Targets of Neutrophil Influx and Weaponry: Therapeutic Opportunities for Chronic Obstructive Airway Disease

Abstract

Neutrophils are important effector cells of antimicrobial immunity in an acute inflammatory response, with a primary role in the clearance of extracellular pathogens. However, in respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), there is excessive infiltration and activation of neutrophils, subsequent production of reactive oxygen species, and release of serine proteases, matrix metalloproteinases, and myeloperoxidase-resulting in collateral damage as the cells infiltrate into the tissue. Increased neutrophil survival through dysregulated apoptosis facilitates continued release of neutrophil-derived mediators to perpetuate airway inflammation and tissue injury. Several target mechanisms have been investigated to address pathologic neutrophil biology and thereby provide a novel therapy for respiratory disease. These include neutrophil influx through inhibition of chemokine receptors CXCR2, CXCR1, and PI3Kγ signaling and neutrophil weaponry by protease inhibitors, targeting matrix metalloproteinases and neutrophil serine proteases. In addition, neutrophil function can be modulated using selective PI3Kδ inhibitors. This review highlights the latest advances in targeting neutrophils and their function, discusses the opportunities and risks of neutrophil inhibition, and explores how we might better develop future strategies to regulate neutrophil influx and function for respiratory diseases in dire need of novel effective therapies.

Figure 1

Comparison of PI3Kγ versus PI3Kδ inhibition on neutrophil functions. Novel inhibitors with >100-fold selectivity (versus other class 1 PI3K isoforms) for PI3Kγ (squares) or δ (circles) were compared across 3 neutrophil mechanisms. (a) Neutrophil chemotaxis to fMLP. (b) Neutrophil superoxide (SOX) generation following LPS priming and stimulation with fMLP. (c) Neutrophil degranulation (assessed via elastase release) following cytochalasin b priming and stimulation with fMLP. Mean ± standard error of n > 3 experiments are plotted as % inhibition. pIC₅₀ (−logIC₅₀) values for both γ and δ inhibitors are indicated.

Figure 2

Summary illustration of neutrophil targets in chronic lung disease. Activation of NSPs during neutrophil maturation in the bone marrow is via DPP1. Chemotaxis to the lung can be modulated by targeting CXCR2 or PI3Kδ/γ, the latter of which can also inhibit SOX and NSP release.