Targeting oxidative stress for the treatment of COPD and its comorbidities
Creators: name: Bernardo, Ivan
Publisher: name: RMIT University
Year: 2024
Subjects: classificationCode: 320299
subject: Clinical sciences not elsewhere classified

description: Chronic obstructive pulmonary disease (COPD) is an incurable global health burden and is characterised by progressive airflow limitation and loss of lung function.  In addition to the pulmonary impact of the disease, COPD patients often develop comorbid diseases such as cardiovascular disease and skeletal muscle wasting, lung cancer and osteoporosis.  One key feature of COPD, yet often underappreciated, is the contribution of oxidative stress in the onset and development of the disease.  Patients experience an increased burden of oxidative stress due to the combined effects of excess reactive oxygen (ROS) and nitrogen species (RNS) generation, antioxidant depletion and reduced antioxidant enzyme activity.  Currently, there is a lack of effective treatments for COPD, and an even greater lack of research regarding interventions that treat both COPD and its comorbidities.  Due to the involvement of oxidative stress in the pathogenesis of COPD and many of its comorbidities, a unique therapeutic opportunity arises where the treatment of a multitude of diseases may be possible with only one therapeutic target. <br><br>In this thesis, we used an established smoke exposure preclinical model of COPD to assess the effectiveness of two novel antioxidant therapies ebeselen and apocynin. Using these compounds, we aimed to determine whether targeting the oxidant-dependent mechanisms that drive COPD and its co-morbidities would have a positive impact on the pulmonary and extrapulmonary manifestations of the disease, specifically in comorbid skeletal muscle wasting. Using this smoke exposure model, we were able to induce several of the key characteristics of COPD including lung inflammation, systemic inflammation, skeletal muscle wasting and oxidative damage.<br><br>We assessed the effectiveness of two antioxidant therapies that act on different levels of the reactive oxygen species cascade via differing mechanisms of action. In Chapter 3, we first assessed the efficacy of the Gpx-1 mimetic ebselen, exploring the impact of enhanced hydrogen peroxide reduction in an established animal model of COPD. Ebselen successfully reduced smoke-induced increases in lung inflammation, lung inflammatory cytokine and chemokine mRNA expression. In contrast, Ebselen had no effect on smoke-induced skeletal muscle and WAT wasting, expression of muscle growth signaling pathways, muscle contractility and function.<br><br>In Chapter 4, apocynin was used to reduce superoxide production via inhibition of NOX-2 in the same in vivo model of COPD. Apocynin proved to be the more effective compound, as it was able to treat both pulmonary and skeletal muscle manifestations in this model. Apocynin successfully reduced CS-induced increases in lung inflammation, lung inflammatory cytokine and chemokine mRNA expression, and lung mass. Apocynin also reduced smoke-induced skeletal muscle and WAT wasting, improved muscle contractility and function, and reduced oxidative damage to muscle tissue. In addition to this, we explored the use of an in vitro hydrogen peroxide exposure model in C2C12 myotube cells to investigate the mechanisms behind oxidant-dependent alterations in skeletal muscle.<br><br>In Chapter 5, we designed, developed and validated a novel methodology of assessing cardiac morphology and function in rodents using transthoracic echocardiography, and aimed to eventually use this methodology to assess the effect of antioxidant therapy in cardiovascular comorbidities of COPD. We demonstrated that examination using the modified mid-right ventricle views has the potential to provide a comprehensive assessment of the RV particularly when standard transthoracic views are often suboptimal. We found that these views enable a large section of the right ventricle free wall to be imaged, enabling assessment of dilatation, wall hypertrophy and also demonstrated that strain analysis is feasible in rodent models of disease.<br><br>Because of the unique interplay between oxidative stress and these diseases, oxidative stress represents a novel target for the treatment of COPD and its comorbidities. The primary findings of this thesis highlight the use of novel antioxidant compounds as viable therapeutic alternatives for the treatment of both pulmonary and extrapulmonary manifestations of COPD. Additionally, validated methods for the identification of the mechanisms that drive the onset and development of comorbidities were established, providing a framework for future studies.