Supersulphide airway protection in viral and chronic lung diseases
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ABSTRACT:
INSTRUMENT(S): 6520 Quadrupole Time-of-Flight LC/MS
ORGANISM(S): Escherichia Coli
SUBMITTER: 
Seiryo Ogata
LAB HEAD: Takaaki Akaike
PROVIDER: PXD043607 | Pride | 2023-07-14
REPOSITORIES: Pride
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Project description:Background: Tissue remodeling induced by airway inflammation is a main trigger of pathogenesis in various chronic lung diseases like asthma, COPD, IPF, and pulmonary hypertension. The role of human airway smooth muscle cells (HASMCs) in this context is unclear. Hypothesis: HASMCs participate in linking inflammation with remodeling. Methods: The inflammatory responses of ex vivo-cultivated HASMCs to TNFα were investigated by whole-genome-microarray analyses. Diferrential regulation of genes associated with airway inflammation and remodeling were verified by qRT-PCR and ELISA. Results: TNFa induced the expression of 18 cytokines/chemokines and five tissue remodeling genes involved in (severe/corticosteroid-insensitive) asthma, COPD, IPF and/or pulmonary hypertension. Conclusion: HASMCs participate in the interaction of inflammation and tissue remodeling. HASMCs might be considered as targets in therapies of chronic inflammatory lung diseases with regard to attenuating inflammation-induced remodeling processes leading to the development of emphysema or fibrosis. HASMCs of eight donors were left untreated of were stimulated with TNFa at 20 ng/ml. Total RNA was subjected after eight hours of stimulation to whole-human-genome oligo microarray analysis.
2013-05-01 | E-GEOD-45251 | biostudies-arrayexpress
Project description:Background: Tissue remodeling induced by airway inflammation is a main trigger of pathogenesis in various chronic lung diseases like asthma, COPD, IPF, and pulmonary hypertension. The role of human airway smooth muscle cells (HASMCs) in this context is unclear. Hypothesis: HASMCs participate in linking inflammation with remodeling. Methods: The inflammatory responses of ex vivo-cultivated HASMCs to TNFα were investigated by whole-genome-microarray analyses. Diferrential regulation of genes associated with airway inflammation and remodeling were verified by qRT-PCR and ELISA. Results: TNFa induced the expression of 18 cytokines/chemokines and five tissue remodeling genes involved in (severe/corticosteroid-insensitive) asthma, COPD, IPF and/or pulmonary hypertension. Conclusion: HASMCs participate in the interaction of inflammation and tissue remodeling. HASMCs might be considered as targets in therapies of chronic inflammatory lung diseases with regard to attenuating inflammation-induced remodeling processes leading to the development of emphysema or fibrosis.
2013-05-01 | GSE45251 | GEO
Project description:The human small airway epithelium (SAE) plays a central role in the early events in the pathogenesis of most chronic inherited and acquired lung disorders. Little is known about the molecular phenotypes of the specific cell populations comprising the SAE, and the contribution of specific cell populations to the pathogenesis of human disease. There was cell type-specific expression of the genes relevant to the pathogenesis of the inherited pulmonary disorders, genes associated with risk of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), and (non-mutated) driver genes for lung cancers. Some unexpected observations included high expression of CFTR (cystic fibrosis) and SCNN1A and B (bronchiectasis) in ionocytes, DTNBP1 (Hermansky-Pudlak syndrome) in mast cells, FAM13A (COPD) in neuroendocrine cells, RIN3 (COPD) in mast cells, NSPA1L (IPF) in neuroendocrine cells and a variety of lung cancer-related genes expressed in different cell types that, if mutated, become driver genes. Cigarette smoking significantly altered the cell-specific transcriptome of the different cell populations. Many of the genes relevant to the hereditary and acquired disorders exhibited cell-specific modulation by cigarette smoking, including MUC5B (IPF) down-regulation specifically in intermediate, club and mucus-producing cells and SFTPB (surfactant deficiency) up-regulation in ionocytes.
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Project description:Background: Chronic obstructive pulmonary disease (COPD) is a serious chronic disease of the airways that affects many people worldwide and have limited treatment options. While small animal models provide a platform for therapeutic investigations into COPD, their deficiencies continue to impede clinical translation. Alternatively, as a large animal model, sheep have a respiratory system anatomically and physiologically similar to that of humans, encouraging their use in airway disease research. The aim of this study was to better understand disease pathology in a large animal (sheep) experimental model of COPD. Methods: COPD was induced in sheep following lung exposure to porcine elastase (PE) and repeated weekly lung exposures to lipopolysaccharide (LPS) over a period of 8 weeks. Bronchoalveolar fluid and blood samples were collected for immune analyses. Lung function was assessed and lung tissues were collected for histopathology and RNA sequencing. Results: Lung neutrophil levels were elevated in response to repeated airway exposure to PE/LPS, accompanied by a significant decline in ventilation over time. Histological evidence of COPD-like disease changes included chronic inflammation with increased airway and tissue inflammation scores, together with significantly larger airway wall area measures, increased connective tissue deposition and dysregulated gene expression. Conclusions: These studies demonstrate sustained chronic airway inflammation and pathophysiological lung changes in a sheep model of COPD, providing many similarities to that seen in COPD patients. This work opens a pathway for future translational studies using this unique large animal model of COPD, which will serve to bridge the gap between smaller animal models and humans.
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Project description:BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease consisting of emphysema, small airway obstruction, and/or chronic bronchitis that results in significant loss of lung function over time. METHODS: In order to gain insights into the molecular pathways underlying progression of emphysema and explore computational strategies for identifying COPD therapeutics, we profiled gene expression in lung tissue samples obtained from regions within the same lung with varying amounts of emphysematous destruction from smokers with COPD (8 regions x 8 lungs = 64 samples). Regional emphysema severity was quantified in each tissue sample using the mean linear intercept (Lm) between alveolar walls from micro-CT scans. RESULTS: We identified 127 genes whose expression levels were significantly associated with regional emphysema severity while controlling for gene expression differences between individuals. Genes increasing in expression with increasing emphysematous destruction included those involved in inflammation, such as the B-cell receptor signaling pathway, while genes decreasing in expression were enriched in tissue repair processes, including the transforming growth factor beta (TGF beta) pathway, actin organization, and integrin signaling. We found concordant differential expression of these emphysema severity-associated genes in four cross-sectional studies of COPD. Using the Connectivity Map, we identified GHK as a compound that can reverse the gene-expression signature associated with emphysematous destruction and induce expression patterns consistent with TGF beta pathway activation. Treatment of human fibroblasts with GHK recapitulated TGF beta-induced gene-expression patterns, led to the organization of the actin cytoskeleton, and elevated the expression of integrin beta1. Furthermore, addition of GHK or TGF beta restored collagen I contraction and remodeling by fibroblasts derived from COPD lungs compared to fibroblasts from former smokers without COPD. CONCLUSIONS: These results demonstrate that gene-expression changes associated with regional emphysema severity within an individual¿s lung can provide insights into emphysema pathogenesis and identify novel therapeutic opportunities for this deadly disease. They also suggest the need for additional studies to examine the mechanisms by which TGF beta and GHK each reverse the gene-expression signature of emphysematous destruction and the effects of this reversal on disease progression. Paired samples were obtained from 8 regions at regular intervals between the apex and base of each explanted lung from six patients with severe COPD and two donors. The degree of emphysematous destruction was quantified in one sample from each region by mean linear intercept (Lm), while gene expression was profiled in the adjacent sample from the same region using the Affymetrix Human Exon 1.0 ST GeneChip. Human fibroblast cell lines (HLF-1) were treated with GHK or TGF-Beta1 for 48 hours and profiled using the Affymetrix Human Gene 1.0 ST GeneChip.
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