Defining molecular pathways regulating musculoskeletal disorders in COPD and acute exacerbation
Creators: name: Mou, Kevin
Publisher: name: RMIT University
Year: 2024
Subjects: classificationCode: 320103
subject: Respiratory diseases
classificationCode: 321401
subject: Basic pharmacology

description: Chronic obstructive pulmonary disease (COPD) is currently the third leading cause of death globally and is characterised by persistent airflow limitation and lung inflammation that causes a progressive, irreversible decline in lung function. The pathology of COPD is predominantly due to exposure of the lungs to noxious particles and gases such as from cigarette smoke (CS), which induces structural damages and persistent inflammation of the airways and lung parenchyma. This leads to airway remodelling and parenchymal destruction, and results in excessive production of reactive oxygen species and inflammatory molecules. Patients with COPD are also more susceptible to viral respiratory infections, leading to episodes of aggravated respiratory symptoms termed acute exacerbations of COPD (AECOPD) which further amplify lung inflammation and ROS production. Spill-over of pro-inflammatory mediators from the lungs into the systemic circulation impacts on the homeostatic balance of distal organs and tissues, which leads to both onset and progression of comorbidities such as musculoskeletal disorders.

Musculoskeletal disorders including loss of muscle mass and strength, and osteoporosis, are common in patients with COPD. Muscle dysfunction occurs in up 40% of patients with COPD and is associated with muscle weakness and reduced exercise tolerance. COPD patients with muscle wasting have impaired functional capacity which negatively affects their quality of life. Importantly, clinical data has shown that reduced muscle mass and strength are strong predictors of mortality in COPD patients independent of lung function impairment. Following an episode of AECOPD, skeletal muscle outcomes are often further deteriorated and may only be partially recovered even long after discharge from hospital. Furthermore, the likelihood of subsequent hospital admission for AECOPD is correlated with reduced muscle mass at time of previous discharge, highlighting the significance of muscle dysfunction in AECOPD. The interconnected nature of muscle and bone tissues implies a close anatomical relationship. Furthermore, recent studies have suggested that muscle and bone are able to communicate through the release of chemokines and cytokines. Moreover, outcomes related to bone health such as fracture and fall risk, and subsequent recovery, are closely linked to the status of the muscle, and are commonly worsened in individuals with COPD compared to healthy counterparts, especially following AECOPD. Despite this, the mechanisms driving skeletal muscle dysfunction and bone loss in AECOPD remain poorly defined.
 
In this thesis, a pre-established preclinical in ameliorating pulmonary and extrapulmonary manifestations. Oxidative stress has been implicated as a significant driver of not only the excessive pulmonary inflammation present in individuals with stable and AECOPD, but also the peripheral comorbidities such as musculoskeletal dysfunction. This proof-of-concept study characterised the negative impacts of viral exacerbation on muscle and bone tissue, thus supporting the rationale of oxidative stress-modulating therapeutic strategies to manage and treat AECOPD-associated muscle and bone deteriorations. 

In Chapter 3, we investigated the effects of viral-induced AECOPD on muscle mass and function. CS exposure followed by influenza A infection further increased immune cell infiltration into the lungs, indicative of an exacerbation phenotype reminiscent of human AECOPD. We demonstrated a further reduction of muscle contractile strength during the peak of the airway inflammation, which was independent of changes in muscle mass and physical activity. These changes were associated with altered muscle phenotype, enhanced oxidative stress, and increased expression of muscle wasting markers.
 
In Chapter 4, we further assessed the impact of airway inflammation on myogenic signalling, based on our observation in Chapter 3 that despite peak airway inflammation, muscle mass was not further affected. A novel in vitro cell model was developed which encapsulates the proposed ‘spill-over’ phenomenon that is responsible for the onset of extrapulmonary comorbidities including musculoskeletal disorders. We demonstrated a disconnection between heightened airway inflammation and disruption to myogenic signalling, suggesting muscle weakness during AECOPD maybe independent of airway inflammation, affirming our finding in the previous chapter. 

In Chapter 5, we examined the effectiveness of targeting oxidative stress in alleviating airway inflammation and muscle dysfunction by viral-induced AECOPD. Prophylactic administration of ebselen was found to suppress the excessive recruitment of neutrophils into the alveoli, while also preventing the exacerbation-induced worsening of muscle contractile dysfunction. 

In Chapter 6, we investigated the impact of viral-induced AECOPD on bone structure due to the close anatomical relationship between muscle and bone. We found that CS exposure or influenza A infection alone was sufficient to cause a decreased bone volume, which is the likely outcome of an imbalanced bone turnover. This thesis highlights the potential of ebselen as a therapeutic agent and the targeting oxidative stress as a management strategy for the pulmonary and musculoskeletal manifestations during stable COPD and AECOPD. We have also established and characterised a preclinical AECOPD model which recapitulates key aspects of the human disease, thus permitting more in-depth mechanistic investigation regarding the development and progression of musculoskeletal disorders, in the future.