PhD ceremony: Mr. T. Pera, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen
Dissertation: Inflammation and remodelling in experimental models of COPD. Mechanisms and therapeutic perspectives
Promotor(s): prof. H. Meurs, prof. J. Zaagsma
Faculty: Mathematics and Natural Sciences
Chronic obstructive pulmonary disease (COPD), primarily caused by smoking, is characterized by a progressive decline of lung function. Pulmonary inflammation in this disease leads to the development of structural abnormalities, including emphysema and airway remodelling, which contribute to the airflow limitation. This thesis explores novel mechanisms involved in the pathophysiology of COPD.
Using chronic intranasal instillation of lipopolysaccharide (LPS) in guinea pigs, a new animal model of COPD was developed. Using this model, we demonstrated that inhalation of the long-acting anticholinergic bronchodilator, tiotropium, inhibits the development of airway inflammation and remodelling. These results suggest a major role for endogenous acetylcholine in the pathophysiology of COPD and reveal potential mechanisms underlying the non-bronchodilator effects of tiotropium, as found recently in a large clinical trial. In addition, we demonstrated increased pulmonary activity of the enzyme arginase in our COPD model. Inhalation of a specific arginase inhibitor reduced airway inflammation, remodelling and right ventricular hypertrophy, indicating for the first time that increased arginase activity contributes to the pathophysiology of COPD as well.
Since increased airway smooth muscle (ASM) mass is a feature of airway remodelling in COPD, our in vitro studies focused on molecular mechanisms of ASM cell proliferation and pro-inflammatory cytokine release. Exposure of ASM to cigarette smoke extract (CSE) or LPS in vitro induced a proliferative ASM phenotype, in a mitogen-activated protein kinase (MAPK)-dependent manner. Furthermore, TGF-β-activated kinase 1 (TAK1) was identified as a key mediator of growth factor-induced MAPK signalling as well as of CSE-induced MAPK and NF-κB signalling, resulting in ASM phenotypic modulation and pro-inflammatory cytokine production, respectively.
To summarize, within the framework of this thesis we developed new in vitro and in vivo models for COPD and used these to identify novel mechanisms of inflammation and remodelling in this disease.
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