Activated MCTC mast cells infiltrate diseased lung areas in cystic fibrosis and idiopathic pulmonary fibrosis

Abstract

BackgroundAlthough mast cells are regarded as important regulators of inflammation and tissue remodelling, their role in cystic fibrosis (CF) and idiopathic pulmonary fibrosis (IPF) has remained less studied. This study investigates the densities and phenotypes of mast cell populations in multiple lung compartments from patients with CF, IPF and never smoking controls.MethodsSmall airways, pulmonary vessels, and lung parenchyma were subjected to detailed immunohistochemical analyses using lungs from patients with CF (20 lung regions; 5 patients), IPF (21 regions; 7 patients) and controls (16 regions; 8 subjects). In each compartment the densities and distribution of MCT and MCTC mast cell populations were studied as well as the mast cell expression of IL-6 and TGF-β.ResultsIn the alveolar parenchyma in lungs from patients with CF, MCTC numbers increased in areas showing cellular inflammation or fibrosis compared to controls. Apart from an altered balance between MCTC and MCT cells, mast cell in CF lungs showed elevated expression of IL-6. In CF, a decrease in total mast cell numbers was observed in small airways and pulmonary vessels. In patients with IPF, a significantly elevated MCTC density was present in fibrotic areas of the alveolar parenchyma with increased mast cell expression of TGF-β. The total mast cell density was unchanged in small airways and decreased in pulmonary vessels in IPF. Both the density, as well as the percentage, of MCTC correlated positively with the degree of fibrosis. The increased density of MCTC, as well as MCTC expression of TGF-β, correlated negatively with patient lung function.ConclusionsThe present study reveals that altered mast cell populations, with increased numbers of MCTC in diseased alveolar parenchyma, represents a significant component of the histopathology in CF and IPF. The mast cell alterations correlated to the degree of tissue remodelling and to lung function parameters. Further investigations of mast cells in these diseases may open for new therapeutic strategies.

Mechanical stress-induced mast cell degranulation activates TGF-β1 signalling pathway in pulmonary fibrosis

“…This result is consistent with previous studies that also found increased mast cells14–16 and their TGF-β1-positive phenotype in IPF lungs 15. Our decellularised lung experiments also showed that mouse BMMC or rat PMCs were activated while reseeded in fibrotic matrix as shown by an increase in the secretion of active and total TGF-β1.…”

A Novel Genomic Signature with Translational Significance for Human Idiopathic Pulmonary Fibrosis

“…An increase of mast cells has been reported in the airways of patients with IPF (48,49), and the density of mast cells was recently shown to be higher in IPF lung than in other fibrotic lung disease (50). Interestingly, patients with IPF that had a high mast cell density had a higher degree of fibrosis, and the number of mast cells correlated negatively with patient lung function (51). We compared the microarray time course expression data in the bleomycin model with microarray data from human IPF biopsies to identify molecular markers with translational relevance, and demonstrated that the highest similarity of gene expression between bleomycin-induced lung fibrosis and IPF in animals occurs at 7 days after bleomycin administration.…”

Proteolytic Processing of Interleukin-1 Family Cytokines: Variations on a Common Theme

“…Of note, IL-1a processing activity is readily detected in the bronchoalveolar lavage fluids from patients with cystic fibrosis or bronchiectasis (Afonina et al, 2011). In addition to neutrophils, emerging evidence points to an important role for mast cells in pulmonary fibrosis (Andersson et al, 2011;Overed-Sayer et al, 2013). Importantly, Pseudomonas aeruginosa, a common respiratory pathogen in cystic fibrosis, has been reported to upregulate IL-1a and IL-1b in mast cells, further facilitating neutrophil transendothelial migration (Lin et al, 2002).…”