Neutrophils in the initiation and resolution of acute pulmonary inflammation: understanding biological function and therapeutic potential

Abstract

Acute respiratory distress syndrome (ARDS) is the often fatal sequelae of a broad range of precipitating conditions. Despite decades of intensive research and clinical trials there remain no therapies in routine clinical practice that target the dysregulated and overwhelming inflammatory response that characterises ARDS. Neutrophils play a central role in the initiation, propagation and resolution of this complex inflammatory environment by migrating into the lung and executing a variety of pro-inflammatory functions. These include degranulation with liberation of bactericidal proteins, release of cytokines and reactive oxygen species as well as production of neutrophil extracellular traps. Although these functions are advantageous in clearing bacterial infection, the consequence of associated tissue damage, the contribution to worsening acute inflammation and prolonged neutrophil lifespan at sites of inflammation are deleterious. In this review, the importance of the neutrophil will be considered, together with discussion of recent advances in understanding neutrophil function and the factors that influence them throughout the phases of inflammation in ARDS. From a better understanding of neutrophils in this context, potential therapeutic targets are identified and discussed. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Keywords: ARDS; DAMP; PAMP; apoptosis; chemokine; inflammation; interleukin; leukotriene; neutrophil; neutrophil extracellular trap; reactive oxygen species; toll-like receptor.

Figure 1

Initiation and resolution of neutrophil‐mediated inflammation in ARDS. (A) The healthy alveolar unit facilitates rapid gas transfer with the presence of resident alveolar macrophages providing rapid response to pulmonary infection and injury. (B) Following infection and/or tissue injury, release of PAMPs and/or DAMPs directly induces neutrophil recruitment into the alveolar space in addition to a range of chemokines and mediators secreted by macrophages and epithelial cells. (C) Neutrophils exert multiple pro‐inflammatory functions with the release of ROS, proteases, NETs and cytokines, as well as phagocytosis of bacteria. This is accompanied by accumulation of oedema within the alveolus, endothelial dysfunction and epithelial cell death. (D) Resolution of inflammation occurs through neutrophil apoptosis and macrophage clearance of apoptotic cells (efferocytosis) and inflammatory debris. The role of neutrophil reverse migration remains to be fully characterised in ARDS.