Neutrophils and tissue damage: is hypoxia the key to excessive degranulation?

Neutrophils are the first innate immune cells recruited into sites of infection and inflammation, and although they are critical for host defence against microbial pathogens, they have also been associated with local tissue damage. Predominant neutrophilic inflammation is a key hallmark of many respiratory diseases, and the release of proteinases and reactive oxygen species (ROS) from primed neutrophils has been implicated in mediating the damage to surrounding tissue.1 Inflammation is further accompanied by severe hypoxia (lack of oxygen) within the affected tissue, and is a characteristic of both acute and chronic lung diseases, such as acute respiratory distress syndrome (ARDS),2 COPD3 and cystic fibrosis (CF).4 Considering that tissue hypoxia is part of a normal inflammatory response, innate immune cells such as neutrophils and macrophages possess important cellular and molecular mechanisms that enable them to function effectively at low oxygen concentrations.5 There is considerable interplay between the molecular pathways that regulate hypoxia and inflammation. In previous studies, mice exposed to hypoxic conditions (5% O2 for 1 hour) demonstrated increased levels of interleukin 6 (IL-6), tumour necrosis factor and IL-1 in both serum and isolated macrophages.6 In humans, increased levels of IL-6, IL-1RA and C-reactive protein were detected in serum after volunteers experienced three overnight stays at altitude.7 Moreover, infiltrating neutrophils directly increase their oxygen consumption in order to assemble the nicotinamide adenine dinucleotide phosphate oxidase complex that generates ROS and, in conjunction with superoxide dismutase and myeloperoxidase (MPO), hydrogen peroxide (H2O2) and hypochlorous acid (HClO), thereby depleting local levels of oxygen.8 ,9 Neutrophils are also thought to influence the tissue microenvironment during episodes of hypoxia. For example, neutrophil migration across epithelia increases the transcriptional activity of hypoxia-inducible genes in epithelial cells, which in turn influence the …