scholarly journals Cross-talk of inflammatory mediators and airway epithelium reveals CFTR as a major target

2021 ◽  
pp. 00247-2021
Author(s):  
Filipa B. Simões ◽  
Arthur Kmit ◽  
Margarida D. Amaral
Keyword(s):  
Cross Talk ◽  
Inflammatory Mediators ◽  
Airway Epithelium ◽  
Airway Epithelial Cells ◽  
Epithelial Differentiation ◽  
Ciliated Cells ◽  
Mucus Production ◽  
Airway Diseases ◽  
Club Cells ◽  
Chronic Airway

Airway inflammation, mucus hyperproduction and epithelial remodelling are hallmarks of many chronic airway diseases, including asthma, Chronic Obstructive Pulmonary Disease and Cystic Fibrosis. While several cytokines are dysregulated in these diseases, most studies focus on the response of airways to IL-4 and IL-13, which were shown to induce mucus hyperproduction and shift the airway epithelium towards a hypersecretory phenotype.We hypothesised that other cytokines might induce the expression of chloride (Cl−) channels/transporters, regulate epithelial differentiation and mucus production. To this end, fully-differentiated human airway basal cells (BCi-NS1.1) were treated with cytokines identified as dysregulated in those diseases, namely interleukins-8, 1β, 4, 17A, 10, 22, and tumour necrosis factor-α (TNF-α).Our results show that CFTR is the main Cl− channel modulated by inflammation, in contrast to TMEM16A, whose levels only changed with IL-4. Furthermore, we identified novel roles for IL-10 and IL-22 by influencing epithelial differentiation towards ciliated cells and away from pulmonary ionocytes. Contrarily, IL-1β and IL-4 reduced the number of ciliated cells while increasing club cells. Interestingly, while IL-1β, IL-4 and IL-10 upregulated CFTR expression, IL-4 was the only cytokine that increased both its function and the number of CFTR-expressing club cells, suggesting that this cell-type may be the main contributor for CFTR function. Additionally, all cytokines assessed increased mucus production through a differential upregulation of MUC5AC and MUC5B transcript levels.Altogether, this study reveals a novel insight into differentiation resulting from the cross-talk of inflammatory mediators and airway epithelial cells, which is particularly relevant for chronic airway diseases.

scholarly journals Subtype-specific expression patterns of inositol 1,4,5-trisphosphate receptors in rat airway epithelial cells.

1996 ◽  
Vol 44 (11) ◽  
pp. 1237-1242 ◽  
Author(s):  
T Sugiyama ◽  
M Yamamoto-Hino ◽  
K Wasano ◽  
K Mikoshiba ◽  
M Hasegawa
Keyword(s):  
Epithelial Cells ◽  
Airway Epithelium ◽  
Airway Epithelial Cells ◽  
Clara Cell ◽  
Specific Cell ◽  
Airway Epithelial ◽  
Clara Cells ◽  
Ciliated Cells ◽  
Inositol 1,4,5 Trisphosphate

We investigated the immunohistochemical localization of inositol 1,4,5-trisphosphate receptor (IP3R) Types 1, 2, and 3 in rat airway epithelium using the monoclonal antibodies KM1112, KM1083, and KM1082 specific for each type of IP3R. The epithelium from trachea to distal intrapulmonary airways (bronchioles) showed positive immunoreactivity for all types of IP3R. However, cell type as well as subcellular site immunoreactivity for each type of IP3R varied. IP3R Type 1 was found only in the apical thin cytoplasmic area of ciliated cells throughout all airway levels. IP3R Type 2 was exclusively localized to the entire cytoplasm of ciliated cells from the trachea to bronchioles. IP3R Type 3 was expressed mainly in the supranuclear cytoplasm not only of ciliated cells at all airway levels but also in Clara cells of the bronchiolar epithelium. Double fluorescent staining using combinations of KM1083 and Wisteria floribunda lectin or anti-rat 10-KD Clara cell-specific protein antibody confirmed that the IP3R Type 2-positive cells were neither seromucous cells nor Clara cells. These results indicate that the expression of three types of IP3Rs in different cell types and subcellular sites may reflect diverse physiological functions of IP3Rs within airway epithelial cells. The double staining studies suggested that the anti-IP3R Type 2 monoclonal antibody KM1083 would be a specific cell marker for ciliated cells of the airway epithelium.

scholarly journals Interleukin-1α drives the dysfunctional cross-talk of the airway epithelium and lung fibroblasts in COPD

2016 ◽  
Vol 48 (2) ◽  
pp. 359-369 ◽  
Author(s):  
Emmanuel T. Osei ◽  
Jacobien A. Noordhoek ◽  
Tillie L. Hackett ◽  
Anita I.R. Spanjer ◽  
Dirkje S. Postma ◽  
...  
Keyword(s):  
Inflammatory Mediators ◽  
Airway Epithelium ◽  
Fetal Lung ◽  
Bronchial Epithelial Cell ◽  
Airway Epithelial Cells ◽  
Lung Fibroblast ◽  
Lung Fibroblasts ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
And Control

Chronic obstructive pulmonary disease (COPD) has been associated with aberrant epithelial–mesenchymal interactions resulting in inflammatory and remodelling processes. We developed a co-culture model using COPD and control-derived airway epithelial cells (AECs) and lung fibroblasts to understand the mediators that are involved in remodelling and inflammation in COPD.AECs and fibroblasts obtained from COPD and control lung tissue were grown in co-culture with fetal lung fibroblast or human bronchial epithelial cell lines. mRNA and protein expression of inflammatory mediators, pro-fibrotic molecules and extracellular matrix (ECM) proteins were assessed.Co-culture resulted in the release of pro-inflammatory mediators interleukin (IL)-8/CXCL8 and heat shock protein (Hsp70) from lung fibroblasts, and decreased expression of ECM molecules (e.g. collagen, decorin) that was not different between control and COPD-derived primary cells. This pro-inflammatory effect was mediated by epithelial-derived IL-1α and increased upon epithelial exposure to cigarette smoke extract (CSE). When exposed to CSE, COPD-derived AECs elicited a stronger IL-1α response compared with control-derived airway epithelium and this corresponded with a significantly enhanced IL-8 release from lung fibroblasts.We demonstrate that, through IL-1α production, AECs induce a pro-inflammatory lung fibroblast phenotype that is further enhanced with CSE exposure in COPD, suggesting an aberrant epithelial–fibroblast interaction in COPD.

scholarly journals Human Cellular Models for the Investigation of Lung Inflammation and Mucus Production in Cystic Fibrosis

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Stefano Castellani ◽  
Sante Di Gioia ◽  
Lorena di Toma ◽  
Massimo Conese
Keyword(s):  
Cystic Fibrosis ◽  
Inflammatory Response ◽  
Airway Epithelium ◽  
Disease Modeling ◽  
Respiratory Infections ◽  
Airway Remodeling ◽  
Three Dimensional ◽  
Airway Epithelial Cells ◽  
Mucus Production ◽  
Cellular Models

Chronic inflammation, oxidative stress, mucus plugging, airway remodeling, and respiratory infections are the hallmarks of the cystic fibrosis (CF) lung disease. The airway epithelium is central in the innate immune responses to pathogens colonizing the airways, since it is involved in mucociliary clearance, senses the presence of pathogens, elicits an inflammatory response, orchestrates adaptive immunity, and activates mesenchymal cells. In this review, we focus on cellular models of the human CF airway epithelium that have been used for studying mucus production, inflammatory response, and airway remodeling, with particular reference to two- and three-dimensional cultures that better recapitulate the native airway epithelium. Cocultures of airway epithelial cells, macrophages, dendritic cells, and fibroblasts are instrumental in disease modeling, drug discovery, and identification of novel therapeutic targets. Nevertheless, they have to be implemented in the CF field yet. Finally, novel systems hijacking on tissue engineering, including three-dimensional cocultures, decellularized lungs, microfluidic devices, and lung organoids formed in bioreactors, will lead the generation of relevant human preclinical respiratory models a step forward.

scholarly journals Respiratory Syncytial Virus Infection of Human Airway Epithelial Cells Is Polarized, Specific to Ciliated Cells, and without Obvious Cytopathology

2002 ◽  
Vol 76 (11) ◽  
pp. 5654-5666 ◽  
Author(s):  
Liqun Zhang ◽  
Mark E. Peeples ◽  
Richard C. Boucher ◽  
Peter L. Collins ◽  
Raymond J. Pickles
Keyword(s):  
Gene Transfer ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Airway Epithelium ◽  
Airway Epithelial Cells ◽  
Apical Surface ◽  
Airway Epithelial ◽  
Ciliated Cells ◽  
Transfer Vectors ◽  
Syncytial Virus

ABSTRACT Gene therapy for cystic fibrosis (CF) lung disease requires efficient gene transfer to airway epithelial cells after intralumenal delivery. Most gene transfer vectors so far tested have not provided the efficiency required. Although human respiratory syncytial virus (RSV), a common respiratory virus, is known to infect the respiratory epithelium, the mechanism of infection and the epithelial cell type targeted by RSV have not been determined. We have utilized human primary airway epithelial cell cultures that generate a well-differentiated pseudostratified mucociliary epithelium to investigate whether RSV infects airway epithelium via the lumenal (apical) surface. A recombinant RSV expressing green fluorescent protein (rgRSV) infected epithelial cell cultures with high gene transfer efficiency when applied to the apical surface but not after basolateral inoculation. Analyses of the cell types infected by RSV revealed that lumenal columnar cells, specifically ciliated epithelial cells, were targeted by RSV and that cultures became susceptible to infection as they differentiated into a ciliated phenotype. In addition to infection of ciliated cells via the apical membrane, RSV was shed exclusively from the apical surface and spread to neighboring ciliated cells by the motion of the cilial beat. Gross histological examination of cultures infected with RSV revealed no evidence of obvious cytopathology, suggesting that RSV infection in the absence of an immune response can be tolerated for >3 months. Therefore, rgRSV efficiently transduced the airway epithelium via the lumenal surface and specifically targeted ciliated airway epithelial cells. Since rgRSV appears to breach the lumenal barriers encountered by other gene transfer vectors in the airway, this virus may be a good candidate for the development of a gene transfer vector for CF lung disease.

scholarly journals β2-Adrenoceptor signaling in airway epithelial cells promotes eosinophilic inflammation, mucous metaplasia, and airway contractility

2017 ◽  
Vol 114 (43) ◽  
pp. E9163-E9171 ◽  
Author(s):  
Long P. Nguyen ◽  
Nour A. Al-Sawalha ◽  
Sergio Parra ◽  
Indira Pokkunuri ◽  
Ozozoma Omoluabi ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Airway Epithelium ◽  
Cell Types ◽  
Airway Epithelial Cells ◽  
Airway Smooth Muscle Cells ◽  
Airway Epithelial ◽  
Eosinophilic Inflammation ◽  
Mucus Production ◽  
Asthma Phenotype ◽  
Transgenic Expression

The mostly widely used bronchodilators in asthma therapy are β2-adrenoreceptor (β2AR) agonists, but their chronic use causes paradoxical adverse effects. We have previously determined that β2AR activation is required for expression of the asthma phenotype in mice, but the cell types involved are unknown. We now demonstrate that β2AR signaling in the airway epithelium is sufficient to mediate key features of the asthmatic responses to IL-13 in murine models. Our data show that inhibition of β2AR signaling with an aerosolized antagonist attenuates airway hyperresponsiveness (AHR), eosinophilic inflammation, and mucus-production responses to IL-13, whereas treatment with an aerosolized agonist worsens these phenotypes, suggesting that β2AR signaling on resident lung cells modulates the asthma phenotype. Labeling with a fluorescent β2AR ligand shows the receptors are highly expressed in airway epithelium. In β2AR−/− mice, transgenic expression of β2ARs only in airway epithelium is sufficient to rescue IL-13–induced AHR, inflammation, and mucus production, and transgenic overexpression in WT mice exacerbates these phenotypes. Knockout of β-arrestin-2 (βarr-2−/−) attenuates the asthma phenotype as in β2AR−/− mice. In contrast to eosinophilic inflammation, neutrophilic inflammation was not promoted by β2AR signaling. Together, these results suggest β2ARs on airway epithelial cells promote the asthma phenotype and that the proinflammatory pathway downstream of the β2AR involves βarr-2. These results identify β2AR signaling in the airway epithelium as capable of controlling integrated responses to IL-13 and affecting the function of other cell types such as airway smooth muscle cells.

scholarly journals The role of pulmonary mesenchymal cells in airway epithelium regeneration during injury repair

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Suyun Fang ◽  
Suhong Zhang ◽  
Haiting Dai ◽  
Xiaoxiang Hu ◽  
Changgong Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Airway Epithelium ◽  
Cell Types ◽  
Mesenchymal Cells ◽  
Ciliated Cells ◽  
Epithelial Stem Cells ◽  
Injury Repair ◽  
Club Cells

Abstract Background The airways of mammalian lung are lined with highly specialized cell types that are the target of airborne toxicants and injury. Several epithelial cell types and bone marrow-derived mesenchymal stem cells have been identified to serve as stem cells during injury repair. However, the contributions of endogenous mesenchymal cells to recruitment, expansion or differentiation of stem cells, and repair and reestablishment of the normal composition of airway epithelium following injury have not been addressed. Methods The role of mouse pulmonary mesenchymal cells was investigated by lineage tracing using Dermo1-Cre; ROSAmTmG mice. In experimental models of lung injury by lipopolysaccharide and naphthalene, GFP-labeled Dermo1+ mesenchymal cells were traced during injury repair. In vitro lung explant culture treated with or without lipopolysaccharide was also used to verify in vivo data. Results During injury repair, a subgroup of GFP-labeled Dermo1+ mesenchymal cells were found to contribute to normal repair of the airway epithelium and differentiated into Club cells, ciliated cells, and goblet cells. In Club cell-specific naphthalene injury model, the process of Dermo1+ stem cell regenerating epithelial cells was dissected. The Dermo1+ stem cells was migrated into the airway epithelium layer sooner after injury, and sequentially differentiated transitionally to epithelial stem cells, such as neuroendocrine cells, and finally to newly differentiated Club cells, ciliated cells, and goblet cells in injury repair. Conclusion In this study, a population of Dermo1+ mesenchymal stem cell was identified to serve as stem cells in airway epithelial cell regeneration during injury repair. The Dermo1+ mesenchymal stem cell differentiated into epithelial stem cells before reestablishing various epithelial cells. These findings have implications for understanding the regulation of lung repair and the potential for usage of mesenchymal stem cells in therapeutic strategies for lung diseases.

scholarly journals Ezrin/Exocyst Complex Regulates Mucin 5AC Secretion Induced by Neutrophil Elastase in Human Airway Epithelial Cells

2015 ◽  
Vol 35 (1) ◽  
pp. 326-338 ◽  
Author(s):  
Qi Li ◽  
Na Li ◽  
Chun-Yi Liu ◽  
Rui Xu ◽  
Victor P. Kolosov ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Neutrophil Elastase ◽  
Airway Epithelial Cells ◽  
Specific Marker ◽  
Airway Epithelial ◽  
Mucin Secretion ◽  
Airway Diseases ◽  
Exocyst Complex ◽  
Cell Surface Structures ◽  
Chronic Airway

Background/Aim: Increased mucin secretion is a characteristic feature of many chronic airway diseases, particularly during periods of exacerbation; however, the exact mechanism of mucin secretion remains unclear. Ezrin, which is a specific marker of apical membranes, is predominantly concentrated in exocyst-rich cell surface structures, crosslinking the actin cytoskeleton with the plasma membrane. In the present study, we examined whether Ezrin is involved in mucin 5AC (MUC5AC) secretion after neutrophil elastase (NE) attack, and we investigated the role of the exocyst complex docking protein Sec3 in this process. Methods: NE was used as a stimulator in a 16HBE14o- cell culture model. The expression and location of Ezrin and Sec3 were investigated, and the interaction between Ezrin and Sec3 in 16HBE14o-cells was assayed after treatment with NE, Ezrin siRNA, Sec3 siRNA, neomycin or PIP2-Ab. Results: We found that Ezrin was highly expressed in the bronchi of humans with chronic airway diseases. NE induced robust MUC5AC protein secretion. The Ezrin siRNA, Sec3 siRNA, and neomycin treatments led to impaired MUC5AC secretion in cells. Both Ezrin and Sec3 were recruited primarily to the cytoplasmic membrane after NE stimulation, and the neomycin and PIP2-Ab treatments abrogated this effect. Immunoprecipitation analysis revealed that Ezrin and Sec3 combined to form complexes; however, these complexes could not be detected in Ezrin∆1-333 mutant-transfected cells, even when PIP2 was added. Conclusions: These results demonstrate that Ezrin/Sec3 complexes are essential for MUC5AC secretion in NE-stimulated airway epithelial cells and that PIP2 is of critical importance in the formation of these complexes.

scholarly journals Autophagy plays an essential role in cigarette smoke-induced expression of MUC5AC in airway epithelium

2016 ◽  
Vol 310 (11) ◽  
pp. L1042-L1052 ◽  
Author(s):  
Jie-Sen Zhou ◽  
Yun Zhao ◽  
Hong-Bin Zhou ◽  
Yong Wang ◽  
Yin-Fang Wu ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cigarette Smoke ◽  
Critical Role ◽  
Airway Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Cigarette Smoke Exposure ◽  
Pathological Feature ◽  
Mucus Production ◽  
Mucin Expression ◽  
Chronic Airway

Mucus hypersecretion is a common pathological feature of chronic airway inflammatory diseases including chronic obstructive pulmonary disease (COPD). However, the molecular basis for this condition remains incompletely understood. We have previously demonstrated a critical role of autophagy in COPD pathogenesis through mediating apoptosis of lung epithelial cells. In this study, we aimed to investigate the function of autophagy as well as its upstream and downstream signals in cigarette smoke-induced mucus production in human bronchial epithelial (HBE) cells and in mouse airways. Cigarette smoke extract (CSE), as well as the classical autophagy inducers starvation or Torin-1, significantly triggered MUC5AC expression, and inhibition of autophagy markedly attenuated CSE-induced mucus production. The CSE-induced autophagy was mediated by mitochondrial reactive oxygen species (mitoROS), which regulated mucin expression through the JNK and activator protein-1 pathway. Epidermal growth factor receptor (EGFR) was also required for CSE-induced MUC5AC in HBE cells, but it exerted inconsiderable effects on the autophagy-JNK signaling cascade. Airways of mice with dysfunctional autophagy-related genes displayed a markedly reduced number of goblet cells and attenuated levels of Muc5ac in response to cigarette smoke exposure. These results altogether suggest that mitoROS-dependent autophagy is essential for cigarette smoke-induced mucus hyperproduction in airway epithelial cells, and reemphasize autophagy inhibition as a novel therapeutic strategy for chronic airway diseases.

New Ultrastructural Observations on Injury and Regeneration of Cilia in Mammalian Conducting Airway Epithelium

1981 ◽  
Vol 39 ◽  
pp. 624-625
Author(s):  
J.L. Carson ◽  
A.M. Collier
Keyword(s):  
Respiratory Tract ◽  
Airway Epithelium ◽  
Defense Mechanisms ◽  
Normal Growth ◽  
Fetal Lung ◽  
Secretory Cells ◽  
Airway Epithelial ◽  
Ciliated Cells ◽  
Conducting Airway ◽  
Conducting Airways

The ciliated cells lining the conducting airways of mammals are integral to the defense mechanisms of the respiratory tract, functioning in coordination with secretory cells in the removal of inhaled and cellular debris. The effects of various infectious and toxic agents on the structure and function of airway epithelial cell cilia have been studied in our laboratory, both of which have been shown to affect ciliary ultrastructure.These observations have led to questions about ciliary regeneration as well as the possible induction of ciliogenesis in response to cellular injury. Classical models of ciliogenesis in the conducting airway epithelium of the mammalian respiratory tract have been based primarily on observations of the developing fetal lung. These observations provide a plausible explanation for the embryological generation of ciliary beds lining the conducting airways but do little to account for subsequent differentiation of ciliated cells and ciliogenesis during normal growth and development.

scholarly journals Pulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ian T. Stancil ◽  
Jacob E. Michalski ◽  
Duncan Davis-Hall ◽  
Hong Wei Chu ◽  
Jin-Ah Park ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Airway Epithelium ◽  
Cell Types ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Airway Epithelia ◽  
Chronic Lung Diseases ◽  
Distal Airway ◽  
Signaling Axis

AbstractThe airway epithelium serves as the interface between the host and external environment. In many chronic lung diseases, the airway is the site of substantial remodeling after injury. While, idiopathic pulmonary fibrosis (IPF) has traditionally been considered a disease of the alveolus and lung matrix, the dominant environmental (cigarette smoking) and genetic (gain of function MUC5B promoter variant) risk factor primarily affect the distal airway epithelium. Moreover, airway-specific pathogenic features of IPF include bronchiolization of the distal airspace with abnormal airway cell-types and honeycomb cystic terminal airway-like structures with concurrent loss of terminal bronchioles in regions of minimal fibrosis. However, the pathogenic role of the airway epithelium in IPF is unknown. Combining biophysical, genetic, and signaling analyses of primary airway epithelial cells, we demonstrate that healthy and IPF airway epithelia are biophysically distinct, identifying pathologic activation of the ERBB-YAP axis as a specific and modifiable driver of prolongation of the unjammed-to-jammed transition in IPF epithelia. Furthermore, we demonstrate that this biophysical state and signaling axis correlates with epithelial-driven activation of the underlying mesenchyme. Our data illustrate the active mechanisms regulating airway epithelial-driven fibrosis and identify targets to modulate disease progression.

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