Neutrophil dynamics in pulmonary fibrosis: pathophysiological and therapeutic perspectives

Abstract

The shared pathobiological mechanisms driving progressive fibrosis in interstitial lung diseases (ILDs) remain unclear. Neutrophils, the most common immune cells in the human body, contain an extensive array of proteinases that are important for cell function, including tissue repair and remodelling. Increasing observational studies have reported elevated neutrophil counts in the respiratory tract and circulation of patients with ILD and suggest a role as a biomarker of disease severity. Neutrophils and their contents (including the formation of neutrophil extracellular traps (NETs)) are present in fibrotic lung tissue. Proteinases and NETs may drive fibrogenesis in animal and in vitro models and may impact transforming growth factor-β1 activation. However, the effect of neutrophil action, whether reparative or pathologically destructive to the delicate lung architecture, has yet to be determined. This review aims to summarise the current literature surrounding the potential role of the neutrophil as a biomarker and contributor to the pathogenesis of ILD. There is currently a paucity of treatment options in ILD driven by the knowledge gap underlying the overall disease mechanisms. This review concludes that neutrophils warrant further evaluation as manipulation of recruitment and function could provide a novel and much needed therapeutic strategy.

FIGURE 1

Outline of the pathophysiology of idiopathic pulmonary fibrosis. 1) Repetitive insults damage type II alveolar epithelial cells which undergo dysregulated apoptosis and repair [11], which triggers 2) pro-fibrotic pathways including release of the pro-fibrotic growth factor transforming growth factor (TGF)-β [12]. 3) TGF-β drives mesenchymal cell, particularly fibroblast and myofibroblast proliferation and activation [13]. 4) This results in a self-perpetuating cycle of remodelling, regulated by metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) and increasing deposition of extracellular matrix material [14]. The role of macrophages is becoming increasingly evident [15].

FIGURE 2

Stages of wound repair. Following tissue injury, immune cells, including neutrophils are recruited a) to remove pathogens/unwanted debris, and release cytokines, such as interleukin-8 and transforming growth factor (TGF)-β, and proteinase/anti-proteinases. b) Fibroblasts/myofibroblasts migrate, proliferate and deposit extracellular matrix material. c) Extracellular matrix material, particularly collagen, is remodelled resulting in increased tensile strength and organised fibrotic tissue. This process is dependent on a delicate balance of proteinases and anti-proteinases [56].

FIGURE 3

Potential mechanisms by which neutrophils drive lung fibrosis. Upon neutrophil activation (degranulation and/or neutrophil extracellular trap (NET) formation) there may be release of 1) proteinases, such as neutrophil elastase and matrix metalloproteinases (MMPs); 2) reactive oxygen species; and 3) citrullinated (cit) histones. All these substances may promote fibrosis through altering the balance of MMPs/tissue inhibitors of metalloproteinases (TIMPs), driving fibroblast proliferation and activation, and increasing the bioavailability of transforming growth factor (TGF)-β1. Active TGF-β1 may perpetuate this process by driving NET formation. ^.O₂⁻: superoxide anion; ^.OH: hydroxyl free radical; pSmad2/3: phosphorylated Smad2/3.

FIGURE 4

Proposed pathway of neutrophil response to injured alveoli in interstitial lung diseases. 1) Neutrophils are produced by the bone marrow in response to factors such as granulocyte colony-stimulating factor (G-CSF) [94, 95], and 2) migrate to the site of alveoli injury down a chemotactic gradient. 3) Neutrophils extravasate from the pulmonary capillaries into the alveoli interstitium [96] in response to chemokines and danger signalling molecules released from damaged type II alveolar epithelial cells [16, 97, 98]. 4) On arrival, neutrophils are activated, degranulating and/or undergoing neutrophil extracellular trap formation (NETosis) [55], which releases enzymes, such as proteinases, transforming growth factor (TGF)-β1 and reactive oxygen species (ROS). These mediators attempt to drive repair processes including extracellular matrix remodelling. This may activate fibroblasts and result in fibrotic deposition [69, 91]. 5) Following activation, neutrophil clearance through reverse transmigration out of the lungs and/or apoptosis is required to maintain homeostasis. Factors such as hypoxia [99] may reduce the homeostatic clearance of senescent neutrophils. IL: interleukin; GCP: granulocyte chemotactic protein.