Uncontrolled asthmatics have increased FceRI⁺ and TGF‐β–positive MC_TC mast cells and collagen VI in the alveolar parenchyma

Abstract

Summary Background Asthma has been associated with increased collagen deposition in both conducting airways and alveolar parenchyma. Mast cells (MCs) are key effector cells in asthma and have the ability to affect collagen synthesis. However, the link between clinical control and changes in bronchial and alveolar MC phenotypes and specific collagens in controlled and uncontrolled asthma remains unknown. Objective To investigate MC phenotypes in correlation with deposition of specific collagen subtypes in patients with controlled and uncontrolled asthma as well as to healthy controls. Methods The tissue expression of IgE+, FcεRI+ and TGF‐β+ MCs, as well as immunoreactivity of collagen I, III and VI, was assessed using immunohistochemistry on bronchial and transbronchial biopsies from controlled asthmatics (n = 9), uncontrolled asthmatics (n = 16) and healthy controls (n = 8). Results In the alveolar parenchyma, the total number of MCs, as well as the number of FcεRI+ MCs and pro‐fibrotic TGF‐β+ MCTC, was significantly increased in uncontrolled asthma compared to both controlled asthma and healthy controls. The proportion of TGF‐β+ MCTC correlated positively to an increased immunoreactivity of alveolar collagen VI but not collagen I and III. Collagen VI was increased in the alveolar parenchyma of uncontrolled asthmatics compared to controlled asthmatics. Controlled asthmatics had an increased deposition of alveolar collagen I. In bronchi, the immunoreactivity of collagen I was increased in both controlled and uncontrolled asthmatics while collagen III was increased only in controlled asthmatics. Conclusions Patients with uncontrolled atopic asthma have an altered pro‐fibrotic MCTC phenotype in the alveolar parenchyma that is associated with alveolar collagen VI. The present data thus support distal lung mast cell and matrix changes as histopathological features of asthma that may be of particular clinical relevance in patients who have remaining symptoms despite conventional inhaler therapy.

Mast Cell-Mediated Orchestration of the Immune Responses in Human Allergic Asthma: Current Insights

“…[57] [9] IL-33 IL-33 enhances IgE/Ag-, monomeric IgE-, C5a-, SCF-, and NGF-mediated cytokine production in human MCs, and HMC-1.…”

“…Unlike the healthy subjects, MCs in individuals with asthma express FcεRI and surface bound IgE [7]. The increase in number of MCs in asthmatics is associated with evidence of TH2-skewed inflammation [8] and remodeling with interstitial fibrosis [9]. The participation of MCs in pathogenesis of asthma is supported by the results of tissue biopsies obtained from infants dying of viral bronchiolitis that revealed the presence of large number of tissue resident MCs.…”

Nanoparticle-based thymulin gene therapy therapeutically reverses key pathology of experimental allergic asthma

“…Current clinical guidelines recommend management of symptoms at best (2). However, advanced standard-of-care palliative options, such as anti-inflammatory agents and long-acting 2 agonists, cannot effectively control disease progression as a stand-alone therapy, ultimately leading to progressive matrix changes (i.e., remodeling and/or fibrosis), a key histopathologic hallmark of asthma (3,4). Alternatively, gene therapy is a potential means to intervene or even reverse the development of this lifethreatening pathologic feature in asthmatic lungs by providing stable expression of therapeutic mediators (5).…”

PDE3 Inhibition Reduces Epithelial Mast Cell Numbers in Allergic Airway Inflammation and Attenuates Degranulation of Basophils and Mast Cells

“…The presence of MCs in the epithelium or in close proximity to smooth muscle airway cells (Brightling et al, 2002;Bradding et al, 2006;Bradding and Brightling, 2007) contributes to smooth muscle hyperplasia via TGFb and b-tryptase (Woodman et al, 2008). In uncontrolled allergic asthma patients the total number of MCs and MC TC (MC containing tryptase and chymase) in the alveolar parenchyma was found to correlate negatively with FEV1% predicted (Andersson et al, 2011;Andersson et al, 2018). In these patients the numbers of mast cells expressing FceR1 and TGFb are increased.…”