Development of multi-cellular human lung models to study inflammatory mechanisms and cell-cell interactions
Author: Ji, Jie
Date: 2018-06-08
Location: Farmakologens föreläsningssal, Nanna Svartz väg 2, Karolinska Institutet, Solna.
Time: 9.00
Department: Institutet för miljömedicin / Institute of Environmental Medicine
View/ Open:
Thesis (5.155Mb)
Abstract
It is well known that exposure to toxicants in the environment is associated with a wide range of health effects. The airway epithelium which forms the first line of defense, plays critical roles in the defence against inhaled particles, pathogens and toxic agents. Therefore, good and valid human airway models need to be developed to study pathophysiological mechanisms of pulmonary toxicity mediated by xenobiotics. In this thesis, unique systems which combine different human airway cell models (ex vivo and in vitro) and different exposure methods were developed. After exposure, inflammatory and oxidative stress responses, interaction between different cell types, as well as the roles of Toll-like receptors (TLR) were addressed.
In Paper I, we found that TLR ligands increased the release of pro-inflammatory cytokines and chemokines in alveolar macrophage (AMQ) from both healthy non-smokers and smokers with and without chronic obstructive pulmonary disease (COPD), and this induction was attenuated by co-stimulation with glucocorticosteroids. Glucocorticosteroids alone or combined with TLR ligands upregulated the TLR2 expression in AMQ from smokers with and without COPD. Hence glucocorticosteroids both exert an anti-inflammatory effect by inhibiting the inflammatory response and improvement of the host defense response by increasing the TLR2 expression. This may be a contributing mechanism for the positive effect of glucocorticosteroids in the treatment of acute exacerbation caused by microorganisms in COPD.
In Paper II-III, we succeeded in establishing human bronchial epithelial models (primary bronchial epithelial cell cultured at air-liquid interface (PBEC-ALI) with/without fibroblasts). In Paper IV, we built multi-cellular human bronchial models (PBEC-ALI co-cultured with macrophages (MQ); PBEC-ALI/MQ). After airlifting, the bronchial epithelial cells differentiated into ciliated cells, basal cells, mucus producing cells, and Club (Clara) cells which all are cell types present bronchial epithelium in vivo. Interleukin 13 (IL-13) induces mucus producing cell metaplasia and hyperplasia and was used to build up chronic bronchitis-like models including an increased number of mucus-producing cells. By combining these models with a controlled aerosol exposure system (XposeALI), we developed an in vitro testing strategy to mimic in vivo conditions, a strategy which substantially reduces the need for animal models.
In Paper II and III, we demonstrated that the induced inflammatory and oxidative stress responses and altered tissue injury/repair might be responsible for palladium/carbon nanoparticle mediated pulmonary toxicity. In addition, by comparison of inflammatory and oxidative stress response between normal and chronic bronchitis-like models, we found the latter to be more sensitive to particles exposure than the normal models. These results indicated that a pre-existing condition like chronic bronchitis, might lead to an increased risk of nanoparticle mediated health effect indicating an enhanced susceptibility to air pollution exposure in individuals with chronic lung disease compared with healthy subjects.
In Paper IV, we showed that diesel exhaust particles, in PBEC-ALI models, induced inflammatory and oxidative stress responses that were attenuated in the presence of MQ. In PBEC-ALI/MQ, diesel exhaust particle exposure increased the mRNA expression of M2-MQ markers which was not observed in mono-cultures (PBEC-ALI or MQ). These findings indicate that the cross-talk between epithelial cells and MQ, together with particle exposure can drive MQ polarization towards M2-subtype. Therefore, interactions between PBEC and MQ play an important role in resolution of the inflammatory response upon particle exposure.
Taken together, this thesis indicates the role of TLR mediated inflammatory response and oxidative signaling pathway as well as cell-cell interactions after exposure to various toxic components on different lung cell models related to COPD and chronic bronchitis.
In Paper I, we found that TLR ligands increased the release of pro-inflammatory cytokines and chemokines in alveolar macrophage (AMQ) from both healthy non-smokers and smokers with and without chronic obstructive pulmonary disease (COPD), and this induction was attenuated by co-stimulation with glucocorticosteroids. Glucocorticosteroids alone or combined with TLR ligands upregulated the TLR2 expression in AMQ from smokers with and without COPD. Hence glucocorticosteroids both exert an anti-inflammatory effect by inhibiting the inflammatory response and improvement of the host defense response by increasing the TLR2 expression. This may be a contributing mechanism for the positive effect of glucocorticosteroids in the treatment of acute exacerbation caused by microorganisms in COPD.
In Paper II-III, we succeeded in establishing human bronchial epithelial models (primary bronchial epithelial cell cultured at air-liquid interface (PBEC-ALI) with/without fibroblasts). In Paper IV, we built multi-cellular human bronchial models (PBEC-ALI co-cultured with macrophages (MQ); PBEC-ALI/MQ). After airlifting, the bronchial epithelial cells differentiated into ciliated cells, basal cells, mucus producing cells, and Club (Clara) cells which all are cell types present bronchial epithelium in vivo. Interleukin 13 (IL-13) induces mucus producing cell metaplasia and hyperplasia and was used to build up chronic bronchitis-like models including an increased number of mucus-producing cells. By combining these models with a controlled aerosol exposure system (XposeALI), we developed an in vitro testing strategy to mimic in vivo conditions, a strategy which substantially reduces the need for animal models.
In Paper II and III, we demonstrated that the induced inflammatory and oxidative stress responses and altered tissue injury/repair might be responsible for palladium/carbon nanoparticle mediated pulmonary toxicity. In addition, by comparison of inflammatory and oxidative stress response between normal and chronic bronchitis-like models, we found the latter to be more sensitive to particles exposure than the normal models. These results indicated that a pre-existing condition like chronic bronchitis, might lead to an increased risk of nanoparticle mediated health effect indicating an enhanced susceptibility to air pollution exposure in individuals with chronic lung disease compared with healthy subjects.
In Paper IV, we showed that diesel exhaust particles, in PBEC-ALI models, induced inflammatory and oxidative stress responses that were attenuated in the presence of MQ. In PBEC-ALI/MQ, diesel exhaust particle exposure increased the mRNA expression of M2-MQ markers which was not observed in mono-cultures (PBEC-ALI or MQ). These findings indicate that the cross-talk between epithelial cells and MQ, together with particle exposure can drive MQ polarization towards M2-subtype. Therefore, interactions between PBEC and MQ play an important role in resolution of the inflammatory response upon particle exposure.
Taken together, this thesis indicates the role of TLR mediated inflammatory response and oxidative signaling pathway as well as cell-cell interactions after exposure to various toxic components on different lung cell models related to COPD and chronic bronchitis.
List of papers:
I. Ji J, von Schéele I, Billing B, Dahlén B, Lantz AS, Larsson K, Palmberg L. Effects of budesonide on toll-like receptor expression in alveolar macrophages from smokers with and without COPD. Int J Chron Obstruct Pulmon Dis. 2016; 11: 1035–1043.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Ji J, Hedelin A, Malmlöf M, Kessler V, Seisenbaeva G, Gerde P, Palmberg L. Development of Combining of Human Bronchial Mucosa Models with XposeALI® for Exposure of Air Pollution Nanoparticles. PLoS One. 2017 Jan 20; 12(1).
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Ji J, Ganguly K, Mihai X, Jitong S, Malmlöf M, Gerde P, Upadhyay S, Palmberg L. Exposure of normal and chronic bronchitis-like mucosa models to aerosolized carbon nanoparticle : Comparison of pro-inflammatory and oxidative stress response. [Manuscript]
IV. Ji J, Upadhyay S, Xiong X, Malmlöf M, Sandström T, Gerde P, Palmberg L. Multi-cellular Human Bronchial Models Exposed to Diesel Exhaust Particles : Assessment of Inflammation, Oxidative Stress and Macrophage Polarization. Particle and Fibre Toxicology. 2018 May; 15:19.
Fulltext (DOI)
Pubmed
View record in Web of Science®
I. Ji J, von Schéele I, Billing B, Dahlén B, Lantz AS, Larsson K, Palmberg L. Effects of budesonide on toll-like receptor expression in alveolar macrophages from smokers with and without COPD. Int J Chron Obstruct Pulmon Dis. 2016; 11: 1035–1043.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Ji J, Hedelin A, Malmlöf M, Kessler V, Seisenbaeva G, Gerde P, Palmberg L. Development of Combining of Human Bronchial Mucosa Models with XposeALI® for Exposure of Air Pollution Nanoparticles. PLoS One. 2017 Jan 20; 12(1).
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Ji J, Ganguly K, Mihai X, Jitong S, Malmlöf M, Gerde P, Upadhyay S, Palmberg L. Exposure of normal and chronic bronchitis-like mucosa models to aerosolized carbon nanoparticle : Comparison of pro-inflammatory and oxidative stress response. [Manuscript]
IV. Ji J, Upadhyay S, Xiong X, Malmlöf M, Sandström T, Gerde P, Palmberg L. Multi-cellular Human Bronchial Models Exposed to Diesel Exhaust Particles : Assessment of Inflammation, Oxidative Stress and Macrophage Polarization. Particle and Fibre Toxicology. 2018 May; 15:19.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Palmberg, Lena
Co-supervisor: Larsson, Kjell
Issue date: 2018-05-17
Rights:
Publication year: 2018
ISBN: 978-91-7831-051-7
Statistics
Total Visits
Views | |
---|---|
Development ...(legacy) | 954 |
Development ... | 687 |
Total Visits Per Month
September 2023 | October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | |
---|---|---|---|---|---|---|---|
Development ... | 24 | 21 | 12 | 17 | 15 | 16 | 19 |
File Visits
Views | |
---|---|
Thesis_Jie_Ji.pdf | 2924 |
Thesis_Jie_Ji.pdf(legacy) | 563 |
null(legacy) | 1 |
Top country views
Views | |
---|---|
Sweden | 518 |
United States | 219 |
Denmark | 202 |
Germany | 87 |
Ireland | 67 |
Australia | 65 |
United Kingdom | 62 |
China | 39 |
Canada | 27 |
France | 26 |
Top cities views
Views | |
---|---|
Copenhagen | 84 |
Ashburn | 73 |
Dublin | 63 |
Sydney | 61 |
Stockholm | 44 |
Alingsås | 27 |
Spånga | 20 |
Menlo Park | 19 |
Montreal | 19 |
Lane | 14 |