Novel Strategies in the Treatment of COPD: Focus on oxidative stress and a-kinase anchoring proteins

Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation and airway inflammation. Since the current medications are not always effective and fail to reduce the progression of COPD, studies for novel strategies are necessary. The objective of this thesis was to investigate possible targets for the treatments of COPD, with a focus on the involvement of A-kinase anchoring proteins (AKAPs) and oxidative stress.
AKAPs enable compartmentalized cAMP signaling, which plays an important role in regulation of processes that are involved in the pathophysiology of COPD, such as airway smooth muscle (ASM) contraction and ASM proliferation.
By interrupting AKAP-PKA interactions, the peptide st-Ht31 increased ASM contraction. This is likely caused by the fact the st-Ht31 increased the expression of contractile proteins, such as α-SMA and calponin on a post-transcriptional level, in a complex that presumably also involves proteasomes. Moreover, st-Ht31 increased proliferative markers, presumably by lowering the expression of AKAP8 which is known to regulate the cell cycle.
Overproduction of reactive oxygen species (ROS) can induce oxidative stress, which is believed to play a central role in the pathophysiology of COPD. By directly neutralizing ROS, we found that the novel compound Sul-121 reduced activation of NF-κB, thereby preventing IL-8 release and subsequent airway neutrophilia in lipopolysaccharide (LPS)-treated guinea pigs as an animal model for COPD. Moreover, Sul-121 prevented LPS-induced airway hyperresponsiveness in this guinea pig model of COPD, presumably by inhibiting the LPS-induced lung inflammation.
The studies described in this thesis by Bing Han highlight new insights in the pathophysiology of COPD that may lead to novel treatments for COPD.