Secretory cells are the primary source of pIgR in small airways
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE196341 | GEO | 2022/02/11
REPOSITORIES: GEO
Similar Datasets
Project description:Maintenance of intestinal homeostasis requires a healthy relationship between the commensal gut microbiota and the host immune system. Breast milk supplies the first source of antigen-specific immune protection in the gastrointestinal tract of suckling mammals, in the form of secretory immunoglobulin A (SIgA). SIgA is transported across glandular and mucosal epithelial cells into external secretions by the polymeric immunoglobulin receptor (pIgR). Here, a breeding scheme with pIgR-sufficient and -deficient mice was used to study the effects of breast milk-derived SIgA on development of the gut microbiota and host intestinal immunity. Early exposure to maternal SIgA prevented the translocation of aerobic bacteria from the neonatal gut into draining lymph nodes, including the opportunistic pathogen Ochrobactrum anthropi. By the age of weaning, mice that received maternal SIgA in breast milk had a significantly different gut microbiota from mice that did not receive SIgA, and these differences were magnified when the mice reached adulthood. Early exposure to SIgA in breast milk resulted in a pattern of intestinal epithelial cell gene expression in adult mice that differed from that of mice that were not exposed to passive SIgA, including genes associated with intestinal inflammatory diseases in humans. Maternal SIgA was also found to ameliorate colonic damage caused by the epithelial-disrupting agent dextran sulfate sodium. These findings reveal unique mechanisms through which SIgA in breast milk may promote lifelong intestinal homeostasis, and provide additional evidence for the benefits of breastfeeding. We used microarrays to determine the effects of passive and active secretory IgA, in the presence or absence of the epithelial-disrupting agent dextran sulfate sodium, on gene expression in intestinal epithelial cells of mice A breeding scheme was used that involved crosses between mouse dams and sires that were deficient or sufficient for expression of the polymeric immunoglobulin receptor (Pigr), a protein that is required for transport of secretory IgA (SIgA) into external secretions. Offspring of these crosses were genotyped for Pigr alleles, and littermate offspring were distributed into 4 groups based on early exposure to passive SIgA in mother's milk (P-yes and P-no) and ability to carry out Pigr-mediated endogenous transport of active SIgA (A-yes and A-no). Seventy-day-old gender-matched Pigr+/- and Pigr-/- offspring of Pigr+/- and Pigr-/- dams were left untreated or given 2% dextran sulfate sodium (DSS) in drinking water for 8 days. Colonic epithelial cells were isolated, and total cellular RNA was purified. RNA was pooled from 3 mice for each of 2 biological replicates for microarray analysis.
2014-01-25 | E-GEOD-54371 | biostudies-arrayexpress
Project description:Secretory cells are the primary source of pIgR in small airways
| PRJNA804479 | ENA
Project description:Maintenance of intestinal homeostasis requires a healthy relationship between the commensal gut microbiota and the host immune system. Breast milk supplies the first source of antigen-specific immune protection in the gastrointestinal tract of suckling mammals, in the form of secretory immunoglobulin A (SIgA). SIgA is transported across glandular and mucosal epithelial cells into external secretions by the polymeric immunoglobulin receptor (pIgR). Here, a breeding scheme with pIgR-sufficient and -deficient mice was used to study the effects of breast milk-derived SIgA on development of the gut microbiota and host intestinal immunity. Early exposure to maternal SIgA prevented the translocation of aerobic bacteria from the neonatal gut into draining lymph nodes, including the opportunistic pathogen Ochrobactrum anthropi. By the age of weaning, mice that received maternal SIgA in breast milk had a significantly different gut microbiota from mice that did not receive SIgA, and these differences were magnified when the mice reached adulthood. Early exposure to SIgA in breast milk resulted in a pattern of intestinal epithelial cell gene expression in adult mice that differed from that of mice that were not exposed to passive SIgA, including genes associated with intestinal inflammatory diseases in humans. Maternal SIgA was also found to ameliorate colonic damage caused by the epithelial-disrupting agent dextran sulfate sodium. These findings reveal unique mechanisms through which SIgA in breast milk may promote lifelong intestinal homeostasis, and provide additional evidence for the benefits of breastfeeding. We used microarrays to determine the effects of passive and active secretory IgA, in the presence or absence of the epithelial-disrupting agent dextran sulfate sodium, on gene expression in intestinal epithelial cells of mice
2014-01-25 | GSE54371 | GEO
Project description:Objectives: Therapies being safe, effective and not vulnerable to develop resistance are highly desirable to counteract bacterial infections. Host-directed therapeutics is an alternative to conventional antibiotics based on perturbing host pathways subverted by pathogens during their life cycle by the use of host-directed drugs to counteract microbial infections. This study sought to identify cellular genes and pathways differentially expressed during airways epithelial infection by nontypable Haemophilus influenzae (NTHi). NTHi is an opportunistic pathogen that is an important cause of exacerbation of chronic obstructive pulmonary disease (COPD). Based on the proposed relationship between NTHi intracellular location and persistence, the antimicrobial potential of a panel of drugs perturbing host pathways used by NTHi to enter epithelial cells was investigated. Methods: We screened for host genes differentially expressed upon infection by the clinical isolate NTHi375 by analyzing A549 cell whole genome expression profiling, and identified a panel of host target candidates which were pharmacologically modulated. Interfering drugs were tested for their bactericidal effect, cytotoxicity, effect on the interplay NTHi-epithelial cell, and effect on NTHi respiratory infection in vivo, by assessing lung bacterial loads in a murine intranasal infection model. Results: The sirtuin-1 activator resveratrol showed a bactericidal effect against NTHi; the PDE4 inhibitor rolipram showed therapeutic efficacy by lowering NTHi375 counts both intracellularly and in the lungs of infected mice. Conclusions: PDE4 inhibition is currently prescribed in COPD; resveratrol is a geroprotector attractive for COPD treatment by preventing lung aging. This work provides evidence for the antimicrobial potential of rolipram and resveratrol against NTHi respiratory infection.
2015-09-23 | GSE69134 | GEO
Project description:Objectives: Therapies being safe, effective and not vulnerable to develop resistance are highly desirable to counteract bacterial infections. Host-directed therapeutics is an alternative to conventional antibiotics based on perturbing host pathways subverted by pathogens during their life cycle by the use of host-directed drugs to counteract microbial infections. This study sought to identify cellular genes and pathways differentially expressed during airways epithelial infection by nontypable Haemophilus influenzae (NTHi). NTHi is an opportunistic pathogen that is an important cause of exacerbation of chronic obstructive pulmonary disease (COPD). Based on the proposed relationship between NTHi intracellular location and persistence, the antimicrobial potential of a panel of drugs perturbing host pathways used by NTHi to enter epithelial cells was investigated. Methods: We screened for host genes differentially expressed upon infection by the clinical isolate NTHi375 by analyzing A549 cell whole genome expression profiling, and identified a panel of host target candidates which were pharmacologically modulated. Interfering drugs were tested for their bactericidal effect, cytotoxicity, effect on the interplay NTHi-epithelial cell, and effect on NTHi respiratory infection in vivo, by assessing lung bacterial loads in a murine intranasal infection model. Results: The sirtuin-1 activator resveratrol showed a bactericidal effect against NTHi; the PDE4 inhibitor rolipram showed therapeutic efficacy by lowering NTHi375 counts both intracellularly and in the lungs of infected mice. Conclusions: PDE4 inhibition is currently prescribed in COPD; resveratrol is a geroprotector attractive for COPD treatment by preventing lung aging. This work provides evidence for the antimicrobial potential of rolipram and resveratrol against NTHi respiratory infection. Haemophilus influenzae clinical strain NTHi375 induced gene expression in A549 human type II pneumocyte cell line was measured at 2 h post-infection. Non infected cells were used as a control. Four independent experiments were performed for each condition.
2015-09-23 | E-GEOD-69134 | biostudies-arrayexpress
Project description:The earliest morphologic evidence of changes in the airways associated with chronic cigarette smoking is in the small airways. To help understand how smoking modifies small airway structure and function, we developed a strategy using fiberoptic bronchoscopy and brushing to sample the human small airway (10th-12th order) bronchial epithelium to assess gene expression (Affymetrix HG-U133A array) in phenotypically normal smokers (n=6, 24 ± 4 pack-yr) compared to matched non-smokers (n=5). Compared to samples from the large (2nd to 3rd order) bronchi, the small airway samples had a higher proportion of ciliated cells, but less basal, undifferentiated, and secretory cells. The small, but not large, airway samples included Clara cells, a cell found only in the small airway epithelium, and the small, but not the large, airway epithelium expressed genes for the surfactant apoproteins. Despite the fact that the smokers were phenotypically normal, analysis of the small airway epithelium of the smokers compared to the non-smokers demonstrated up- and -down-regulation of genes in multiple categories relevant to the pathogenesis of chronic obstructive lung disease (COPD), including genes coding for cytokines/innate immunity, apoptosis, pro-fibrosis, mucin, responses to oxidants and xenobiotics, antiproteases and general cellular processes. In the context that COPD starts in the small airways, these changes in gene expression in the small airway epithelium in phenotypically normal smokers are candidates for the development of therapeutic strategies to prevent the onset of COPD. Experiment Overall Design: 6 smokers Experiment Overall Design: 5 non-smokers Experiment Overall Design: no replicates
2007-09-06 | E-GEOD-3320 | biostudies-arrayexpress
Project description:The earliest morphologic evidence of changes in the airways associated with chronic cigarette smoking is in the small airways. To help understand how smoking modifies small airway structure and function, we developed a strategy using fiberoptic bronchoscopy and brushing to sample the human small airway (10th-12th order) bronchial epithelium to assess gene expression (Affymetrix HG-U133A array) in phenotypically normal smokers (n=6, 24 ± 4 pack-yr) compared to matched non-smokers (n=5). Compared to samples from the large (2nd to 3rd order) bronchi, the small airway samples had a higher proportion of ciliated cells, but less basal, undifferentiated, and secretory cells. The small, but not large, airway samples included Clara cells, a cell found only in the small airway epithelium, and the small, but not the large, airway epithelium expressed genes for the surfactant apoproteins. Despite the fact that the smokers were phenotypically normal, analysis of the small airway epithelium of the smokers compared to the non-smokers demonstrated up- and -down-regulation of genes in multiple categories relevant to the pathogenesis of chronic obstructive lung disease (COPD), including genes coding for cytokines/innate immunity, apoptosis, pro-fibrosis, mucin, responses to oxidants and xenobiotics, antiproteases and general cellular processes. In the context that COPD starts in the small airways, these changes in gene expression in the small airway epithelium in phenotypically normal smokers are candidates for the development of therapeutic strategies to prevent the onset of COPD. Keywords: response to cigarette smoking
2005-10-30 | GSE3320 | GEO
Project description:Rationale: Multiciliated cell (MCC) loss/dysfunction is common in the small airways of patients with COPD but it is unclear if this contributes to COPD lung pathology. Objectives: To determine whether loss of MCCs causes a COPD-like phenotype in mice and explore a potential role for the transcription factor p73 in COPD. Methods: p73floxE7-E9 mice were crossed with Shh-Cre mice to generate mice lacking MCCs in the airway epithelium. The resulting p73airway mice were analyzed using electron microscopy, flow cytometry, morphometry, forced oscillation technique, and single-cell RNA sequencing. Further, the effects of cigarette smoke on p73 transcript and protein expression were examined using in vitro and in vivo models and in studies including airway epithelium from smokers and COPD patients. Measurements and Main Results: Loss of functional p73 in the respiratory epithelium resulted in a near-complete absence of MCCs in p73airway mice. In adulthood, these mice spontaneously developed neutrophilic inflammation and emphysema-like lung remodeling and had progressive loss of secretory cells. Exposure of normal airway epithelium cells to cigarette smoke rapidly and durably suppressed p73 expression in vitro and in vivo. Further, TP73 mRNA expression was reduced in the airways of current smokers (n=82) compared to former smokers (n=69) and p73-expressing MCCs were reduced in the small airways of COPD patients (n=11) compared non-COPD controls (n=12). Conclusions: Loss of functional p73 in murine airway epithelium results in the absence of MCCs and promotes COPD-like lung pathology. In smokers and patients with COPD, loss of p73 may contribute to MCC loss or dysfunction.
2023-11-20 | GSE240096 | GEO
Project description:Rationale: DNA methylation is an epigenetic modification that is highly disrupted in response to cigarette smoke and involved in a wide spectrum of malignant and non-malignant diseases, but surprisingly not previously assessed in small airways of patients with chronic obstructive pulmonary disease (COPD). Small airways are the primary sites of airflow obstruction in COPD. We sought to determine whether DNA methylation patterns are disrupted in small airway epithelia of COPD patients, and evaluate whether changes in gene expression are associated with these disruptions. Methods: Genome-wide methylation and gene expression analysis were performed on small airway epithelial DNA and RNA obtained from the same patient during bronchoscopy, using Illumina's Infinium HM27 and Affymetrix's Genechip Human Gene 1.0 ST arrays. To control for known effects of cigarette smoking on DNA methylation, methylation and gene expression profiles were compared between former smokers (FS) with and without COPD matched for age, pack years and years of smoking cessation. Results: Our results indicate that aberrant DNA methylation is i) a genome-wide phenomenon in small airways of patients with COPD and ii) associated with altered expression of genes and pathways important to COPD, such as the Nrf2 oxidative response pathway. Conclusions: DNA methylation is likely an important mechanism contributing to modulation of genes important to COPD pathology. Since these methylation events may underlie disease-specific gene-expression changes, their characterization is a critical first step towards the development of epigenetic markers and an opportunity for developing novel epigenetic therapeutic interventions for COPD. Bisulphite converted DNA from small airway (airways less than <2 mm in diameter) from 38 former smokers: 15 subjects with COPD (post bronchodilator FEV1/FVC ratio <70% and FEV1 predicted M-bM-^IM-$ 80%) and 21 with normal lung function, were hybridized to the Illumina Infinium 27k Human Methylation Beadchip.
2014-02-28 | E-GEOD-55454 | biostudies-arrayexpress