Neutrophilic inflammation in bronchiectasis

Abstract

Noncystic fibrosis bronchiectasis, hereafter referred to as bronchiectasis, is a chronic, progressive lung disease that can affect people of all ages. Patients with clinically significant bronchiectasis have chronic cough and sputum production, as well as recurrent respiratory infections, fatigue and impaired health-related quality of life. The pathophysiology of bronchiectasis has been described as a vicious vortex of chronic inflammation, recurring airway infection, impaired mucociliary clearance and progressive lung damage that promotes the development and progression of the disease. This review describes the pivotal role of neutrophil-driven inflammation in the pathogenesis and progression of bronchiectasis. Delayed neutrophil apoptosis and increased necrosis enhance dysregulated inflammation in bronchiectasis and failure to resolve this contributes to chronic, sustained inflammation. The excessive release of neutrophil serine proteases, such as neutrophil elastase, cathepsin G and proteinase 3, promotes a protease-antiprotease imbalance that correlates with increased inflammation in bronchiectasis and contributes to disease progression. While there are currently no licensed therapies to treat bronchiectasis, this review will explore the evolving evidence for neutrophilic inflammation as a novel treatment target with meaningful clinical benefits.

FIGURE 1

The vicious vortex in bronchiectasis. The vicious vortex in bronchiectasis consists of four components, namely chronic airway inflammation, airway destruction, impaired mucociliary clearance and chronic airway infection. All components of the cycle interact with and influence one another. Each of these components represents a potential aetiological entry point for conditions that can lead to bronchiectasis (e.g. allergic bronchopulmonary aspergillosis (ABPA) leading to chronic airway inflammation). IBD: inflammatory bowel disease; NTM: nontuberculous mycobacteria.

FIGURE 2

Neutrophil generation, maturation and granule formation. The neutrophil population in the bone marrow consists of the haematopoietic stem cell (HSC) pool, the mitotic pool, and the post-mitotic pool. Haematopoietic stem cells differentiate into granulocyte-macrophage progenitor cells (GMPs), which differentiate into myeloblasts that, in turn, differentiate into neutrophils. As they differentiate, neutrophils gradually acquire different types of granules containing key antimicrobial components. CD11b: integrin alpha M; CD14: cluster of differentiation 14; CD16: Fc-gamma receptor III; CD-18: integrin beta chain-2; CR: complement receptor; NRAMP1: natural resistance-associated macrophage protein 1.

FIGURE 3

Neutrophil effector functions. Neutrophils control and eliminate pathogens via various mechanisms, including phagocytosis, degranulation and reactive oxygen species (ROS) generation, the formation of neutrophil extracellular traps (NETs), microvesicle production and cytokine release.

FIGURE 4

Neutrophil efferocytosis. Efferocytosis involves the removal of apoptotic cells by phagocytes such as macrophages.

FIGURE 5

An overview of the downstream effects of neutrophilic pro-inflammatory mediators. Neutrophil effector functions result in the release of various neutrophil-derived mediators and potent proteases such as LL-37, myeloperoxidase (MPO), azurocidin (AZU) and neutrophil serine proteases (NSPs). LL-37 and MPO can contribute to tissue damage in the lungs. AZU acts as a chemoattractant for T-cells and aids epithelial dysfunction. NSPs contribute to the protease–antiprotease imbalance observed in bronchiectasis by cleaving and inactivating protease inhibitors such as secretory leukocyte protease inhibitor (SLPI) and alpha-1 antitrypsin (A1AT). NSPs activate matrix metalloproteinases (MMPs), which can also inhibit antiproteases such as A1AT, as well contribute to the destruction of the extracellular matrix (ECM). High, uncontrolled NSP levels can impair pathogen clearance in the lungs, resulting in chronic infection. NSPs also promote the generation of inflammatory effectors such as cytokines and chemokines, which amplify inflammation. NSPs also contribute to epithelial dysfunction by decreasing ciliary motility and damaging ciliary structures. Neutrophil elastase (NE) contributes to ECM destruction and remodelling by degrading elastin fibres as well as collagen and laminin. NE increases the expression of the gel-forming mucin 5AC (MUC5AC), which leads to mucus hypersecretion. CatG: cathepsin G; ROS: reactive oxygen species.