Neutrophils are the key effector cells of innate immunity, rapidly recruited to defend the host against invading pathogens. They deploy pre-formed proteases packaged within cytoplasmic granules, generate reactive oxygen species and release neutrophil extracellular traps (NETs). However, these anti-microbial strategies can also cause substantial bystander tissue injury. Infected and inflamed tissues are profoundly hypoxic, and this oxygen depletion both compromises neutrophil-mediated bacterial killing and enhances the secretion of destructive granule contents. Persistent neutrophilic infiltration of hypoxic tissues characterises diseases such as chronic obstructive pulmonary disease (COPD), which is also associated with endothelial dysfunction. Proteases such as neutrophil elastase (NE) have been implicated in COPD pathogenesis but the precise mechanisms of neutrophil-mediated tissue damage are unknown. In this thesis, I show that hypoxia synergises with neutrophil priming agents to enhance the release of NE in a PI3Kγ-dependent manner, with hypoxic supernatants inducing substantial endothelial cell dysfunction and death. To further identify potential histotoxic mediators, I used a proteomics approach to provide a full (and entirely novel) characterisation of the hypoxic versus normoxic neutrophil secretome, revealing upregulation of a number of protein candidates (both granule-associated and, surprisingly, a subset of cytoplasmic proteins) following hypoxic incubation and stimulation. As this unexpected pattern of protein release did not segregate with neutrophil granule contents, alternative secretion mechanisms were examined; however, hypoxia did not enhance the release of NETs or neutrophil-derived microvesicles. Importantly, neutrophils isolated from exacerbating COPD patients, compared with those from healthy controls, exhibited even further augmented release of selected cytotoxic granule (NE, resistin and neutrophil gelatinase-associated lipocalin) and cytoplasmic (cyclophilin A) proteins under hypoxia. Furthermore, a plasma signature of increased protease (NE and proteinase 3) activity was identified in COPD versus healthy control plasma. In conclusion, hypoxia engenders a destructive neutrophil phenotype, with enhanced release of histotoxic proteins and increased capacity to cause endothelial injury. This may contribute to local and distant tissue damage in the clinical setting of COPD, with further relevance to a wide range of chronic inflammatory diseases, underpinned by endothelial dysfunction.