Cystic fibrosis airway epithelium remodelling: involvement of inflammation

Abstract

Chronic inflammation is a hallmark of cystic fibrosis (CF) lung disease and airway epithelium damage and remodelling are important components of lung pathology progression in CF. Whether this remodelling is secondary to deleterious infectious and inflammatory mediators, or to alterations of CF human airway epithelial (HAE) cells, such as their hyper inflammatory phenotype or their basic cystic fibrosis transmembrane conductance regulator (CFTR) default, remains debated. In this study, we evaluated the involvement of alterations of CF HAE cells in airway epithelium remodelling. HAE cells from non-CF and CF patients were cultured in an air-liquid interface, with and without inflammatory stimulation, along the regeneration process, and the remodelling of the reconstituted epithelium was analysed. We confirmed that CF HAE cells showed a hyperinflammatory phenotype which was lost with time. In comparison to non-CF epithelium, CF epithelium regeneration in the absence of exogenous inflammation was higher and exhibited basal cell hyperplasia. This remodelling was mimicked by inflammatory stimulation of non-CF cells and was absent when CF HAE cells were no longer hyperinflamed. Moreover, the number of goblet cells was similar in non-CF and CF cultures and increased equally under inflammatory stimulation. Finally, whatever the inflammatory environment, CF cultures showed a delay in ciliated cell differentiation. In conclusion, alterations of CF HAE cells partly regulate airway epithelium remodelling following injury and regeneration. This remodelling, together with goblet cell hyperplasia induced by exogenous inflammation and alteration of ciliated cell differentiation, may worsen mucociliary clearance impairment, leading to injury.

Airway epithelial homeostasis and planar cell polarity signaling depend on multiciliated cell differentiation

“…We first tested whether the treatment of healthy ALI-cultured human nasal epithelial cells (HNECs) with inflammatory cytokines, which models some of the changes that take place in the respiratory epithelium during chronic inflammation (3), will affect PCP acquisition. We found that healthy HNECs treated during differentiation with IL-1β, IL-13, or TNF-α, inflammatory cytokines commonly detected in CF epithelia (36–38), have no or greatly decreased numbers of MCCs, and VANGL1 shows little or no asymmetry (Figures 4C and 2B for IL-13–treated MTECs).…”

“…These events contribute to severe, chronic inflammation and to cycles of repeated injury and imperfect repair. These in turn bring about epithelial dysfunction, which includes structural and functional changes such as hyperplasia of mucus-secreting cells, decrement in MCC numbers, abnormal tissue architecture with scarring, diminished barrier function, and decreased regenerative capacity (3). CF patients march down an inevitable slope of chronic cough, dyspnea, sinusitis, recurrent antibiotic and steroid use, and oxygen dependence.…”

CFTR Involvement in Cell Migration and Epithelial Restitution

“…Reduced pathogen clearance facilitates infection that induces neutrophilic inflammation, leading to progressive epithelial damage within the conducting airways [16][17][18][19]. Over time, a recurrent cycle of intense inflammation, epithelial injury and airway remodeling produce irrevocable damage that dramatically compromises lung function [20][21][22]. Mounting evidence from in vitro studies and animal models of CF indicate that CFTR malfunction appears to alter the innate immune response of the airways leading to increased release of proinflammatory mediators evoking an amplified, yet less effective inflammatory reaction that is unable to eliminate airway pathogens [17,18].…”

A novel regulatory role for tissue transglutaminase in epithelial-mesenchymal transition in cystic fibrosis

“…This is particularly important since uncontrolled airway remodelling occurs in CF patients which is now recognized to start early in life and is linked to a poor pulmonary outcome with extensive fibrosis [27]. A similar process in CF patients also known to start in babyhood is the destruction of the pancreas which is driven by fibrosis and noted when the disease was first recognized.…”