Title: The role of hypoxia in neutrophil-mediated endothelial dysfunction: application to inflammatory lung disease
Funder: The Academy of Medical Sciences

Abstract: The aim of my proposal is to investigate the mechanism(s) by which hypoxia drives neutrophil-mediated endothelial dysfunction in inflammatory lung disease. My specific objectives are i) to investigate how hypoxia increases neutrophil degranulation of histotoxic proteins, using phospho-proteomics and RNA-sequencing to interrogate the hypoxic regulation of granule trafficking pathways and using transgenic mice to confirm whether this response is hypoxia inducible factor (HIF)-dependent, and ii) to investigate whether manipulation of hypoxia-modulated degranulation signalling can mitigate neutrophil-mediated endothelial dysfunction, using static and flow-perfusion co-culture assays in combination with relevant small molecule inhibitors. Acute and chronic inflammatory lung diseases characterised by persistent blood and airway neutrophilia (e.g. ARDS and COPD) are associated with profound systemic and local tissue hypoxia, and excess cardiovascular risk. Hypoxia prolongs neutrophil survival and compromises their bactericidal capacity, resulting in increased potential for bystander tissue damage. I have previously shown that hypoxia also enhances neutrophil degranulation of histotoxic proteins in a PI3Kγ-dependent manner, and that supernatants from these cells have increased capacity to cause endothelial damage and promote neutrophil-endothelial interaction. This destructive hyper-secretory hypoxic neutrophil phenotype is even more pronounced in cells from exacerbating COPD patients. However, the mechanism(s) by which hypoxia modulates PI3Kγ-dependent neutrophil degranulation pathways and the precise mechanism(s) of neutrophil-mediated endothelial activation/injury are incompletely understood. My proposal aims to provide a deeper understanding of the impact of hypoxia on neutrophil degranulation signalling, both at the genetic and protein level, which will enable exploration of novel therapeutic avenues to target neutrophil-mediated endothelial dysfunction for patient benefit.

Lay abstract: Patients with inflammatory lung diseases, such as severe pneumonia or chronic damage due to smoking (COPD), have high numbers of white blood cells called neutrophils present in the blood and airways. These patients frequently have extremely low oxygen levels and also suffer increased heart and blood vessel (cardiovascular) complications, which reduce life expectancy. The primary job of neutrophils is to protect us from infection by releasing toxic proteins that kill invading bacteria. However, release of these toxic proteins can also damage the delicate structures of the surrounding airways, lung tissue and blood vessels. I have found that low oxygen levels make neutrophils release an increased range of toxic proteins, causing substantial damage to the cells lining blood vessels, and likely contributing to the increased cardiovascular complications seen in patients with lung diseases. I have identified some of the proteins responsible for this damage, which are particularly important in neutrophils from COPD patients. I have also identified a signalling pathway that is hyper-activated in low oxygen environments and is responsible for toxic protein release. However, we do not have a complete understanding of neutrophil signalling pathways and, importantly, treatments to prevent this blood vessel damage are lacking. My project aims to provide an in depth understanding of how low oxygen levels cause increased release of toxic proteins from neutrophils and how this leads to blood vessel damage. This research aims to identify new drug targets to help treat or prevent cardiovascular complications in patients with a range of inflammatory lung diseases.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY