| 1. |
- Andersson, Cecilia K, et al.
(författare)
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Activated MCTC mast cells infiltrate diseased lung areas in cystic fibrosis and idiopathic pulmonary fibrosis
- 2011
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Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 12:139
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Tidskriftsartikel (refereegranskat)abstract
- Background: Although mast cells are regarded as important regulators of inflammation and tissue remodelling, their role in cystic fibrosis (CF) and idiopathic pulmonary fibrosis (IPF) has remained less studied. This study investigates the densities and phenotypes of mast cell populations in multiple lung compartments from patients with CF, IPF and never smoking controls. Methods: Small airways, pulmonary vessels, and lung parenchyma were subjected to detailed immunohistochemical analyses using lungs from patients with CF (20 lung regions; 5 patients), IPF (21 regions; 7 patients) and controls (16 regions; 8 subjects). In each compartment the densities and distribution of MCT and MCTC mast cell populations were studied as well as the mast cell expression of IL-6 and TGF-beta. Results: In the alveolar parenchyma in lungs from patients with CF, MCTC numbers increased in areas showing cellular inflammation or fibrosis compared to controls. Apart from an altered balance between MCTC and MCT cells, mast cell in CF lungs showed elevated expression of IL-6. In CF, a decrease in total mast cell numbers was observed in small airways and pulmonary vessels. In patients with IPF, a significantly elevated MCTC density was present in fibrotic areas of the alveolar parenchyma with increased mast cell expression of TGF-beta. The total mast cell density was unchanged in small airways and decreased in pulmonary vessels in IPF. Both the density, as well as the percentage, of MCTC correlated positively with the degree of fibrosis. The increased density of MCTC, as well as MCTC expression of TGF-beta, correlated negatively with patient lung function. Conclusions: The present study reveals that altered mast cell populations, with increased numbers of MCTC in diseased alveolar parenchyma, represents a significant component of the histopathology in CF and IPF. The mast cell alterations correlated to the degree of tissue remodelling and to lung function parameters. Further investigations of mast cells in these diseases may open for new therapeutic strategies.
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| 2. |
- Andersson Sjöland, Annika, et al.
(författare)
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Fibrocytes are associated with vascular and parenchymal remodelling in patients with obliterative bronchiolitis.
- 2009
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Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 10:Oct 30
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The aim of the present study was to explore the occurrence of fibrocytes in tissue and to investigate whether the appearance of fibrocytes may be linked to structural changes of the parenchyme and vasculature in the lungs of patients with obliterative bronchiolitis (OB) following lung or bone marrow transplantation. METHODS: Identification of parenchyme, vasculature, and fibrocytes was done by histological methods in lung tissue from bone marrow or lung-transplanted patients with obliterative bronchiolitis, and from controls. RESULTS: The transplanted patients had significantly higher amounts of tissue in the alveolar parenchyme (46.5 +/- 17.6%) than the controls (21.7 +/- 7.6%) (p < 0.05). The patients also had significantly increased numbers of fibrocytes identified by CXCR4/prolyl4-hydroxylase, CD45R0/prolyl4-hydroxylase, and CD34/prolyl4-hydroxylase compared to the controls (p < 0.01). There was a correlation between the number of fibrocytes and the area of alveolar parenchyma; CXCR4/prolyl 4-hydroxylase (p < 0.01), CD45R0/prolyl 4-hydroxylase (p < 0.05) and CD34/prolyl 4-hydroxylase (p < 0.05). In the pulmonary vessels, there was an increase in the endothelial layer in patients (0.31 +/- 0.13%) relative to the controls (0.037 +/- 0.02%) (p < 0.01). There was a significant correlation between the number of fibrocytes and the total area of the endothelial layer CXCR4/prolyl 4-hydroxylase (p < 0.001), CD45R0/prolyl 4-hydroxylase (p < 0.001) and CD34/prolyl 4-hydroxylase (p < 0.01). The percent areas of the lumen of the vessels were significant (p < 0.001) enlarged in the patient with OB compared to the controls. There was also a correlation between total area of the lumen and number of fibrocytes, CXCR4/prolyl 4-hydroxylase (p < 0.01), CD45R0/prolyl 4-hydroxylase (p < 0.001) and CD34/prolyl 4-hydroxylase (p < 0.01). CONCLUSION: Our results indicate that fibrocytes are associated with pathological remodelling processes in patients with OB and that tissue fibrocytes might be a useful biomarker in these processes.
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| 3. |
- Hallgren, Oskar, et al.
(författare)
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Altered fibroblast proteoglycan production in COPD
- 2010
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Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Airway remodeling in COPD includes reorganization of the extracellular matrix. Proteoglycans play a crucial role in this process as regulators of the integrity of the extracellular matrix. Altered proteoglycan immunostaining has been demonstrated in COPD lungs and this has been suggested to contribute to the pathogenesis. The major cell type responsible for production and maintenance of ECM constituents, such as proteoglycans, are fibroblasts. Interestingly, it has been proposed that central airways and alveolar lung parenchyma contain distinct fibroblast populations. This study explores the hypothesis that altered depositions of proteoglycans in COPD lungs, and in particular versican and perlecan, is a result of dysregulated fibroblast proteoglycan production. Methods: Proliferation, proteoglycan production and the response to TGF-beta(1) were examined in vitro in centrally and distally derived fibroblasts isolated from COPD patients (GOLD stage IV) and from control subjects. Results: Phenotypically different fibroblast populations were identified in central airways and in the lung parenchyma. Versican production was higher in distal fibroblasts from COPD patients than from control subjects (p < 0.01). In addition, perlecan production was lower in centrally derived fibroblasts from COPD patients than from control subjects (p < 0.01). TGF-beta(1) triggered similar increases in proteoglycan production in distally derived fibroblasts from COPD patients and control subjects. In contrast, centrally derived fibroblasts from COPD patients were less responsive to TGF-beta(1) than those from control subjects. Conclusions: The results show that fibroblasts from COPD patients have alterations in proteoglycan production that may contribute to disease development. Distally derived fibroblasts from COPD patients have enhanced production of versican that may have a negative influence on the elastic recoil. In addition, a lower perlecan production in centrally derived fibroblasts from COPD patients may indicate alterations in bronchial basement membrane integrity in severe COPD.
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| 4. |
- Hallgren, Oskar, et al.
(författare)
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Enhanced ROCK1 dependent contractility in fibroblast from chronic obstructive pulmonary disease patients
- 2012
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: During wound healing processes fibroblasts account for wound closure by adopting a contractile phenotype. One disease manifestation of COPD is emphysema which is characterized by destruction of alveolar walls and our hypothesis is that fibroblasts in the COPD lungs differentiate into a more contractile phenotype as a response to the deteriorating environment. Methods: Bronchial (central) and parenchymal (distal) fibroblasts were isolated from lung explants from COPD patients (n = 9) (GOLD stage IV) and from biopsies from control subjects and from donor lungs (n = 12). Tissue-derived fibroblasts were assessed for expression of proteins involved in fibroblast contraction by western blotting whereas contraction capacity was measured in three-dimensional collagen gels. Results: The basal expression of rho-associated coiled-coil protein kinase 1 (ROCK1) was increased in both centrally and distally derived fibroblasts from COPD patients compared to fibroblasts from control subjects (p < 0.001) and (p < 0.01), respectively. Distally derived fibroblasts from COPD patients had increased contractile capacity compared to control fibroblasts (p < 0.01). The contraction was dependent on ROCK1 activity as the ROCK inhibitor Y27632 dose-dependently blocked contraction in fibroblasts from COPD patients. ROCK1-positive fibroblasts were also identified by immunohistochemistry in the alveolar parenchyma in lung tissue sections from COPD patients. Conclusions: Distally derived fibroblasts from COPD patients have an enhanced contractile phenotype that is dependent on ROCK1 activity. This feature may be of importance for the elastic dynamics of small airways and the parenchyma in late stages of COPD.
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