Unit of Lung and Airway Research
Environmental Impact on Host Defense in Chronic Airway Diseases: Role of IL-17 Signaling and Toll-Like Receptors
Inhaled agents constitute an important cause of chronic obstructive pulmonary disease (COPD). For this global killer, tobacco smoking is the major cause in in industrialised countries. However, approximately 15% of all cases of COPD are due to occupational exposure and a substantial fraction relates to the farming environment. Both COPD and asthma, the other truly common chronic airway disease in industrialized countries, display underlying pathology with common characteristics. This pathology leads to bacterial colonisation and results in an increased rate of respiratory infections. For COPD and for severe asthma, these infections are closely linked to the clinical course of the disease. This is particularly true for patients that have chronic bronchitis on top of their COPD or asthma. Most unfortunately, there is no effective pharmacotherapy to treat the susceptibility to infections for COPD and severe asthma.
We know that the malfunction of pulmonary host defense is signified by an excess accumulation and activation of innate effector cells in both COPD and severe asthma. This accumulation includes both macrophages and neutrophils. However, whereas it is likely that the inability of these effector cells to fight bacteria is critical for the pathogenesis and clinical course of both diseases, the exact nature of the underlying immunological aberrations are uncertain. It remains unknown what particular aspects of the mobilization of innate effector cells that are failing.
Several clinical studies suggest that the immunological malfunction in COPD and severe asthma is associated with an altered release of coordinating cytokines; including cytokines that are produced by lymphocytes. Our first line of research is centered round the idea that long-term exposure to environmental agents, such as smoke, organic dust and particulate matter, alters the ability of adaptive immune cells to coordinate innate immune cells via specific cytokines. We believe that this is important for the pathogenesis in COPD and severe asthma, and that novel therapeutic targets can be identified among the molecular mechanisms involved in this immunological malfunction. For this line of research, our key hypothesis is that the ability of specific subsets of T lymphocytes to signal via interleukin(IL)-17 during bacterial infections is distorted by environmental agents.
The immunological malfunction in COPD and severe asthma is likely also to include aberrations in the responsiveness in the innate effector cells per se. Our second line of research is centered on the idea that these aberrations involve Toll-like receptors (TLR); a range of more than 10 receptors that recognise and bind microbes and their products at bronchial epithelial cells and macrophages, as well as on neutrophils. Of key importance: It is known that airway macrophages and neutrophils from patients with COPD and from healthy smokers express less TLR2 compared to healthy non-smoking controls. It is also known that swine farmers, subjects heavily exposed to organic dust, express lower levels of TLR in blood and respiratory tract compared to healthy controls. However, the regulatory mechanisms behind this phenomenon remain unknown. For this line of research, our key hypothesis is that down regulated expression of TLR2 in smokers and farmers increases susceptibility to bacterial infection as well as colonization, and that this is linked to the pathogenesis behind COPD including chronic bronchitis.
It was early recognized that anticholinergic agents were useful for the prevention of COPD exacerbations. The relationship between clinical therapy and immunological malfunction in COPD remains poorly understood, in particular with reference to anti-cholinergic therapy. Recently, functional muscarinic receptors and the presence of choline acetyl transferase and acetylcholine esterase in inflammatory cells have been documented. Our third line of research is therefore focused on the immunological importance of cholinergic mechanism in COPD. Here, the key hypothesis is that the preventive effect of anticholinergic agents on exacerbations relates to interactions with innate effector mechanisms.
In the unit of Lung and Airway Research (LAR), we conduct translational studies of human airways, using short- and long-term exposure models and clinical settings to characterize the inherent and induced release of IL-17 and associated cytokines, expression of TLR and cholinergic mechanisms in relation to clinical parameters including pulmonary function. We also dissect the cellular and molecular mechanisms behind these events, in primary human cells cultured in 3D-models and in genetically altered cells, as well as animal models. Our long term goal is to characterize the impact of exposure to tobacco smoke, wood fire smoke, organic dust, as well as particulate matter from industrial and metropolitan environments.
By identifying and characterizing cellular and molecular events behind the malfunction in local host defense in COPD and severe asthma, we can identify novel targets for specific pharmacotherapy against chronic airway diseases. Hopefully, novel targets for the diagnosis and monitoring of chronic airway disorders can be identified as well. Moreover, added knowledge about the significance of cholinergic interactions with inflammatory mechanisms in COPD will increase the possibilities to develop the use of existing as well new variants of anti-cholinergic drugs against chronic airway diseases in the near future.
Head of Unit
|Anna Hedelin||PhD student|
|Jie Ji||PhD student|
|Bettina Levänen||Senior lab manager|
|Anders Lindén||Professor/senior physician|
|Lena Palmberg||Senior researcher|
|Britt-Marie Sundblad||Senior researcher|
- Th17-associated cytokines and host defense in smokers
- The IL-36 family of cytokines in chronic obstructive pulmonary disease
- Cadmium as a pathogenic factor in tobacco smokers
- Lung development and COPD
- Inflammatory mechanisms in chronic bronchitis – studies in vivo and in vitro
- New systems for exposing human 3D-models of airway mucosa in health and disease to particulate- and gaseous air pollutants
- Detailed study on Toll-like receptor (TLR) mediated immune and pro-inflammatory response to carbon nanoparticle exposure in vitro