| 1. |
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
- Balgoma, D, et al.
(author)
-
Linoleic acid-derived lipid mediators increase in a female-dominated subphenotype of COPD
- 2016
-
In: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 47:6, s. 1645-1656
-
Journal article (peer-reviewed)abstract
- Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality; however, the role of inflammatory mediators in its pathobiology remains unclear. The aim of this study was to investigate the influence of gender in COPD on lipid mediator levels.Bronchoalveolar lavage fluid (BALF) and serum were obtained from healthy never-smokers, smokers and COPD patients (Global Initiative for Chronic Obstructive Lung Disease stage I–II/A–B) (n=114). 94 lipid mediators derived from the cytochrome-P450, lipoxygenase, and cyclooxygenase pathways were analysed by liquid chromatography-mass spectrometry.Multivariate modelling identified a 9-lipid panel in BALF that classified female smokers with COPD from healthy female smokers (p=6×10−6). No differences were observed for the corresponding male population (p=1.0). These findings were replicated in an independent cohort with 92% accuracy (p=0.005). The strongest drivers were the cytochrome P450-derived epoxide products of linoleic acid (leukotoxins) and their corresponding soluble epoxide hydrolase (sEH)-derived products (leukotoxin-diols). These species correlated with lung function (r=0.87; p=0.0009) and mRNA levels of enzymes putatively involved in their biosynthesis (r=0.96; p=0.003). Leukotoxin levels correlated with goblet cell abundance (r=0.72; p=0.028).These findings suggest a mechanism by which goblet cell-associated cytochrome-P450 and sEH activity produce elevated leukotoxin-diol levels, which play a putative role in the clinical manifestations of COPD in a female-dominated disease sub-phenotype.
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
|
|
| 11. |
|
|
| 12. |
|
|
| 13. |
|
|
| 14. |
|
|
| 15. |
|
|
| 16. |
|
|
| 17. |
|
|
| 18. |
- Fredriksson, K, et al.
(author)
-
Red blood cells increase secretion of matrix metalloproteinases from human lung fibroblasts in vitro
- 2006
-
In: American journal of physiology. Lung cellular and molecular physiology. - : American Physiological Society. - 1040-0605 .- 1522-1504. ; 290:2, s. L326-L333
-
Journal article (peer-reviewed)abstract
- Tissue remodeling is an important process in many inflammatory and fibrotic lung disorders. RBC may in these conditions interact with extracellular matrix (ECM). Fibroblasts can produce and secrete matrix components, matrix-degrading enzymes (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Imbalance in matrix synthesis/degradation may result in rearrangement of tissue architecture and lead to diseases such as emphysema or fibrosis. Neutrophil elastase (NE), a protease released by neutrophils, is known to activate MMP. We hypothesized that RBC can stimulate secretion of MMPs from human lung fibroblasts and that NE can augment this effect. Human fetal lung fibroblasts were cultured in floating collagen gels with or without RBC. After 4 days, the culture medium was analyzed with gelatin zymography, Western blot, and ELISA for MMP-1, -2, -3 and TIMP-1, -2. RBC augmented NE-induced fibroblast-mediated collagen gel contraction compared with NE alone (18.4 ± 1.6%, 23.7 ± 1.4% of initial gel area, respectively). A pan-MMP inhibitor (GM-6001) completely abolished the stimulating effect of NE. Gelatin zymography showed that RBC stimulated MMP-2 activity and that NE enhanced conversion to the active form. Addition of GM-6001 completely inhibited MMP-2 activity in controls, whereas it only partially altered RBC-induced MMP activity. Western blot confirmed the presence of MMP-1 and MMP-3 in fibroblasts stimulated with RBC, and ELISA confirmed increased concentrations of pro-MMP-1. We conclude that stimulation of MMP secretion by fibroblasts may explain the ability of RBC to augment fibroblast-mediated collagen gel contraction. This might be a potential mechanism by which hemorrhage in inflammatory conditions leads to ECM remodeling.
|
|
| 19. |
|
|
| 20. |
|
|
| 21. |
|
|
| 22. |
|
|
| 23. |
|
|
| 24. |
|
|
| 25. |
|
|
| 26. |
|
|
| 27. |
|
|
| 28. |
|
|
| 29. |
|
|
| 30. |
|
|
| 31. |
- Karimi, R, et al.
(author)
-
Differences in regional air trapping in current smokers with normal spirometry
- 2017
-
In: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 49:1
-
Journal article (peer-reviewed)abstract
- We investigated regional air trapping on computed tomography in current smokers with normal spirometry. It was hypothesised that presence of regional air trapping may indicate a specific manifestation of smoking-related changes.40 current smokers, 40 patients with chronic obstructive pulmonary disease (COPD), and 40 healthy never- smokers underwent computed tomography scans. Regional air trapping was assessed on end-expiratory scans and emphysema, micronodules and bronchial wall thickening on inspiratory scans. The ratio of expiratory and inspiratory mean lung attenuation (E/I) was calculated as a measure of static (fixed) air trapping.Regional air trapping was present in 63% of current smokers, in 45% of never smokers and in 8% of COPD patients (p<0.001). Current smokers with and without regional air trapping had E/I ratio of 0.81 and 0.91, respectively (p<0.001). Forced expiratory volume in 1 s (FEV1) was significantly higher and emphysema less frequent in current smokers with regional air trapping.Current smokers with regional air trapping had higher FEV1 and less emphysema on computed tomography. In contrast, current smokers without regional air trapping resembled COPD. Our results highlight heterogeneity among smokers with normal spirometry and may contribute to early detection of smoking related structural changes in the lungs.
|
|
| 32. |
|
|
| 33. |
|
|
| 34. |
|
|
| 35. |
|
|
| 36. |
|
|
| 37. |
|
|
| 38. |
- Lensmar, C, et al.
(author)
-
Leukocyte counts and macrophage phenotypes in induced sputum and bronchoalveolar lavage fluid from normal subjects
- 1998
-
In: The European respiratory journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 12:3, s. 595-600
-
Journal article (peer-reviewed)abstract
- It is unclear whether leukocytes in induced sputum (IS) and bronchoalveolar lavage (BAL) represent the same cell populations. To compare leukocyte counts and macrophage phenotypes and investigate any measurable dithiothreitol (DTT)-mediated effect on macrophage immunocytochemical staining results, IS and BAL samples from nine healthy smokers and seven nonsmokers were examined. BAL and IS samples were processed and cell viability and cell counts were assessed. The macrophages were characterized by seven monoclonal antibodies (RFD1, RFD7, CD11b, CD54, CD68, CD71 and HLA-DR) using an indirect immunoalkaline phosphatase method. Intraindividual comparison of IS and BAL showed that IS samples from smokers and nonsmokers contained a lower total cell count (p<0.01 smokers, p<0.05 nonsmokers), a lower percentage of macrophages (both p<0.05) and a higher percentage of neutrophils (both p<0.05) than BAL samples. In addition, nonsmokers sputum samples contained a lower proportion of lymphocytes (p<0.05) than BAL. The macrophage expression of RFD7 and CD71 was higher in smokers sputum samples (both p<0.05) than in BAL, while nonsmokers sputum macrophages showed a higher expression of CD54 and CD71 (both p<0.05) than BAL macrophages. DTT-incubated BAL samples showed no difference in macrophage antigen expression from BAL samples not exposed to DTT. In conclusion, the relative proportions of leukocytes and the macrophage phenotypes differed between induced sputum and bronchoalveolar lavage suggesting that the methods provide samples from different lung compartments, inhabited by cells with different phenotypes.
|
|
| 39. |
|
|
| 40. |
|
|
| 41. |
- Li, CX, et al.
(author)
-
Integration of multi-omics datasets enables molecular classification of COPD
- 2018
-
In: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 51:5
-
Journal article (peer-reviewed)abstract
- Chronic obstructive pulmonary disease (COPD) is an umbrella diagnosis caused by a multitude of underlying mechanisms, and molecular sub-phenotyping is needed to develop molecular diagnostic/prognostic tools and efficacious treatments.The objective of these studies was to investigate whether multi-omics integration improves the accuracy of molecular classification of COPD in small cohorts.Nine omics data blocks (comprising mRNA, micro RNA, proteomes and metabolomes) collected from several anatomical locations from 52 female subjects were integrated by similarity network fusion (SNF). Multi-omics integration significantly improved the accuracy of group classification of COPD patients from healthy never-smokers and from smokers with normal spirometry, reducing required group sizes from n=30 to n=6 at 95% power. Seven different combinations of four to seven omics platforms achieved >95% accuracy.For the first time, a quantitative relationship between multi-omics data integration and accuracy of data-driven classification power has been demonstrated across nine omics data blocks. Integrating five to seven omics data blocks enabled 100% correct classification of COPD diagnosis with groups as small as n=6 individuals, despite strong confounding effects of current smoking. These results can serve as guidelines for the design of future systems-based multi-omics investigations, with indications that integrating five to six data blocks from several molecular levels and anatomical locations suffices to facilitate unsupervised molecular classification in small cohorts.
|
|
| 42. |
|
|
| 43. |
- Li, CX, et al.
(author)
-
miRNA-mRNA-protein dysregulated network in COPD in women
- 2022
-
In: Frontiers in genetics. - : Frontiers Media SA. - 1664-8021. ; 13, s. 1010048-
-
Journal article (peer-reviewed)abstract
- Rationale: Chronic obstructive pulmonary disease (COPD) is a complex disease caused by a multitude of underlying mechanisms, and molecular mechanistic modeling of COPD, especially at a multi-molecular level, is needed to facilitate the development of molecular diagnostic and prognostic tools and efficacious treatments.Objectives: To investigate the miRNA–mRNA–protein dysregulated network to facilitate prediction of biomarkers and disease subnetwork in COPD in women.Measurements and Results: Three omics data blocks (mRNA, miRNA, and protein) collected from BAL cells from female current-smoker COPD patients, smokers with normal lung function, and healthy never-smokers were integrated with miRNA–mRNA–protein regulatory networks to construct a COPD-specific dysregulated network. Furthermore, downstream network topology, literature annotation, and functional enrichment analysis identified both known and novel disease-related biomarkers and pathways. Both abnormal regulations in miRNA-induced mRNA transcription and protein translation repression play roles in COPD. Finally, the let-7-AIFM1-FKBP1A pathway is highlighted in COPD pathology.Conclusion: For the first time, a comprehensive miRNA–mRNA–protein dysregulated network of primary immune cells from the lung related to COPD in females was constructed to elucidate specific biomarkers and disease pathways. The multi-omics network provides a new molecular insight from a multi-molecular aspect and highlights dysregulated interactions. The highlighted let-7-AIFM1-FKBP1A pathway also indicates new hypotheses of COPD pathology.
|
|
| 44. |
|
|
| 45. |
|
|
| 46. |
|
|
| 47. |
|
|
| 48. |
|
|
| 49. |
|
|
| 50. |
- Lundahl, J, et al.
(author)
-
Human blood monocytes, but not alveolar macrophages, reveal increased CD11b/CD18 expression and adhesion properties upon receptor-dependent activation
- 1996
-
In: The European respiratory journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 9:6, s. 1188-1194
-
Journal article (peer-reviewed)abstract
- The beta 2 integrin receptor CD11b/CD18 mediates adhesion to the endothelial lining as well as to extracellular matrix components. The present study was undertaken to investigate peripheral human blood monocytes (BMs) and alveolar macrophages (AMs) with respect to quantitative levels of CD11b/CD18 and adhesion properties in relation to the state of activation. BMs and AMs were recruited from healthy subjects. Quantitative analysis of the surface expression of CD11b/CD18 by flow cytometric technique and adhesion properties to albumin-coated surfaces were performed both on resting and N-formyl-methionyl-leucyl-phenylalanine (fMLP)-activated cells. Receptor independent stimuli (phorbol-12-myristate-13-acetate (PMA) and ionomycin) were used in additional experiments. Intracellular stored CD11b/CD18 was evaluated by flow cytometry and immunofluorescence microscopy. The surface expression of CD11b/CD18 on resting BMs increased fivefold (p < 0.01) upon fMLP activation. On resting AMs, the surface expression of CD11b/CD18 was significantly higher (p < 0.01) compared to resting BMs but did not increase further upon activation with fMLP, PMA or ionomycin. In contrast to BMs, no evidence for an additional intracellular pool of CD11b/CD18 was found in AMs. The adherence of resting BMs did not significantly differ from the adherence of resting AMs. After fMLP activation, the adherence of BMs, but not AMs, increased significantly (p < 0.05). Our results indicate that in vivo differentiation of human blood monocytes into alveolar macrophages implies reduced responsiveness to fMLP in terms of CD11b/CD18 upregulation and adhesion properties, and that the lack of upregulation of CD11b/CD18 on alveolar macrophages presumably depends on the absence of an additional intracellular pool.
|
|
