Novel Pharmacological Strategies to Treat Cigarette Smoking-induced Atherogenesis in Chronic Obstructive Pulmonary Disease

Abstract

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory condition characterised by persistent airflow limitation and chronic lung inflammation, primarily driven by exposure to noxious particles and gases such as cigarette smoke (CS). Repeated CS exposure induces oxidative stress and disrupts pulmonary barrier integrity, leading to the “spill-over” of inflammatory mediators into the systemic circulation. This systemic inflammation contributes to vascular dysfunction and platelet activation, which are key drivers of cardiovascular disease (CVD) - a major comorbidity in COPD. This thesis investigated the mechanistic links between CS-induced oxidative stress, systemic inflammation, and vascular pathology using a validated preclinical model of COPD. It further evaluated the therapeutic potential of antioxidant and lifestyle-based interventions, including apocynin, carnosine supplementation, and exercise intervention, with a focus on sex-specific responses. In Chapter 3, apocynin - a NADPH oxidase inhibitor - was shown to attenuate CS-induced airway inflammation, preserve endothelial-dependent vasodilation, and reduce platelet activation, highlighting oxidative stress as a modifiable trait in COPD. Chapter 4 demonstrated that carnosine supplementation or exercise alone reduced airway inflammation and partially restored vascular function, while Chapter 5 revealed that their combination produced synergistic benefits. The combined intervention significantly preserved body weight, improved endothelial function, and prevented platelet activation, outperforming either treatment alone. Chapter 6 explored sex-specific responses to CS and intervention. Males exhibited heightened neutrophilic inflammation, vascular dysfunction, and platelet adhesion, whereas females showed greater lymphocytosis and epithelial thickening. The combined therapy mitigated these effects in both sexes, though the magnitude and mechanisms of response varied, underscoring the importance of sex as a biological variable in COPD research. In conclusion, this thesis provides mechanistic evidence that CS-induced oxidative stress and systemic inflammation drive vascular dysfunction and platelet activation in COPD. It establishes that combining carnosine supplementation with exercise offers a promising strategy to protect vascular integrity and reduce systemic inflammation. The observed sex differences further support the need for personalised therapeutic approaches in COPD management.