnic voluntary hyperpnoea (EVH) test and that this increase will be larger in winter compared to summer athletes. Forty two female athletes – 28 summer athletes (age 31.1+/-1.7yr (SEM), training volume 9+/-1.1h/wk) and 14 winter athletes (age 21.4+/-0.8yr, training volume 12.0 ± 1.10h/wk) – took part in this study. They all performed an 8-min EVH test at a target ventilation rate of 30 times their baseline forced expiratory volume in one second (FEV1). After the challenge, FEV1 was measured in duplicate at 2, 5, 10, 15, 20, 30, 60 and 90min. A sustained decrease in FEV1 of at least 10% from baseline was considered positive. Urine samples were collected at baseline and at 30, 60 and 90min recovery. CC16 concentration was measured by enzyme immunoassay. Ten summer athletes had a positive test (max FEV1 fall = 19.6+/-2.4%), whilst eighteen of the summer athletes and all the winter athletes were negative (max FEV1 fall = 5.7+/-0.7% and 5.3+/-0.7%, respectively). CC16 increased significantly after the challenge in all three groups (P<0.01) with no difference between groups: delta CC16 (max post-EVH minus baseline) in summer EVH negative athletes was 0.241+/-0.1 ng/μmol creatinine, 0.292+/-0.085 ng/μmol creatinine in summer EVH positive athletes, and 0.123+/-0.047ng/μmol creatinine in winter EVH negative athletes (P=0.415)In conclusion, a short period of hyperpnoea of dry air is associated with an increased rate of CC16 excretion in urine in both winter and summer athletes. This suggests that the integrity of the airway epithelium might be compromised by loss of airway surface lining fluid when athletes inhale dry air at high flow rates. This appears to occur irrespective of the degree of bronchoconstriction or regular training environment.
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| 17. |
- Che, Karlhans Fru, et al.
(författare)
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The neutrophil-mobilizing cytokine interleukin-26 in the airways of long-term tobacco smokers
- 2018
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Ingår i: Clinical Science. - 0143-5221. ; 132:9, s. 959-983
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Tidskriftsartikel (refereegranskat)abstract
- Long-term tobacco smokers with chronic obstructive pulmonary disease (COPD) or chronic bronchitis display an excessive accumulation of neutrophils in the airways; an inflammation that responds poorly to established therapy. Thus, there is a need to identify new molecular targets for the development of effective therapy. Here, we hypothesized that the neutrophil-mobilizing cytokine interleukin (IL)-26 (IL-26) is involved in airway inflammation amongst long-term tobacco smokers with or without COPD, chronic bronchitis or colonization by pathogenic bacteria. By analyzing bronchoalveolar lavage (BAL), bronchail wash (BW) and induced sputum (IS) samples, we found increased extracellular IL-26 protein in the airways of long-term smokers in vivo without further increase amongst those with clinically stable COPD. In human alveolar macrophages (AM) in vitro, the exposure to water-soluble tobacco smoke components (WTC) enhanced IL-26 gene and protein. In this cell model, the same exposure increased gene expression of the IL-26 receptor complex (IL10R2 and IL20R1) and nuclear factor κ B (NF-κB); a proven regulator of IL-26 production. In the same cell model, recombinant human IL-26 in vitro caused a concentration-dependent increase in the gene expression of NF-κB and several pro-inflammatory cytokines. In the long-term smokers, we also observed that extracellular IL-26 protein in BAL samples correlates with measures of lung function, tobacco load, and several markers of neutrophil accumulation. Extracellular IL-26 was further increased in long-term smokers with exacerbations of COPD (IS samples), with chronic bronchitis (BAL samples ) or with colonization by pathogenic bacteria (IS and BW samples). Thus, IL-26 in the airways emerges as a promising target for improving the understanding of the pathogenic mechanisms behind several pulmonary morbidities in long-term tobacco smokers.
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| 18. |
- Diamant, Zuzana, et al.
(författare)
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Toward clinically applicable biomarkers for asthma : An EAACI position paper
- 2019
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Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : Wiley. - 0105-4538 .- 1398-9995. ; 74:10, s. 1835-1851
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation, structural, and functional abnormalities within the airways are key features of asthma. Although these processes are well documented, their expression varies across the heterogeneous spectrum of asthma. Type 2 inflammatory responses are characterized by increased levels of eosinophils, FeNO, and type 2 cytokines in blood and/or airways. Presently, type 2 asthma is the best-defined endotype, typically found in patients with allergic asthma, but surprisingly also in nonallergic patients with (severe) asthma. The etiology of asthma with non-type 2 inflammation is less clear. During the past decade, targeted therapies, including biologicals and small molecules, have been increasingly integrated into treatment strategies of severe asthma. These treatments block specific inflammatory pathways or single mediators. Single or composite biomarkers help to identify patients who will benefit from these treatments. So far, only a few inflammatory biomarkers have been validated for clinical application. The European Academy of Allergy & Clinical Immunology Task Force on Biomarkers in Asthma was initiated to review different biomarker sampling methods and to investigate clinical applicability of new and existing inflammatory biomarkers (point-of-care) to support diagnosis, targeted treatment, and monitoring of severe asthma. Subsequently, we discuss existing and novel targeted therapies for asthma as well as applicable biomarkers.
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| 19. |
- Diamant, Zuzana, et al.
(författare)
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Which Biomarkers Are Effective for Identifying Th2-Driven Inflammation in Asthma?
- 2013
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Ingår i: Current Allergy and Asthma Reports. - : Springer Science and Business Media LLC. - 1534-6315 .- 1529-7322. ; 13:5, s. 477-486
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Forskningsöversikt (refereegranskat)abstract
- Recognition of asthma as a heterogeneous disease revealed different potential molecular targets and urged the development of targeted, customized treatment modalities. Evidence was provided for different inflammatory subsets of asthma and more recently, further refined to T helper (Th)2-high and Th2-low subphenotypes with different responsiveness to standard and targeted pharmacotherapy. Given these differences in immunology and pathophysiology, proof of concept studies of novel treatment modalities for asthma should be performed in adequate, well-defined phenotypes. In this review, we describe both existing and novel biomarkers of Th2-inflammation in asthma that can be applied to classify asthma subphenotypes in clinical studies and for treatment monitoring.
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| 20. |
- Eklund, Linda, et al.
(författare)
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An experimental exposure study revealing composite airway effects of physical exercise in a subzero environment
- 2021
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Ingår i: International Journal of Circumpolar Health. - : Taylor & Francis. - 1239-9736 .- 2242-3982. ; 80:1
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Tidskriftsartikel (refereegranskat)abstract
- Exposure to a cold climate is associated with an increased morbidity and mortality, but the specific mechanisms are largely unknown. People with cardiopulmonary disease and winter endurance athletes are particularly vulnerable. This study aimed to map multiple domains of airway responses to exercise in subzero temperature in healthy individuals.Thirty-one healthy subjects underwent whole-body exposures for 50 minutes on two occasions in an environmental chamber with intermittent moderate-intensity exercise in +10 °C and -10 °C. Lung function, plasma/urine CC16 , and symptoms were investigated before and after exposures.Compared to baseline, exercise in -10 °C decreased FEV1 (p=0.002), FEV1/FVC (p<0.001), and increased R20Hz (p=0.016), with no differences between exposures. Reactance increased after +10 °C (p=0.005), which differed (p=0.042) from a blunted response after exercise in -10 °C. Plasma CC16 increased significantly within exposures, without differences between exposures. Exercise in -10 °C elicited more intense symptoms from the upper airways, compared to +10 °C. Symptoms from the lower airways were few and mild. Short-duration moderate-intensity exercise in -10 °C induces mild symptoms from the lower airways, no lung function decrements or enhanced leakage of biomarkers of airway epithelial injury, and no peripheral bronchodilatation, compared to exercise in +10 °C.
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| 21. |
- Eklund, Linda M., et al.
(författare)
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Cold air exposure at -15 °C induces more airway symptoms and epithelial stress during heavy exercise than rest without aggravated airway constriction
- 2022
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Ingår i: European Journal of Applied Physiology. - : Springer. - 1439-6319 .- 1439-6327. ; 122:12, s. 2533-2544
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Exposure to cold air may harm the airways. It is unclear to what extent heavy exercise adds to the cold-induced effects on peripheral airways, airway epithelium, and systemic immunity among healthy individuals. We investigated acute effects of heavy exercise in sub-zero temperatures on the healthy airways.Methods: Twenty-nine healthy individuals underwent whole body exposures to cold air in an environmental chamber at − 15 °C for 50 min on two occasions; a 35-min exercise protocol consisting of a 5-min warm-up followed by 2 × 15 min of running at 85% of VO2max vs. 50 min at rest. Lung function was measured by impulse oscillometry (IOS) and spirometry before and immediately after exposures. CC16 in plasma and urine, and cytokines in plasma were measured before and 60 min after exposures. Symptoms were surveyed pre-, during and post-trials.Results: FEV1 decreased after rest (− 0.10 ± 0.03 L, p < 0.001) and after exercise (− 0.06 ± 0.02 L, p = 0.012), with no difference between trials. Exercise in − 15 °C induced greater increases in lung reactance (X5; p = 0.023), plasma CC16 (p < 0.001) as well as plasma IL-8 (p < 0.001), compared to rest. Exercise induced more intense symptoms from the lower airways, whereas rest gave rise to more general symptoms.Conclusion: Heavy exercise during cold air exposure at − 15 °C induced signs of an airway constriction to a similar extent as rest in the same environment. However, biochemical signs of airway epithelial stress, cytokine responses, and symptoms from the lower airways were more pronounced after the exercise trial.
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| 22. |
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| 23. |
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| 24. |
- Eriksson, Göran, et al.
(författare)
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A new approach to assess COPD by identifying lung function break-points.
- 2015
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Ingår i: The International Journal of Chronic Obstructive Pulmonary Disease. - 1178-2005. ; 10, s. 2193-2202
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Tidskriftsartikel (refereegranskat)abstract
- COPD is a progressive disease, which can take different routes, leading to great heterogeneity. The aim of the post-hoc analysis reported here was to perform continuous analyses of advanced lung function measurements, using linear and nonlinear regressions.
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| 25. |
- Eriksson, Göran, et al.
(författare)
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A new maximal bicycle test using a prediction algorithm developed from four large COPD studies
- 2020
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Ingår i: European clinical respiratory journal. - : Informa UK Limited. - 2001-8525. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Maximum exercise workload (WMAX) is today assessed as the first part of Cardiopulmonary Exercise testing. The WMAX test exposes patients with COPD, often having cardiovascular comorbidity, to risks. Our research project was initiated with the final aim to eliminate the WMAX test and replace this test with a predicted value of WMAX, based on a prediction algorithm of WMAX derived from multicentre studies. Methods: Baseline data (WMAX, demography, lung function parameters) from 850 COPD patients from four multicentre studies were collected and standardized. A prediction algorithm was prepared using Random Forest modelling. Predicted values of WMAX were used in a new WMAX test, which used a linear increase in order to reach the predicted WMAX within 8 min. The new WMAX test was compared with the standard stepwise WMAX test in a pilot study including 15 patients with mild/moderate COPD. Results: The best prediction algorithm of WMAX included age, sex, height, weight, and six lung function parameters. FEV1 and DLCO were the most important predictors. The new WMAX test had a better correlation (R2 = 0.84) between predicted and measured WMAX than the standard WMAX test (R2 = 0.66), with slopes of 0.50 and 0.46, respectively. The results from the new WMAX test and the standard WMAX test correlated well. Conclusion: A prediction algorithm based on data from four large multicentre studies was used in a new WMAX test. The prediction algorithm provided reliable values of predicted WMAX. In comparison with the standard WMAX test, the new WMAX test provided similar overall results.
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| 26. |
- Garcia-Ryde, Martin, et al.
(författare)
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Expression of Stress-Induced Genes in Bronchoalveolar Lavage Cells and Lung Fibroblasts from Healthy and COPD Subjects
- 2024
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Ingår i: International Journal of Molecular Sciences. - 1422-0067. ; 25:12, s. 1-16
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Tidskriftsartikel (refereegranskat)abstract
- Chronic obstructive pulmonary disease (COPD) is commonly caused from smoking cigarettes that induce biological stress responses. Previously we found disorganized endoplasmic reticulum (ER) in fibroblasts from COPD with different responses to chemical stressors compared to healthy subjects. Here, we aimed to investigate differences in stress-related gene expressions within lung cells from COPD and healthy subjects. Bronchoalveolar lavage (BAL) cells were collected from seven COPD and 35 healthy subjects. Lung fibroblasts were derived from 19 COPD and 24 healthy subjects and exposed to cigarette smoke extract (CSE). Gene and protein expression and cell proliferation were investigated. Compared to healthy subjects, we found lower gene expression of CHOP in lung fibroblasts from COPD subjects. Exposure to CSE caused inhibition of lung fibroblast proliferation in both groups, though the changes in ER stress-related gene expressions (ATF6, IRE1, PERK, ATF4, CHOP, BCL2L1) and genes relating to proteasomal subunits mostly occurred in healthy lung fibroblasts. No differences were found in BAL cells. In this study, we have found that lung fibroblasts from COPD subjects have an atypical ER stress gene response to CSE, particularly in genes related to apoptosis. This difference in response to CSE may be a contributing factor to COPD progression.
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| 27. |
- Garcia-Ryde, Martin, et al.
(författare)
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Lung Fibroblasts from Chronic Obstructive Pulmonary Disease Subjects Have a Deficient Gene Expression Response to Cigarette Smoke Extract Compared to Healthy
- 2023
-
Ingår i: International journal of chronic obstructive pulmonary disease. - 1178-2005. ; 18, s. 2999-3014
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIM: Cigarette smoking is the most common cause of chronic obstructive pulmonary disease (COPD) but more mechanistic studies are needed. Cigarette smoke extract (CSE) can elicit a strong response in many COPD-related cell types, but no studies have been performed in lung fibroblasts. Therefore, we aimed to investigate the effect of CSE on gene expression in lung fibroblasts from healthy and COPD subjects.PATIENTS AND METHODS: Primary lung fibroblasts, derived from six healthy and six COPD subjects (all current or ex-smokers), were either unstimulated (baseline) or stimulated with 30% CSE for 4 h prior to RNA isolation. The mRNA expression levels were measured using the NanoString nCounter Human Fibrosis V2 panel (760 genes). Pathway enrichment was assessed for unique gene ontology terms of healthy and COPD.RESULTS: At baseline, a difference in the expression of 17 genes was found in healthy and COPD subjects. Differential expression of genes after CSE stimulation resulted in significantly less changes in COPD lung fibroblasts (70 genes) than in healthy (207 genes), with 51 genes changed in both. COPD maintained low NOTCH signaling throughout and upregulated JUN >80%, indicating an increase in apoptosis. Healthy downregulated the Mitogen-activated protein kinase (MAPK) signaling cascade, including a ≥50% reduction in FGF2, CRK, TGFBR1 and MEF2A. Healthy also downregulated KAT6A and genes related to cell proliferation, all together indicating possible cell senescence signaling.CONCLUSION: Overall, COPD lung fibroblasts responded to CSE stimulation with a very different and deficient expression profile compared to healthy. Highlighting that stimulated healthy cells are not an appropriate substitute for COPD cells which is important when investigating the mechanisms of COPD.
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| 28. |
- Gauvreau, GM, et al.
(författare)
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Allergen provocation tests in respiratory research: building on 50 years of experience
- 2022
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Ingår i: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 60:2
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Tidskriftsartikel (refereegranskat)abstract
- The allergen provocation test is an established model of allergic airway diseases, including asthma and allergic rhinitis, allowing the study of allergen-induced changes in respiratory physiology and inflammatory mechanisms in sensitised individuals as well as their associations. In the upper airways, allergen challenge is focused on the clinical and pathophysiological sequelae of the early allergic response, and is applied both as a diagnostic tool and in research settings. In contrast, bronchial allergen challenge has almost exclusively served as a research tool in specialised research settings with a focus on the late asthmatic response and the underlying type 2 inflammation. The allergen-induced late asthmatic response is also characterised by prolonged airway narrowing, increased nonspecific airway hyperresponsiveness and features of airway remodelling including the small airways, and hence allows the study of several key mechanisms and features of asthma. In line with these characteristics, allergen challenge has served as a valued tool to study the cross-talk of the upper and lower airways and in proof-of-mechanism studies of drug development. In recent years, several new insights into respiratory phenotypes and endotypes including the involvement of the upper and small airways, innovative biomarker sampling methods and detection techniques, refined lung function testing as well as targeted treatment options further shaped the applicability of the allergen provocation test in precision medicine. These topics, along with descriptions of subject populations and safety, in line with the updated Global Initiative for Asthma 2021 document, will be addressed in this review.
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| 29. |
- Hagman, Cecilia, et al.
(författare)
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Club cell secretory protein (CC16) in gastric fluid at birth and subsequent lung disease in preterm infants
- 2018
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Ingår i: Pediatric Pulmonology. - : Wiley. - 8755-6863. ; 53:10, s. 1399-1406
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundClub cell secretory protein (CC16) probably has a role in protecting the lung from inflammation. AimTo evaluate if low levels of CC16 in gastric fluid at birth, reflecting low levels of CC16 in the lung, would be associated with lung inflammation and respiratory morbidity. MethodsA study of 64 infants with mean gestational age 26.1 weeks. CC16 was analyzed in gastric fluid at birth. CC16, pro-inflammatory cytokines, and MMP-9 were analyzed in tracheal aspirate within 24h from birth. ResultsCC16 in gastric fluid increased with gestational age (P=0.033). Lower concentrations of CC16 in gastric fluid at birth were associated with higher concentrations of IL-1 (P=0.028), TNF- (P=0.034), and MMP-9 (P=0.015) in tracheal aspirate. Infants who needed mechanical ventilation at 24 and 72h of age had lower CC16 in gastric fluid than those not ventilated at these ages (P=0.011 and P=0.024, respectively). Lower CC16 in gastric fluid was associated with higher FiO(2) at 6h (P=0.009), higher PaCO2 at 24h (P=0.03), more ventilator days (P=0.012) and more days with supplemental oxygen (P=0.03). Infants who had either died or were still treated with supplemental oxygen at 36 weeks postmenstrual age had lower CC16 in gastric fluid than infants with none of these outcomes (P=0.049). ConclusionA low CC16 concentration in gastric fluid at birth was associated with increased inflammation in the trachea within the first 24h of life and with more need for respiratory support in the neonatal period.
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| 30. |
- Hagman, Cecilia, et al.
(författare)
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Lung function deficits and bronchodilator responsiveness at 12 years of age in children born very preterm compared with controls born at term
- 2023
-
Ingår i: Pediatric Pulmonology. - 8755-6863. ; 58:11, s. 3156-3170
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Very preterm birth is associated with lung function impairment later in life, but several aspects have not been studied. We aimed to comprehensively assess lung function at school age in very preterm infants and term controls, with special emphasis on bronchopulmonary dysplasia (BPD), sex, and bronchodilator response.METHODS: At 12 years of age, 136 children born very preterm (85 with and 51 without BPD) and 56 children born at term performed spirometry, body plethysmography, impulse oscillometry, measurement of diffusion capacity, and multiple breath washout, before and after bronchodilator inhalation.RESULTS: Airway symptoms and a diagnosis of asthma were more common in children born very preterm. These children had more airflow limitation, seen as lower forced expiratory volume in 1 s (FEV1 ) (p < .001), FEV1 /forced vital capacity (FVC) (p = .011), and mean forced expiratory flow between 25% and 75% of FVC (p < .001), and a higher total and peripheral airway resistance compared with term-born controls. There was no difference in total lung capacity but air trapping and lung clearance index were higher in children born very preterm. Diffusion capacity was lower in children born very preterm, especially in those with a diagnosis of BPD. In most other tests, the differences between preterm-born children with or without BPD were smaller than between children born preterm versus at term. Boys born preterm had more lung function deficits than preterm-born girls. In children born very preterm, airway obstruction was to a large extent reversible.CONCLUSION: At 12 years of age, children born very preterm had lower lung function than children born at term in most aspects and there was only little difference between children with or without BPD. Airway obstruction improved markedly after bronchodilator inhalation.
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| 31. |
- Hagman, Cecilia, et al.
(författare)
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Perinatal inflammation relates to early respiratory morbidity and lung function at 12 years of age in children born very preterm
- 2021
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Ingår i: Acta Paediatrica, International Journal of Paediatrics. - : Wiley. - 0803-5253. ; 110:7, s. 2084-2092
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Very preterm birth may be associated with lung function impairment later in life. It is not known if this is caused by prematurity per se or by associated perinatal events, such as maternal–foetal inflammation and severity of early neonatal lung disease. We assessed these factors in a prospective cohort of very preterm infants followed from birth to middle school age. Methods: In 71 infants with a gestational age of median 27.4 (range 23.9–31.7) weeks, pro-inflammatory and modulatory cytokines were measured in umbilical cord blood and in arterial blood sampled at 6, 24 and 72 h after birth, and cumulated cytokine concentrations were calculated as area under the curve (AUC). At median 12.6 (range 12.3–13.5) years of age, pulmonary function testing was done in 53 children. Results: There was a positive correlation between days on mechanical ventilation and AUC for IL-6 (p = 0.001), IL-8 (p = 0.015) and IL-10 (p = 0.006). Infants with bronchopulmonary dysplasia (BPD; n = 32) had higher AUC for the cytokines IL-6, IL-8 and IL-10 than those without BPD (all p < 0.01). Higher levels of AUC for IL-6 at birth correlated with lower forced expiratory volume in 1 s (p = 0.030) and lower mean expiratory flow rate between 25 and 75% of forced vital capacity (p = 0.034). Conclusion: Perinatal inflammation, assessed by circulating cytokines in the first three days of life, was associated with BPD and with airway obstruction at 12 years of age.
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| 32. |
- Hallgren, Oskar, et al.
(författare)
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Splicosomal and serine and arginine-rich splicing factors as targets for TGF-β
- 2012
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Ingår i: Fibrogenesis & tissue repair. - : Springer Science and Business Media LLC. - 1755-1536. ; 5:1, s. 6-6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Transforming growth factor-β1 (TGF-β1) is a potent regulator of cell growth and differentiation. TGF-β1 has been shown to be a key player in tissue remodeling processes in a number of disease states by inducing expression of extracellular matrix proteins. In this study a quantitative proteomic analysis was undertaken to investigate if TGF-β1 contributes to tissue remodeling by mediating mRNA splicing and production of alternative isoforms of proteins.METHODOLOGY/PRINCIPAL FINDINGS: The expression of proteins involved in mRNA splicing from TGF-β1-stimulated lung fibroblasts was compared to non-stimulated cells by employing isotope coded affinity tag (ICATTM) reagent labeling and tandem mass spectrometry. A total of 1733 proteins were identified and quantified with a relative standard deviation of 11% +/- 8 from enriched nuclear fractions. Seventy-six of these proteins were associated with mRNA splicing, including 22 proteins involved in splice site selection. In addition, TGF-β1 was observed to alter the relative expression of splicing proteins that may be important for alternative splicing of fibronectin. Specifically, TGF-β1 significantly induced expression of SRp20, and reduced the expression of SRp30C, which has been suggested to be a prerequisite for generation of alternatively spliced fibronectin. The induction of SRp20 was further confirmed by western blot and immunofluorescence.CONCLUSIONS: The results show that TGF-β1 induces the expression of proteins involved in mRNA splicing and RNA processing in human lung fibroblasts. This may have an impact on the production of alternative isoforms of matrix proteins and can therefore be an important factor in tissue remodeling and disease progression.
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| 33. |
- Henning, Martin, et al.
(författare)
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Exhaled Breath Temperature Increases after Exercise in Asthmatics and Controls.
- 2012
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Ingår i: Respiration. - : S. Karger AG. - 1423-0356 .- 0025-7931. ; 84:4, s. 283-290
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Tidskriftsartikel (refereegranskat)abstract
- Background: Exhaled breath temperature (EBT) has been suggested as a marker of airway inflammation in asthma. Objectives: The aim of the present study was to investigate EBT in asthmatic subjects compared to healthy controls after an exercise challenge test, and in subjects with exercise-induced bronchoconstriction compared to subjects without, and to compare with body temperatures. Methods: A total of 21 healthy controls and 20 asthmatics were included. Forced expiratory volume in 1 s (FEV(1)), EBT and oral, axillary and auricular temperatures were measured before and after an exercise challenge test. Results: FEV(1) % predicted (%p) was significantly lower in asthmatic subjects compared to healthy controls at all time points after exercise. The largest drop in FEV(1)%p correlated with EBT after 5 min. EBT increased markedly 5 min after exercise and remained high for at least 60 min. In asthmatics whose FEV(1) dropped by >10%, EBT was higher after 60 min compared to the remaining asthmatics. EBT correlated with oral temperature at all time points after exercise, with axillary temperature only at 15, 30 and 60 min, and not at all with auricular temperature. Conclusions: EBT is increased after exercise, and elevated EBT correlated with a drop in FEV(1)%p. The immediate increase in EBT did not differ between asthmatics and controls but remained elevated in the asthmatics whose FEV(1) dropped by >10%, indicating a different vascular response.
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| 34. |
- Härndahl, Ulrika, et al.
(författare)
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The Chloroplast Small Heat Shock Protein-Purification and Characterization of Pea Recombinant Protein
- 1998
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Ingår i: Protein Expression and Purification. - : Elsevier BV. - 1046-5928. ; 14:1, s. 87-96
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Tidskriftsartikel (refereegranskat)abstract
- We report here on a procedure to obtain large amounts of a chloroplast-localized heat shock protein (HSP21) with unknown structure and function, by using anEscherichia coliexpression system for the pea (Pisum sativum) protein and a purification procedure based on perfusion ion-exchange chromatography. After initial precipitation steps, the sample was applied to cation- and anion-exchange on two columns connected in sequence, which allowed rapid purification of HSP21 in one equilibration and one elution step. The purified recombinant protein had an isoelectric point of 5.0 and appeared in assembled, oligomeric form (approximately 200 kDa) composed of 21-kDa monomers, similar to the native HSP21 protein as detected by immunoblotting in plants after heat-stress treatment. This chloroplast-localized heat shock protein belongs to a special group of small heat shock proteins (sHSPs), which share an evolutionary conserved C-terminal domain with the vertebrate eye lens @a-crystallin. The crystallins are known from both crystallographic and spectroscopic data to be all-@b proteins. In contrast, this paper presents circular dichroism spectroscopy data which shows that the purified recombinant HSP21 oligomer has a content of more than 30% @a-helical secondary structure.
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| 35. |
- Jarenbäck, Linnea, et al.
(författare)
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Acinar ventilation heterogeneity in COPD relates to diffusion capacity, resistance and reactance.
- 2016
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Ingår i: Respiratory Medicine. - : Elsevier BV. - 1532-3064 .- 0954-6111. ; 110:nov 11, s. 28-33
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate heterogenic ventilation in the acinar (Sacin) and conductive (Scond) airways of patients with varying chronic obstructive pulmonary disease (COPD) severity and how these relates to advanced lung function parameters, primarily measured by impulse oscillometry (IOS). A secondary aim was to investigate the effects of a short acting beta2-agonist and a muscarinic antagonist on the heterogenic ventilation. Eleven never smoking controls, 12 smoking controls, and 57 COPD patients (7 GOLD 1, 25 GOLD 2, 14 GOLD 3 and 11 GOLD 4) performed flow-volume spirometry, IOS, body plethysmography, single breath carbon monoxide diffusion, and N2-multiple breath washout. Six smoking controls and 13 of the COPD patients also performed double reversibility test by using salbutamol and its combination with ipratropium. Sacin was significantly higher in GOLD 2-4 compared to never smoking controls and smoking controls, but showed similar levels in GOLD 3 and 4. A factor analysis identified 4 components consisting of; 1) IOS parameters, 2) volume parameters, 3) diffusion parameters, Sacin and some IOS parameters and 4) Scond with central obstruction/air trapping. Salbutamol and its combination with ipratropium had no effect on Sacin and Scond. Increased Sacin in COPD was strongly related to diffusion capacity and lung volumes, but also weakly to resistance and reactance, showing a link between ventilation heterogeneity in the acinar airways and parameters measured by IOS.
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| 36. |
- Jarenbäck, Linnea, et al.
(författare)
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Bronchodilator response of advanced lung function parameters depending on COPD severity
- 2016
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Ingår i: International Journal of COPD. - 1176-9106. ; 11:1, s. 2939-2950
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Tidskriftsartikel (refereegranskat)abstract
- Background: COPD is defined as partly irreversible airflow obstruction. The response pattern of bronchodilators has not been followed in advanced lung function parameters. Purpose: The aim of this study was to investigate bronchodilator response pattern in advanced lung function parameters in a continuous fashion along forced expiratory volume in 1 second (FEV1) percent predicted (%p) in COPD patients and controls. Patients and methods: Eighty-one smokers/ex-smokers (41 controls and 40 COPD) performed spirometry, body plethysmography, impulse oscillometry and single-breath helium dilution carbon monoxide diffusion at baseline, after salbutamol inhalation and then after an additional inhalation of ipratropium. Results: Most pulmonary function parameters showed a linear increase in response to decreased FEV1%p. The subjects were divided into groups of FEV1%p<65 and >65, and the findings from continuous analysis were verified. The exceptions to this linear response were inspiratory capacity (IC), forced vital capacity (FVC), FEV1/FVC and expiratory resistance (Rex), which showed a segmented response relationship to FEV1%p. IC and FVC, with break points (BP) of 57 and 58 FEV1%p respectively, showed no response above, but an incresed slope below the BP. In addition, in patients with FEV1%p<65 and >65, response of FEV1%p did not correlate to response of volume parameters. Conclusion: Response of several advanced lung function parameters differs depending on patients’ baseline FEV1%p, and specifically response of volume parameters is most pronounced in COPD patients with FEV1%p<65. Volume and resistance responses do not follow the flow response measured with FEV1 and may thus be used as a complement to FEV1 reversibility to identify flow, volume and resistance responders.
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| 37. |
- Jarenbäck, Linnea, et al.
(författare)
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Flow-Volume Parameters in COPD Related to Extended Measurements of Lung Volume, Diffusion, and Resistance.
- 2013
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Ingår i: Pulmonary Medicine. - : Hindawi Limited. - 2090-1844 .- 2090-1836. ; 2013
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Tidskriftsartikel (refereegranskat)abstract
- Classification of COPD into different GOLD stages is based on forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) but has shown to be of limited value. The aim of the study was to relate spirometry values to more advanced measures of lung function in COPD patients compared to healthy smokers. The lung function of 65 COPD patients and 34 healthy smokers was investigated using flow-volume spirometry, body plethysmography, single breath helium dilution with CO-diffusion, and impulse oscillometry. All lung function parameters, measured by body plethysmography, CO-diffusion, and impulse oscillometry, were increasingly affected through increasing GOLD stage but did not correlate with FEV1 within any GOLD stage. In contrast, they correlated fairly well with FVC%p, FEV1/FVC, and inspiratory capacity. Residual volume (RV) measured by body plethysmography increased through GOLD stages, while RV measured by helium dilution decreased. The difference between these RV provided valuable additional information and correlated with most other lung function parameters measured by body plethysmography and CO-diffusion. Airway resistance measured by body plethysmography and impulse oscillometry correlated within COPD stages. Different lung function parameters are of importance in COPD, and a thorough patient characterization is important to understand the disease.
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| 38. |
- Jarenbäck, Linnea, et al.
(författare)
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Single-nucleotide polymorphisms in the sulfatase-modifying factor 1 gene are associated with lung function and COPD
- 2022
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Ingår i: ERJ open research. - : European Respiratory Society (ERS). - 2312-0541. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Single nucleotide polymorphisms (SNPs) in various genes have been shown to associate with COPD, suggesting a role in disease pathogenesis. Sulfatase modifying factor (SUMF1) is a key modifier in connective tissue remodelling, and we have shown previously that several SNPs in SUMF1 are associated with COPD. The aim of this study was to investigate the association between SUMF1 SNPs and advanced lung function characteristics. Never-, former and current smokers with (n=154) or without (n=405) COPD were genotyped for 21 SNPs in SUMF1 and underwent spirometry, body plethysmography, diffusing capacity of the lung for carbon monoxide ( D LCO) measurement and impulse oscillometry. Four SNPs (rs793391, rs12634248, rs2819590 and rs304092) showed a significantly decreased odds ratio of having COPD when heterozygous for the variance allele, together with a lower forced expiratory volume in 1 s (FEV 1) and FEV 1/forced vital capacity (FVC) ratio and an impaired peripheral resistance and reactance. Moreover, individuals homozygous for the variance allele of rs3864051 exhibited a strong association to COPD, a lower FEV 1/FVC, FEV 1 and D LCO, and an impaired peripheral resistance and reactance. Other SNPs (rs4685744, rs2819562, rs2819561 and rs11915920) were instead associated with impaired lung volumes and exhibited a lower FVC, total lung capacity and alveolar volume, in individuals having the variance allele. Several SNPs in the SUMF1 gene are shown to be associated with COPD and impaired lung function. These genetic variants of SUMF1 may cause a deficient sulfation balance in the extracellular matrix of the lung tissue, thereby contributing to the development of COPD.
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| 39. |
- Jarenbäck, Linnea, et al.
(författare)
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The Efficiency Index (EFFi), based on volumetric capnography, may allow for simple diagnosis and grading of COPD
- 2018
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Ingår i: International Journal of COPD. - 1176-9106. ; 13, s. 2033-2039
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Tidskriftsartikel (refereegranskat)abstract
- Background: Spirometry, the main tool for diagnosis and follow-up of COPD, incompletely describes the disease. Based on volumetric capnography (VCap), an index was developed for the diagnosis and grading of COPD, aimed as a complement or alternative to spirometry. Methods: Nine non-smokers, 10 smokers/former smokers without COPD and 54 smokers/ former smokers with COPD were included in the study. Multiple breath washout of N2 and VCap were studied with Exhalyzer D during tidal breathing. VCap was based on signals for flow rate and CO2 and was recorded during one breath preceding N2 washout. Efficiency Index (EFFi) is the quotient between exhaled CO2 volume and the hypothetical CO2 volume exhaled from a completely homogeneous lung over a volume interval equal to 15% of predicted total lung capacity. Results: EFFi increased with increased Global initiative for chronic Obstructive Lung Disease (GOLD) stage and the majority of subjects in GOLD 2 and all subjects in GOLD 3 and 4 could be diagnosed as having COPD using the lower 95% confidence interval of the healthy group. EFFi also correlated with N2 washout (r=-0.73; p,0.001), forced expiratory volume in 1 second (r=0.70; p,0.001) and diffusion capacity for carbon oxide (r=0.69; p,0.001). Conclusion: EFFi measures efficiency of tidal CO2 elimination that is limited by inhomogeneity of peripheral lung function. EFFi allows diagnosis and grading of COPD and, together with FEV1, may explain limitation of physical performance. EFFi offers a simple, effortless and cost-effective complement to spirometry and might serve as an alternative in certain situations.
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| 40. |
- Jesenak, Milos, et al.
(författare)
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Eosinophils—from cradle to grave
- 2023
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Ingår i: Allergy: European Journal of Allergy and Clinical Immunology. - 0105-4538. ; 78:12, s. 3077-3102
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Tidskriftsartikel (refereegranskat)abstract
- Over the past years, eosinophils have become a focus of scientific interest, especially in the context of their recently uncovered functions (e.g. antiviral, anti-inflammatory, regulatory). These versatile cells display both beneficial and detrimental activities under various physiological and pathological conditions. Eosinophils are involved in the pathogenesis of many diseases which can be classified into primary (clonal) and secondary (reactive) disorders and idiopathic (hyper)eosinophilic syndromes. Depending on the biological specimen, the eosinophil count in different body compartments may serve as a biomarker reflecting the underlying pathophysiology and/or activity of distinct diseases and as a therapy-driving (predictive) and monitoring tool. Personalized selection of an appropriate therapeutic strategy directly or indirectly targeting the increased number and/or activity of eosinophils should be based on the understanding of eosinophil homeostasis including their interactions with other immune and non-immune cells within different body compartments. Hence, restoring as well as maintaining homeostasis within an individual's eosinophil pool is a goal of both specific and non-specific eosinophil-targeting therapies. Despite the overall favourable safety profile of the currently available anti-eosinophil biologics, the effect of eosinophil depletion should be monitored from the perspective of possible unwanted consequences.
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| 41. |
- Jögi, Jonas, et al.
(författare)
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The added value of hybrid ventilation/perfusion SPECT/CT in patients with stable COPD or apparently healthy smokers. Cancer-suspected CT findings in the lungs are common when hybrid imaging is used
- 2015
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Ingår i: The International Journal of Chronic Obstructive Pulmonary Disease. - 1178-2005. ; 10, s. 25-30
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Tidskriftsartikel (refereegranskat)abstract
- Ventilation/perfusion (V/P) single-photon emission computed tomography (SPECT) is recognized as a diagnostic method with potential beyond the diagnosis of pulmonary embolism. V/P SPECT identifies functional impairment in diseases such as heart failure (HF), pneumonia, and chronic obstructive pulmonary disease (COPD). The development of hybrid SPECT/computed tomography (CT) systems, combining functional with morphological imaging through the addition of low-dose CT (LDCT), may be useful in COPD, as these patients are prone to lung cancer and other comorbidities. The aim of this study was to investigate the added value of LDCT among healthy smokers and patients with stable COPD, when examined with V/P SPECT/CT hybrid imaging. Sixty-nine subjects, 55 with COPD (GOLD I-IV) and 14 apparently healthy smokers, were examined with V/P SPECT and LDCT hybrid imaging. Spirometry was used to verify COPD grade. Only one apparently healthy smoker and three COPD patients had a normal or nearly normal V/P SPECT. All other patients showed various degrees of airway obstruction, even when spirometry was normal. The same interpretation was reached on both modalities in 39% of the patients. LDCT made V/P SPECT interpretation more certain in 9% of the patients and, in 52%, LDCT provided additional diagnoses. LDCT better characterized the type of emphysema in 12 patients. In 19 cases, tumor-suspected changes were reported. Three of these 19 patients (ie, 4.3% of all subjects) were in the end confirmed to have lung cancer. The majority of LDCT findings were not regarded as clinically significant. V/P SPECT identified perfusion patterns consistent with decompensated left ventricular HF in 14 COPD patients. In 16 patients (23%), perfusion defects were observed. HF and perfusion defects were not recognized with LDCT. In COPD patients and long-time smokers, hybrid imaging had added value compared to V/P SPECT alone, by identifying patients with lung malignancy and more clearly identifying emphysema. V/P SPECT visualizes comorbidities to COPD not seen with LDCT, such as pulmonary embolism and left ventricular HF.
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| 42. |
- Kasetty, Gopinath, et al.
(författare)
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Osteopontin protects against pneumococcal infection in a murine model of allergic airway inflammation
- 2019
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Ingår i: Allergy: European Journal of Allergy and Clinical Immunology. - : Wiley. - 0105-4538. ; 74:4, s. 663-674
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Tidskriftsartikel (refereegranskat)abstract
- Background: In atopic asthma, chronic Th2-biased inflammation is associated with an increased risk of pneumococcal infection. The anionic phosphoglycoprotein osteopontin (OPN) is highly expressed in asthma and has been ascribed several roles during inflammation. This study aimed to investigate whether OPN affects inflammation and vulnerability to pneumococcal infection in atopic asthma. Methods: House dust mite (HDM) extract was used to induce allergic airway inflammation in both wild-type (Spp1+/+) and OPN knockout (Spp1−/−) C57BL/6J mice, and the airway was then infected with Streptococcus pneumoniae. Parameters reflecting inflammation, tissue injury, and bacterial burden were measured. In addition, samples from humans with allergic asthma were analyzed. Results: Both allergen challenge in individuals with allergic asthma and the intranasal instillation of HDM in mice resulted in increased OPN levels in bronchoalveolar lavage fluid (BALF). More immune cells (including alveolar macrophages, neutrophils, eosinophils, and lymphocytes) and higher levels of proinflammatory cytokines were found in Spp1−/− mice than in Spp1+/+ mice. Moreover, OPN-deficient mice exhibited increased levels of markers reflecting tissue injury. Upon infection with S. pneumoniae, Spp1+/+ mice with allergic airway inflammation had a significantly lower bacterial burden in both BALF and lung tissue than did Spp1−/− mice. Furthermore, Spp1−/− mice had higher levels of cytokines and immune cells in BALF than did Spp1+/+ mice. Conclusion: OPN reduces inflammation, decreases tissue injury, and reduces bacterial loads during concurrent pneumococcal infection and allergic airway inflammation in a murine model. These findings suggest that OPN significantly affects vulnerability to pneumococcal infection in atopic asthma.
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| 43. |
- Kippelen, Pascale, et al.
(författare)
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Urinary CC16 after challenge with dry air hyperpnoea and mannitol in recreational summer athletes
- 2013
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Ingår i: Respiratory Medicine. - : Elsevier BV. - 1532-3064 .- 0954-6111. ; 107:12, s. 1837-1844
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Tidskriftsartikel (refereegranskat)abstract
- Airway epithelial injury is regarded as a key contributing factor to the pathogenesis of exercise-induced bronchoconstriction (EIB) in athletes. The concentration of the pneumoprotein club cell (Clara cell) CC16 in urine has been found to be a non-invasive marker for hyperpnoea-induced airway epithelial perturbation. Exercise-hyperpnoea induces mechanical, thermal and osmotic stress to the airways. We investigated whether osmotic stress alone causes airway epithelial perturbation in athletes with suspected EIB. Twenty-four recreational summer sports athletes who reported respiratory symptoms on exertion performed a standard eucapnic voluntary hyperpnoea test with dry air and a mannitol test (osmotic challenge) on separate days. Median urinary CC16 increased from 120 to 310 rho g mu mol creatinine(-1) after dry air hyperpnoea (P = 0.002) and from 90 to 191 rho g mu mol creatinine(-1) after mannitol (P = 0.021). There was no difference in urinary CC16 concentration between athletes who did or did not bronchoconstrict after dry air hyperpnoea or mannitol. We conclude that, in recreational summer sports athletes with respiratory symptoms, osmotic stress per se to the airway epithelium induces a rise in urinary excretion of CC16. This suggests that hyperosmolarity of the airway surface lining perturbs the airway epithelium in symptomatic athletes. (C) 2013 Elsevier Ltd. All rights reserved.
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| 44. |
- Larsen, Kristoffer, et al.
(författare)
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Antiproliferative heparan sulfate inhibiting hyaluronan and transforming growth factor-β expression in human lung fibroblast cells
- 2005
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Ingår i: Clinical Proteomics. - 1559-0275. ; 1:3-4, s. 271-284
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to examine the effects of heparan sulfate (HS) on factors involved in the remodeling of connective tissue observed in patients with fibrotic respiratory disorders such as asthma. A suitable working model is to stimulate human fetal lung fibroblasts in vitro with structurally different forms of HS. Highly sulfated and iduronic acid (IdoUA)-rich HS specifically decreased cell proliferaton, production of jyaluronan (HA), transforming growth factor (TGF)-β1, and TFF-β-induced α-smooth muscle actin but did not affect the overall proteoglycan production in the cells. These repressed factors are suggested to play a critical role in the early stages of remodeling and myofibroblast activation. Low sulfated and IdoUA-poor HS did not display any effects on these factors. Furthermore, analysis of the protein expression pattern by two-dimensional gel electrophoresis revealed a 70% increased expression of annexin II, which has previously been shown to have a high affinity for both heparin and HS. Heat-shock protein 27 and arsenite translocating factor, both involved in actin organization and polymerization, were also increased in the HS-stimulated cells. Thus, the reduced expression of HA and TGF-β1, both important in the development of fibrosis, seems to be mediated by pecific changes in protein expression of the fibroblast. The observed inhibition of cell proliferation, HA, and TGF-β1 allows speculation of highly sulfated HS as a antifibrotic candidate in the early stage of remodeling.
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| 45. |
- Larsen, Kristoffer, et al.
(författare)
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Presence of activated mobile fibroblasts in bronchoalveolar lavage from patients with mild asthma
- 2004
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Ingår i: American Journal of Respiratory and Critical Care Medicine. - 1535-4970. ; 170:10, s. 1049-1056
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Tidskriftsartikel (refereegranskat)abstract
- Activated fibroblasts are suggested to be involved in the deposition of extracellular matrix in the formation of peribronchial fibrosis in asthma. We report the novel finding of activated elongated fibroblasts accompanied by elevated numbers of eosinophils in bronchoalveolar lavage fluid from 5 out of 12 patients with mild asthma (= 42%), whereas no fibroblasts were observed in the control subjects without asthma (n = 17). The elongated fibroblasts migrated twice as far when compared with fibroblasts from corresponding bronchial biopsies from the same patients, accompanied by an induced expression of RhoA and Rac1, indicating that the increased expression of these proteins are linked to increased migratory capabilities. Moreover, the elongated fibroblasts had an elevated production of the proteoglycans biglycan, versican, perlecan, and decorin, which correlated to an active cytoplasm in these cells. Differential expression patterns between the two fibroblast groups in motility-regulating proteins, such as cofilin, nuclear chloride ion channel protein, and heat-shock protein 20, were identified by two-dimensional electrophoresis and mass spectrometry. These findings indicate the presence of activated and mobile fibroblasts accompanied by an induced inflammatory response outside the airway epithelium in patients with mild asthma, results that may play a role in formation of airway fibrosis.
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| 46. |
- Larsson Callerfelt, Anna-Karin, et al.
(författare)
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iNOS affects matrix production in distal lung fibroblasts from patients with mild asthma.
- 2015
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Ingår i: Pulmonary Pharmacology & Therapeutics. - : Elsevier BV. - 1522-9629 .- 1094-5539. ; 34:sep 9, s. 64-71
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Forskningsöversikt (refereegranskat)abstract
- A high level of exhaled nitric oxide (NO) is a marker for inflammation in the airways of asthmatic subjects. However, little is known about how NO and inducible nitric oxides synthase (iNOS) activity may affect remodelling in the distal lung. We hypothesized that there is a link between iNOS and ongoing remodelling processes in the distal lung of mild asthmatics.
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| 47. |
- Lyngen, Bjørn, et al.
(författare)
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Short term exposure to low amounts of airway irritants in a swine confinement building and inflammatory markers in blood and exhaled air.
- 2014
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Ingår i: Annals of Agricultural and Environmental Medicine. - : Institute of Rural Health. - 1898-2263 .- 1232-1966. ; 21:3, s. 479-484
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Tidskriftsartikel (refereegranskat)abstract
- Introduction and objective. Swine confinement buildings are known to contain large concentrations of airway irritants, and a number of studies have shown acute inflammatory effects in previously unexposed subjects when introduced to the environment in such buildings. However, studies comparing different methods of assessing such reactions are lacking, and it is not known if a measurable response could be found at lower exposure rates. The purpose of this study was to investigate exposure levels in a Norwegian swine confinement building, the airway response to such exposure, and to compare invasive and non-invasive methods of response measurement. Materials and method. Twelve medical students who were previously unexposed to swine dust stayed in a swine confinement building in Norway for 4 hours, and underwent measurements before and after the start of exposure. The same measurements were also performed beforehand, on the same weekday without exposure, in such a manner that the subjects were their own controls. Results. The exposure assessment showed considerably lower concentrations of organic dust and endotoxin than earlier studies. However, small, but significant increases in markers of airway inflammation, were found. Conclusions. Airway response can be measured after lower exposure to airborne irritants in swine confinement buildings than previously known. Further research is needed to assess whether this finding can be utilized for preventive purposes.
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| 48. |
- Malinovschi, Andrei, et al.
(författare)
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Application of nitric oxide measurements in clinical conditions beyond asthma.
- 2015
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Ingår i: European clinical respiratory journal. - : Informa UK Limited. - 2001-8525. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- Fractional exhaled nitric oxide (FeNO) is a convenient, non-invasive method for the assessment of active, mainly Th2-driven, airway inflammation, which is sensitive to treatment with standard anti-inflammatory therapy. Consequently, FeNO serves as a valued tool to aid diagnosis and monitoring in several asthma phenotypes. More recently, FeNO has been evaluated in several other respiratory, infectious, and/or immunological conditions. In this short review, we provide an overview of several clinical studies and discuss the status of potential applications of NO measurements in clinical conditions beyond asthma.
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| 49. |
- Malmström, Erik, et al.
(författare)
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The importance of fibroblasts in remodelling of the human uterine cervix during pregnancy and parturition.
- 2007
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Ingår i: Molecular Human Reproduction. - : Oxford University Press (OUP). - 1460-2407. ; 13, s. 333-341
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Tidskriftsartikel (refereegranskat)abstract
- It is well established that fibroblasts play a crucial role in pathophysiological extracellular matrix remodelling. The aim of this project is to elucidate their role in normal physiological remodelling. Specifically, the remodelling of the human cervix during pregnancy, resulting in an enabled passage of the child, is used as the model system. Fibroblast cultures were established from cervices of non-pregnant women, women after 36 weeks of pregnancy and women directly after partus. The cells were immunostained and quantified by western blots for differentiation markers. The cultures were screened for cytokine and metalloproteinase production and characterized by global proteome analysis. The cell cultures established from partal donors differ significantly from those from non-pregnant donors, which is in accordance with in vivo findings. A decrease in alpha-smooth actin and prolyl-4hydroxylase and an increase in interleukin (IL)-6, IL-8 and matrix metalloproteinases (MMP)-1 and MMP-3 were observed in cultures from partal donors. 2D-gel electrophoresis followed by mass spectrometry showed that the expression of 59 proteins was changed significantly in cultures of partal donors. The regulated proteins are involved in protein kinase C signalling, Ca2+ binding, cytoskeletal organization, angiogenesis and degradation. Our data suggest that remodelling of the human cervix is orchestrated by fibroblasts, which are activated or recruited by the inflammatory processes occurring during the ripening cascade.
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| 50. |
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