Defining and Targeting Pathogenic Myeloid Populations in Novel Models of COPD
Creators: name: Fung, Nok Him
Publisher: name: RMIT University
Year: 2024
Subjects: classificationCode: 320103
subject: Respiratory diseases

description: Chronic Obstructive Pulmonary Disease (COPD) is an incurable chronic inflammatory disease mainly caused by cigarette smoke (CS), where inflammatory myeloid cells including alternatively activated macrophages accumulate in the lungs. Current anti-inflammatory treatments such as corticosteroids are ineffective in blocking the actions of innate myeloid cells, hence new therapies are needed. This thesis utilized mouse models of CS-induced lung inflammation and emphysema to characterise pathogenic myeloid populations which drive the underlying inflammatory response and lung pathology. Inflammatory cell infiltration into the lung lumen was analysed over a 4-week CS period, where an initial influx of neutrophils was gradually replaced with the accumulation of macrophages that was associated with a progressive increase in macrophage elastase (MMP-12) expression. To further characterise these macrophages, mice were then exposed to two weeks of CS, which caused significant lung injury. Flow cytometry was used to identify the expansion of a population of monocyte-derived CD11b+ pulmonary interstitial macrophages (IMs). Next, the therapeutic efficacy of targeting the common beta receptor (βc), the receptor subunit shared by GM-CSF, IL-5, and IL-3, was investigated using transgenic mice expressing the human βc and the monoclonal antibody CSL311 that neutralises the human βc receptor. CSL311 proved very effective in blocking multiple myeloid cells including IMs, neutrophils and eosinophils. This broad anti-inflammatory response markedly reduced lung injury caused by acute smoke exposure. In addition to the inhalation of noxious CS particles, the development of an accelerated COPD phenotype can occur in people who have underlying asthma. Around 30% of COPD patients can have co-existing asthma, and these patients typically present with more severe disease and greater hospital admissions. Since there are no effective treatments for patients with asthma-COPD overlap, a new pre-clinical model was developed to recapitulate this important disease phenotype. CS-induced emphysema in the presence of an aeroallergen (house dust mite extract, HDM) exposure was investigated. Compared with CS exposure only, mice exposed to both CS and HDM displayed significantly greater emphysematous changes as measured by lung volume and alveolar diameter. This was accompanied by expansion of CD11b+ pulmonary interstitial macrophages, and increased expression of MMP-12 and TH2 cytokines. This new pre-clinical model of asthma-COPD overlap (ACO) has identified CD11b+ lung IMs expressing MMP-12 as a major driver of lung inflammation and emphysema, which can be used to understand unique molecular disease drivers and test novel therapies.This thesis elucidated the significance of IMs in experimental COPD by demonstrating their roles in various models of CS and allergen-induced inflammation and emphysema. The targetability of these IMs using highly clinically relevant biologics highlights the translational potential of this work and provides crucial insight that will aid the development of novel treatments for COPD.