Differentiation of bronchial epithelial spheroids in the presence of IL-13 recapitulates characteristic features of asthmatic airway epithelia.
Ontology highlight
ABSTRACT:
SUBMITTER: Pat Y
PROVIDER: S-EPMC9311728 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Asthma is one of the most common immunological diseases and is characterized by airway hyperresponsiveness (AHR), mucus overproduction, and airway eosinophilia. Although mouse models have provided insight into the mechanisms by which type-2 cytokines induce asthmatic airway inflammation, differences between the rodent and human immune systems hamper efforts to improve understanding of human allergic diseases. In this study, we aim to establish a preclinical animal model of asthmatic airway inflammation using humanized IL-3/GM-CSF or IL-3/GM-CSF/IL-5 Tg NOD/Shi-scid-IL2r?null (NOG) mice and investigate the roles of human type-2 immune responses in the asthmatic mice. Several important characteristics of asthma - such as AHR, goblet cell hyperplasia, T cell infiltration, IL-13 production, and periostin secretion - were induced in IL-3/GM-CSF Tg mice by intratracheally administered human IL-33. In addition to these characteristics, human eosinophilic inflammation was observed in IL-3/GM-CSF/IL-5 Tg mice. The asthmatic mechanisms of the humanized mice were driven by activation of human Th2 and mast cells by IL-33 stimulation. Furthermore, treatment of the humanized mice with an anti-human IL-13 antibody significantly suppressed these characteristics. Therefore, the humanized mice may enhance our understanding of the pathophysiology of allergic disorders and facilitate the preclinical development of new therapeutics for IL-33-mediated type-2 inflammation in asthma.
| S-EPMC6238753 | biostudies-other
Project description:IL-17A and IL-19 are highly expressed in chronic inflammatory diseases, such as psoriasis and asthma. IL-19 plays a significant role in the enhancement of T(H)2 cytokine secretion in allergic diseases, but its cellular source in asthmatic patients remains unknown.Our aims were to determine whether the epithelium is a major source of airway mucosal IL-19 and to elucidate the mechanism of gene expression regulation.Immunofluorescent staining was used to determine IL-19 protein expression in tracheal tissue sections of various airway diseases. Well-differentiated primary human bronchial epithelial cultures and a corresponding cell line were used as in vitro models to study gene regulation.We found significantly higher IL-19 expression in airway epithelia of asthmatic patients than in epithelia of patients with other diseases. Using a cytokine panel, we demonstrated the upregulation of IL-19 expression in cultures by two T(H)2 cytokines, IL-4 and IL-13, in addition to the previously found T(H)17 cytokine IL-17A. Moreover, cotreatment of IL-17A and IL-4/IL-13 synergistically upregulated IL-19 expression. Using siRNA and chemical inhibitor approaches, we demonstrated a transcriptional regulation of IL-19 by nuclear factor kappaB and signal transducer and activator of transcription (STAT) 6. The addition of IL-13 to IL-17A stimulation triggers a shift from nuclear factor kappaB-dependent transcriptional regulation to one that is STAT6 based. Using chromatin immunoprecipitation assays, we demonstrated the presence of STAT6-binding elements in the IL-19 promoter region.We propose that an IL-17A- and IL-13-induced synergism in IL-19 stimulation in airway epithelia occurs through a STAT6-dependent pathway.
| S-EPMC4631388 | biostudies-literature
Project description:The onset and development of many airway pathologies affect sound propagation throughout the respiratory system; changes in respiratory sounds are detected primarily by auscultation, which is highly skill dependent. The aim of the present study was to compare healthy and asthmatic pulmonary acoustics by applying a 1D model of wave propagation on CT-based patient-specific geometries. High-resolution CT lung images were acquired in five healthy volunteers and five asthmatic patients at total lung capacity (TLC) and functional residual capacity (FRC). Tracheobronchial trees were reconstructed from CT images. Acoustic pressure, impedance and wall radial velocity were measured by simulating acoustic wave propagation of two external, acoustic pressure waves (1 Pa, 200 and 600 Hz) from the trachea level to the 4th generation. In asthmatic patients, acoustic pressure averaged across the last three generations showed a reduction equal to 29.7% (p<0.01) at FRC, at 200 Hz; input and terminal impedance were 34.5% (p<0.05) higher both at FRC and TLC; wall radial velocity was more than 80% (p<0.05) lower in higher generations both at FRC and TLC. Airway differences in asthma alter acoustic parameters at FRC and TLC, with the greatest difference at FRC and 200 Hz. Acoustic wave propagation analysis represents a quantitative approach that has potential to objectively characterize airway differences in individuals with diseases such as asthma.
| S-EPMC7010248 | biostudies-literature
Project description:The goal of this study was to examine changes to gene expression induced by IL-13 treatment of air-liquid interface cultures of healthy primary human airway epithelia over time.
2023-08-16 | GSE240741 | GEO
Project description:Neutrophil extracellular traps (NETs) provide host defense but can contribute to the pathobiology of diverse human diseases. We sought to determine the extent and mechanism by which NETs contribute to human airway cell inflammation. Primary normal human bronchial epithelial cells (HBEs) grown at air-liquid interface and wild-type (wt)CFBE41o- cells (expressing wtCFTR) were exposed to cell-free NETs from unrelated healthy volunteers for 18 h in vitro. Cytokines were measured in the apical supernatant by Luminex, and the effect on the HBE transcriptome was assessed by RNA sequencing. NETs consistently stimulated IL-8, TNF-α, and IL-1α secretion by HBEs from multiple donors, with variable effects on other cytokines (IL-6, G-CSF, and GM-CSF). Expression of HBE RNAs encoding IL-1 family cytokines, particularly IL-36 subfamily members, was increased in response to NETs. NET exposure in the presence of anakinra [recombinant human IL-1 receptor antagonist (rhIL-1RA)] dampened NET-induced changes in IL-8 and TNF-α proteins as well as IL-36α RNA. rhIL-36RA limited the increase in expression of proinflammatory cytokine RNAs in HBEs exposed to NETs. NETs selectively upregulate an IL-1 family cytokine response in HBEs, which enhances IL-8 production and is limited by rhIL-1RA. The present findings describe a unique mechanism by which NETs may contribute to inflammation in human lung disease in vivo. NET-driven IL-1 signaling may represent a novel target for modulating inflammation in diseases characterized by a substantial NET burden.
| S-EPMC7468846 | biostudies-literature
Project description:Because of its advantage as a minimally invasive procedure, nasal brushings have been increasingly used and proposed as a valuable approach to study lower airway diseases in lieu of bronchial epithelial cells. However, there is limited or conflicting evidence pertaining to whether nasal samples can be surrogates to bronchial samples. The goal of the present study is to test whether nasal epithelial cells have similar antiviral and inflammatory responses to IL-13 treatment and rhinovirus infection, a condition mimicking virally induced asthma exacerbation. Nasal and bronchial airway epithelial cells taken from the same patient were cultured under submerged and air-liquid interface (ALI) culture in the absence or presence of rhinovirus and IL-13 treatment. Inflammatory cytokines IP-10 and eotaxin-3, antiviral gene Mx1 and viral levels were measured.In the absence of IL-13 treatment, nasal and bronchial cells showed a similar IP-10 response in both ALI and submerged cultures. Under the ALI culture, short term (e.g., 3 days) IL-13 treatment had a minimal effect on viral and Mx1 levels in both cell types. However, prolonged (e.g., 14 days) IL-13 treatments in both cell types decreased viral load and Mx1 expression. Under the submerged culture, IL-13 treatment in both cell types has minimal effects on viral load, IP-10 and Mx1. IL-13-induced eotaxin-3 production was similar in both types of cells under either submerged or ALI culture, which was not affected by viral infection.Our data suggest that nasal epithelial cells could serve as a surrogate to bronchial epithelial cells in future studies aimed at defining the role of type 2 cytokine IL-13 in regulating pro-inflammatory and antiviral responses.
| S-EPMC5931947 | biostudies-other
Project description:Aberrant production of the prototypical type 2 cytokines, interleukin (IL)-4 and IL-13 has long been associated with the pathogenesis of allergic disorders. Despite tremendous scientific inquiry, the similarities in their structure, and receptor usage have made it difficult to ascertain the distinct role that these two look-alike cytokines play in the onset and perpetuation of allergic inflammation. However, recent discoveries of differences in receptor distribution, utilization/assembly and affinity between IL-4 and IL-13, along with the discovery of unique innate lymphoid 2 cells (ILC2) which preferentially produce IL-13, not IL-4, are beginning to shed light on these mysteries. The purpose of this chapter is to review our current understanding of the distinct roles that IL-4 and IL-13 play in allergic inflammatory states and the utility of their modulation as potential therapeutic strategies for the treatment of allergic disorders.
| S-EPMC4532591 | biostudies-literature
Project description:In the current COVID-19 pandemic context, proposing and validating effective treatments represents a major challenge. However, the scarcity of biologically relevant pre-clinical models of SARS-CoV-2 infection imposes a significant barrier for scientific and medical progress, including the rapid transition of potentially effective treatments to the clinical setting. We use reconstituted human airway epithelia to isolate and then characterize the viral infection kinetics, tissue-level remodeling of the cellular ultrastructure, and transcriptional early immune signatures induced by SARS-CoV-2 in a physiologically relevant model. Our results emphasize distinctive transcriptional immune signatures between nasal and bronchial HAE, both in terms of kinetics and intensity, hence suggesting putative intrinsic differences in the early response to SARS-CoV-2 infection. Most important, we provide evidence in human-derived tissues on the antiviral efficacy of remdesivir monotherapy and explore the potential of the remdesivir-diltiazem combination as an option worthy of further investigation to respond to the still-unmet COVID-19 medical need.
| S-EPMC7373044 | biostudies-literature
Project description:The goal of this study was to examine changes in cell composition and gene expression with IL-13 treatment over time within different cell types from air-liquid interface cultures from healthy primary human airway epithelia.
2024-04-12 | GSE229202 | GEO
Project description:Childhood asthma represents a worldwide problem, involving genetic, immune defense and environmental components. MicroRNAs (miRs) are non-coding, single-stranded RNAs involved in immune regulation. The aim was to evaluate clinical potential of plasma miR-21 and miR-146a involved in T helper differentiation in childhood asthma and non-asthmatic controls. Group 1 consisted of 27 asthmatic children receiving inhaled corticosteroids (ICSs), which was compared to group 2 with 21 healthy control children. All patients were assessed by pulmonary function tests. miR-21 and miR-146a expression levels were determined by real-time quantitative PCR, and IL-13 was measured using ELISA. Group 1 showed significant up-regulation of plasma miR-21 and miR-146a levels with mean values 42.6-fold and 4.7-fold higher than average expression, respectively, in group 2. miR-21 levels positively correlated with IL-13 levels and eosinophil percentage, while miR-146a only correlated to eosinophil percentage. There was a linear association between each of miR-21 and miR-146a expression and FEV1 (forced expiratory volume in the first second), miR-21 and miR-146a are up-regulated in asthmatic children. miR-21 served as a better asthma biomarker. Association between both markers and FEV1 points to their role in determining asthma outcome following ICS treatment. miR-21 and miR-146a play a role in eosinophilic endotypic classification of asthma.
| S-EPMC6852388 | biostudies-literature