Progress in Model Systems of Cystic Fibrosis Mucosal Inflammation to Understand Aberrant Neutrophil Activity

Abstract

In response to recurrent infection in cystic fibrosis (CF), powerful innate immune signals trigger polymorphonuclear neutrophil recruitment into the airway lumen. Exaggerated neutrophil proteolytic activity results in sustained inflammation and scarring of the airways. Consequently, neutrophils and their secretions are reliable clinical biomarkers of lung disease progression. As neutrophils are required to clear infection and yet a direct cause of airway damage, modulating adverse neutrophil activity while preserving their pathogen fighting function remains a key area of CF research. The factors that drive their pathological behavior are still under investigation, especially in early disease when aberrant neutrophil behavior first becomes evident. Here we examine the latest findings of neutrophils in pediatric CF lung disease and proposed mechanisms of their pathogenicity. Highlighted in this review are current and emerging experimental methods for assessing CF mucosal immunity and human neutrophil function in the laboratory.

Pseudomonas aeruginosa modulates neutrophil granule exocytosis in an in vitro model of airway infection

“…Additionally, we used non‐CF neutrophils in our migration experiments, as we were unable to collect blood from CF donors. While GRIM reprogramming was still observed, CF neutrophils may have additional functional irregularities as a result of CFTR mutations 65 . We are also yet to assess the role of immune signals from neutrophils themselves.…”

“…While GRIM reprogramming was still observed, CF neutrophils may have additional functional irregularities as a result of CFTR mutations. 65 We are also yet to assess the role of immune signals from neutrophils themselves. As such, our model reflects the initial epithelial response to infection followed by the first wave of neutrophil recruitment to the airways.…”

Animal and Cell Culture Models for Cystic Fibrosis

“…Among the available CF models, pigs and ferrets are considered the most physiologically relevant models for lung-based immune research. 75 b-ENaC mice may also provide value for such studies as they demonstrate a neutrophil-dominated immune response in the lungs. 29…”

Understanding Pseudomonas aeruginosa–Host Interactions: The Ongoing Quest for an Efficacious Vaccine

“…The recognition of P. aeruginosa pathogen-associated molecular patterns (PAMPs) elicits a potent inflammatory response, which is critical for the recruitment of neutrophils and macrophages, facilitating the bacterial clearance ( Figure 2). However, an optimal host response is essential; a weak response with inefficient infiltration of phagocytic cells leads to unsuccessful bacterial killing and clearance, while an excessive response causes host tissue damage [49,[70][71][72][73][74]. Massive recruitment of neutrophils into the infected respiratory tract is a hallmark of P. aeruginosa infection.…”

“…In neutropenic mice, the lethal dose of P. aeruginosa was 100,000 times lower than that required by mice with normal neutrophil levels; observations which were replicated in rabbits and humans [71,[75][76][77]. The factors that regulate the recruitment of neutrophils to P. aeruginosa infected sites have not been well characterised, but the recruitment is mediated, at least in part, by the production of ELR + CXC chemokines, which are critical for neutrophil chemotaxis and activation [49,74,78,79]. The most relevant chemokine receptors on neutrophils are CXCR (CXC chemokine receptor) 1 and CXCR2.…”