Studies on neurotrophins in inflammatory pulmonary diseases
Author: Dagnell, Charlotta
Date: 2010-02-05
Location: Thoraxaulan, N2:U1, Karolinska Universitetssjukhuset Solna
Time: 09.00
Department: Institutionen för medicin / Department of Medicine
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thesis.pdf (1.427Mb)
Abstract
Asthma, sarcoidosis and chronic obstructive pulmonary disease (COPD) are
inflammatory pulmonary diseases, all being characterized by tissue
inflammation, tissue damage (airway remodeling) and loss of lung
function. In order to increase possibilities to find new biomarkers, drug
targets and better treatment options for the patients, further research
on the underlying mechanisms driving the inflammation and airway
remodeling in these diseases are required. In the present thesis, a
family of mediators, the neurotrophins, were studied to elucidate how
these mediators are involved in the inflammatory and/or airway remodeling
processes in asthma, sarcoidosis and COPD. The neurotrophin family
consists of NGF, BDNF and NT-3, and these factors were initially
characterized for their essential role as survival factors for nerve
cells. However, they have been shown to display a far broader spectrum of
functions, being mediators also involved in inflammation and tissue
remodeling. Indeed, enhanced levels of neurotrophins have been found in
several inflammatory conditions, including allergic diseases, such as
asthma.
The aim of this thesis was to elucidate if neurotrophin levels are altered in inflammatory pulmonary diseases other than asthma. Therefore, we set up studies to determine the protein levels of NGF, BDNF and NT-3 in bronchoalveolar lavage fluid (BALF) from patients with pulmonary sarcoidosis, patients with COPD, and relevant control subjects, including healthy non-smokers and current smokers with normal lung function. In addition, the aim was to study human bronchial smooth muscle cells, as possible target cells for the effects of the neurotrophins in the airways.
We found that, similarly to asthma, sarcoidosis patients showed enhanced levels of both NGF and NT-3 in the airways as compared to healthy subjects. We also investigated the relation between levels of neurotrophins and clinical as well as inflammatory parameters, and found significant positive correlations between NGF and the concentration of lymphocytes and eosinophils, as well as inflammatory cytokines (IFN-γ, IL-4, IL-10, IL-12) in BALF of sarcoidosis patients. We found that the levels of NT-3 were higher in the sub-groups of patients with a higher risk of developing chronic disease and fibrosis, suggesting that NT-3 levels relate to the risk of developing chronic disease. To further elucidate cellular sources of, and possible targets for, neurotrophins, in the lungs of sarcoidosis patients, we performed immunohistochemistry on lung tissue biopsies. We found that granulomas expressed NGF and NT-3, as well as the corresponding neurotrophin receptors TrkA and TrkC, indicating that the granulomas are possible sources of the enhanced levels of neurotrophins in sarcoidosis, and that the neurotrophins may be able to mediate autocrine functions in the granuloma microenvironment.
In contrast to sarcoidosis, COPD patients, as well as smokers with normal lung function, showed decreased levels of NGF and NT-3 in the airways as compared to healthy non-smokers. This indicated that cigarette-smoke exposure may impact neurotrophin content in human airways. Indeed, when exposing human lung fibroblasts in vitro to cigarette smoke extract, a down-regulation of neurotrophin expression was shown on both transcriptional- and protein levels. Studies on human bronchial smooth muscle cells revealed that they are possible target cells for the neurotrophins in the airways, as they express the neurotrophin receptors TrkA, -B, and C, and we showed that NGF, BDNF and NT-3 enhanced the secretion of the tissue degrading enzyme MMP-9, but not MMP-2. Additionally, BDNF and NT-3, but not NGF, stimulated cell migration. These results support the concept that neurotrophins have pro-fibrotic properties and may be involved in airway tissue remodeling, such as that seen in asthma.
Taken together, the results of the present thesis contributes to a better understanding regarding the involvement of neurotrophins in inflammatory pulmonary diseases, and gives further support to the concept of neurotrophins as being mediators involved in airway inflammation and tissue remodeling.
The aim of this thesis was to elucidate if neurotrophin levels are altered in inflammatory pulmonary diseases other than asthma. Therefore, we set up studies to determine the protein levels of NGF, BDNF and NT-3 in bronchoalveolar lavage fluid (BALF) from patients with pulmonary sarcoidosis, patients with COPD, and relevant control subjects, including healthy non-smokers and current smokers with normal lung function. In addition, the aim was to study human bronchial smooth muscle cells, as possible target cells for the effects of the neurotrophins in the airways.
We found that, similarly to asthma, sarcoidosis patients showed enhanced levels of both NGF and NT-3 in the airways as compared to healthy subjects. We also investigated the relation between levels of neurotrophins and clinical as well as inflammatory parameters, and found significant positive correlations between NGF and the concentration of lymphocytes and eosinophils, as well as inflammatory cytokines (IFN-γ, IL-4, IL-10, IL-12) in BALF of sarcoidosis patients. We found that the levels of NT-3 were higher in the sub-groups of patients with a higher risk of developing chronic disease and fibrosis, suggesting that NT-3 levels relate to the risk of developing chronic disease. To further elucidate cellular sources of, and possible targets for, neurotrophins, in the lungs of sarcoidosis patients, we performed immunohistochemistry on lung tissue biopsies. We found that granulomas expressed NGF and NT-3, as well as the corresponding neurotrophin receptors TrkA and TrkC, indicating that the granulomas are possible sources of the enhanced levels of neurotrophins in sarcoidosis, and that the neurotrophins may be able to mediate autocrine functions in the granuloma microenvironment.
In contrast to sarcoidosis, COPD patients, as well as smokers with normal lung function, showed decreased levels of NGF and NT-3 in the airways as compared to healthy non-smokers. This indicated that cigarette-smoke exposure may impact neurotrophin content in human airways. Indeed, when exposing human lung fibroblasts in vitro to cigarette smoke extract, a down-regulation of neurotrophin expression was shown on both transcriptional- and protein levels. Studies on human bronchial smooth muscle cells revealed that they are possible target cells for the neurotrophins in the airways, as they express the neurotrophin receptors TrkA, -B, and C, and we showed that NGF, BDNF and NT-3 enhanced the secretion of the tissue degrading enzyme MMP-9, but not MMP-2. Additionally, BDNF and NT-3, but not NGF, stimulated cell migration. These results support the concept that neurotrophins have pro-fibrotic properties and may be involved in airway tissue remodeling, such as that seen in asthma.
Taken together, the results of the present thesis contributes to a better understanding regarding the involvement of neurotrophins in inflammatory pulmonary diseases, and gives further support to the concept of neurotrophins as being mediators involved in airway inflammation and tissue remodeling.
List of papers:
I. Dagnell C, Kemi C, Klominek J, Eriksson P, Sköld CM, Eklund A, Grunewald J, Olgart Höglund C (2007). "Effects of neurotrophins on human bronchial smooth muscle cell migration and matrix metalloproteinase-9 secretion." Transl Res 150(5): 303-10. Epub 2007 May 29
Pubmed
II. Dagnell C, Grunewald J, Idali F, Wikén M, Kemi C, Sköld CM, Planck A, Newman LS, Eklund A, Olgart Höglund C (2008). "Increased levels of nerve growth factor in the airways of patients with sarcoidosis." J Intern Med 264(5): 463-71. Epub 2008 Sep 6
Pubmed
III. Dagnell C, Grunewald J, Kramar M, Haugom-Olsen H, Elmberger G, Eklund A, Olgart Höglund C (2010). "Neurotrophins and neurotrophin receptors in pulmonary sarcoidosis - granulomas as a source of expression." (Manuscript)
IV. Dagnell C, Mikko M, Roos-Engstrand E, Löfdahl M, Blomberg A, Sköld CM, Olgart Höglund C (2010). "Airway nerve growth factor and neurotrophin-3 are decreased in patients with COPD and in smokers." (Submitted)
I. Dagnell C, Kemi C, Klominek J, Eriksson P, Sköld CM, Eklund A, Grunewald J, Olgart Höglund C (2007). "Effects of neurotrophins on human bronchial smooth muscle cell migration and matrix metalloproteinase-9 secretion." Transl Res 150(5): 303-10. Epub 2007 May 29
Pubmed
II. Dagnell C, Grunewald J, Idali F, Wikén M, Kemi C, Sköld CM, Planck A, Newman LS, Eklund A, Olgart Höglund C (2008). "Increased levels of nerve growth factor in the airways of patients with sarcoidosis." J Intern Med 264(5): 463-71. Epub 2008 Sep 6
Pubmed
III. Dagnell C, Grunewald J, Kramar M, Haugom-Olsen H, Elmberger G, Eklund A, Olgart Höglund C (2010). "Neurotrophins and neurotrophin receptors in pulmonary sarcoidosis - granulomas as a source of expression." (Manuscript)
IV. Dagnell C, Mikko M, Roos-Engstrand E, Löfdahl M, Blomberg A, Sköld CM, Olgart Höglund C (2010). "Airway nerve growth factor and neurotrophin-3 are decreased in patients with COPD and in smokers." (Submitted)
Issue date: 2010-01-15
Rights:
Publication year: 2010
ISBN: 978-91-7409-768-9
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