Characterising peripheral blood neutrophils and associations with cardiovascular disease in inflammatory lung disorders

Respiratory diseases are frequently associated with an increased risk of cardiovascular disease (CVD). This is recognised in the context of acute and chronic inflammatory conditions, evidenced by elevated risk and burden of CVD in acute COVID-19 and the chronic respiratory disease bronchiectasis. Neutrophils play a prominent role in the pathology of these diseases, and it is hypothesised that neutrophilic inflammation drives the pathophysiology of CVD associated with respiratory conditions. This was investigated in the context of acute (acute COVID-19), subacute (post COVID-19), and chronic (bronchiectasis) inflammatory states. A series of investigations were carried out to characterise neutrophilic inflammation within the systemic circulation of these three patient cohorts. Serum levels of neutrophil and endothelial activation markers were measured. Furthermore, several assays were carried out on neutrophils isolated from peripheral blood to measure their surface markers, functional response, and proteome. In addition, the peripheral blood transcriptome was analysed. In acute COVID-19, a longitudinal study of hospitalised COVID-19 patients was carried out. A progressive and sustained increase in the level of the neutrophil extracellular trap (NET) marker CitH3 and the inflammatory marker ICAM-1 throughout COVID-19 disease was identified. Furthermore, increased levels of these markers were associated with ongoing symptoms post SARS-CoV-2 infection. In addition, an altered peripheral blood transcriptome in COVID-19 patients was observed between those who experienced a major adverse cardiac event (MACE) or not. Genes related to neutrophils were among the most upregulated genes in those who experienced a MACE. In post COVID-19, an altered neutrophil profile and function in post COVID-19 patients was observed. Increased NET induction from peripheral blood neutrophils was significantly increased in those with ongoing fatigue compared to those without. Furthermore, NET induction was significantly correlated with increased surface expression of CXCR2, representing a possible pathological mechanism associated with post COVID-19 complications. In bronchiectasis patients, an altered peripheral blood transcriptome between those with and without CVD was observed. Interestingly genes that were most upregulated in those with CVD were related to neutrophils. Furthermore, an altered neutrophil profile and function was observed in bronchiectasis patients. The activation marker CD11b was significantly reduced in bronchiectasis compared to controls and was significantly associated with clinical characteristics. In conclusion, an altered peripheral blood profile and function in acute and chronic respiratory disease was observed. Furthermore, these results support the role for neutrophils in driving CVD in those with acute COVID-19 and bronchiectasis. These results may be relevant in the context of emerging therapies targeting neutrophilic inflammation for chronic respiratory diseases.