Abstract
Wilfred Poppinga aimed to unravel the role of A-kinase anchoring proteins (AKAPs) in the lung in relation to chronic obstructive pulmonary disease (COPD). COPD is an inflammatory disease particularly caused by cigarette smoking, with patients suffering from chronic and progressive airway obstruction that is treated with bronchodilators, including β2-agonists. AKAPs bind protein kinase A (PKA), which may be important for mediating β2-agonist-induced responses in the airways. Poppinga and colleagues focused on the role of AKAPs in the regulation of bronchodilatory actions of β2-agonists as well as pulmonary inflammation in the context of COPD.
It was found that human airway smooth muscle cells, which play a role both in bronchoconstriction and inflammation, express several AKAPs, including AKAP5 and AKAP12, known to bind the β2-adrenoceptor. Importantly, the amount of AKAP5 and AKAP12 was lower in lungs from COPD patients, which may be related to smoking as cigarette smoke extract reduced their expression in airway smooth muscle cells.
Disruption of AKAP-PKA interactions with st-Ht31 in airway smooth muscle cells increased cigarette smoke extract-induced release of the pro-inflammatory interleukin-8, which attracts neutrophilic inflammatory cells. In line with this, cigarette smoke induced a stronger neutrophilic inflammation in mice that lack AKAP5. Mice lacking AKAP12 already had increased infiltration of inflammatory cells in the lung at baseline.
Mice lacking AKAP12 also showed reduced β2-agonist-induced airway smooth muscle relaxation. In line, different variants (single nucleotide polymorphisms) of the human AKAP12 gene were found, that affect the amino acid sequence but not the gene expression of AKAP12 and that were associated with a varying β2-agonist-induced bronchodilation.
The reduction in AKAP5 and AKAP12 in COPD could therefore contribute to pulmonary inflammation, particularly neutrophilia, and may limit β2-agonist-induced bronchodilation. Therefore, restoring AKAP5 and/or AKAP12 expression could decrease COPD progression and enhance pharmacological treatment of this disease.
It was found that human airway smooth muscle cells, which play a role both in bronchoconstriction and inflammation, express several AKAPs, including AKAP5 and AKAP12, known to bind the β2-adrenoceptor. Importantly, the amount of AKAP5 and AKAP12 was lower in lungs from COPD patients, which may be related to smoking as cigarette smoke extract reduced their expression in airway smooth muscle cells.
Disruption of AKAP-PKA interactions with st-Ht31 in airway smooth muscle cells increased cigarette smoke extract-induced release of the pro-inflammatory interleukin-8, which attracts neutrophilic inflammatory cells. In line with this, cigarette smoke induced a stronger neutrophilic inflammation in mice that lack AKAP5. Mice lacking AKAP12 already had increased infiltration of inflammatory cells in the lung at baseline.
Mice lacking AKAP12 also showed reduced β2-agonist-induced airway smooth muscle relaxation. In line, different variants (single nucleotide polymorphisms) of the human AKAP12 gene were found, that affect the amino acid sequence but not the gene expression of AKAP12 and that were associated with a varying β2-agonist-induced bronchodilation.
The reduction in AKAP5 and AKAP12 in COPD could therefore contribute to pulmonary inflammation, particularly neutrophilia, and may limit β2-agonist-induced bronchodilation. Therefore, restoring AKAP5 and/or AKAP12 expression could decrease COPD progression and enhance pharmacological treatment of this disease.
| Original language | English |
|---|---|
| Qualification | Doctor of Philosophy |
| Awarding Institution |
|
| Supervisors/Advisors |
|
| Award date | 2-Dec-2016 |
| Place of Publication | [Groningen] |
| Publisher | |
| Print ISBNs | 978-90-367-9226-4 |
| Electronic ISBNs | 978-90-367-9227-1 |
| Publication status | Published - 2016 |