Novel pharmacological strategies to treat cognitive dysfunction in chronic obstructive pulmonary disease (COPD)

Chronic obstructive pulmonary disease (COPD) is an irreversible disease characterised by persistent airflow limitation, respiratory symptoms and a significantly reduced quality of life. Currently, COPD is the 3rd leading cause of death globally, contributing to approximately 3.2 million deaths worldwide in 2019 (1, 2). This disease is attributed to chronic pulmonary inflammation and oxidative stress which can subsequently cause emphysema with the destruction of alveolar structures, leading to a decline in lung function and hypoxia (3, 4). Much of the disease burden arises from the chronic inhalation of cigarette smoke (CS), which accounts for ~95% of COPD cases in industrialised countries. Due to the irreversible nature of COPD, much of the research focuses on strategies to prevent or manage symptoms associated with the disease, with much of the burden comprising of the debilitating secondary comorbid conditions. These systemic comorbidities are thought to arise from a “spill-over” of pulmonary inflammatory mediators into the blood and thus impacting on other organs such as the heart and brain. With various comorbidities existing alongside COPD, cognitive dysfunction is seen in 25% - 61% of people with COPD (5-7). The literature largely focuses on clinical outcomes of COPD-induced cognitive dysfunction, however, the mechanisms underlying this condition remain unknown. People with COPD may experience deficits including memory, executive functioning, and attention. Ultimately, these cognitive deficits could lead to neurodegenerative diseases including Alzheimer’s Disease and Vascular Cognitive Impairment and Dementia (VCID), hence an urgency in identifying possible biological mechanisms responsible for cognitive dysfunction in COPD is necessary. Understanding how cognitive deficits arise in murine models of COPD, potentially via the “spill over” of pulmonary inflammation into the systemic circulation can lead to pharmacological interventions to treat this comorbidity. One possible mechanism is the initiation of neuroinflammation within the central nervous system (CNS) following CS exposure, which could lead to cognitive deficits. Hence, this thesis explored the mechanisms underlying cognitive dysfunction in a CS-induced preclinical murine model of COPD. In this thesis we first developed a pre-clinical model of COPD that replicated the hallmark features observed in human COPD including lung dysfunction, inflammation and pathological changes (i.e. emphysema, collagen deposition, airway wall remodelling). Our previously published models of CS-induced lung damage have focused on the inflammatory mechanisms involved in the induction of CS-induced lung inflammation. Once the true COPD phenotype was replicated in mice, we then went on to determine whether our model displayed memory impairments, and if this was associated with a neuroinflammatory and oxidative response within the hippocampus, a key region involved in working memory retention. Furthermore, we investigated whether chronic CS exposure altered other neuropathologies involved in memory retention including astrocyte density, neurogenesis and synaptogenesis. By understanding the mechanisms underlying COPD-induced cognitive dysfunction, we may be able to develop potential therapeutics to manage, treat and prevent such cognitive dysfunction in COPD. Mice exposed to 24 weeks of CS had reduced lung function, emphysema, pulmonary inflammation, increased lung oxidative response and systemic inflammation. Histological analysis of the lungs also revealed increased collagen deposition and alveolar destruction. Lung function analysis showed an increased inspiratory capacity, compliance and expiration capacity suggesting the lungs of CS-exposed mice were able to stretch and inspire more air. We found that in addition to pulmonary impairments, mice exposed chronically to CS had memory impairments. Working memory impairments were identified using the novel object recognition test, however, when assessing spatial memory retention using the spontaneous alternation in the Y-maze and novel object placement, no deficits were observed. Upon molecular assessment, CS-exposed mice had an altered inflammatory profile in the hippocampus, with reduced Itgam expression, a gene responsible for Cd11b, a protein expressed on microglial cells. This correlated with a reduction in microglia number within the hippocampus, and upon morphological assessment, these microglia displayed a more activated morphology. As we established an altered microglial profile in the hippocampus, we further divulged into other glial cells within the CNS. Upon inspection, the astrocytic profile within the hippocampus of CS-exposed mice was altered, showing decreased densities in most regions of the hippocampus except for the molecular region, where there was an increased astrocyte density compared to sham mice. When assessing the neuronal components of the hippocampus, we found no differences in neurogenesis in response to CS but found reductions in synaptophysin and stubby dendritic spines on pyramidal neurons within the CA1 region of the hippocampus, indicating a change in synaptogenesis. We also found that CS exposure caused a reduction in ZO-1 in the hippocampus, a key protein involved in the tight junctional bonds between endothelial cells lining the blood brain barrier (BBB), suggesting that the structural integrity of the BBB was weakened by chronic CS exposure. In conclusion, we found that 24 weeks of CS exposure induced COPD in mice, which was associated with working memory impairments, attributed to alterations in the inflammatory, astrocytic, synaptic profiles within the hippocampus.