Unknown,Transcriptomics,Genomics,Proteomics

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LPS-induced expression in rat lung epithelial cells

ABSTRACT: Acute lung inflammation can alter the pulmonary function of susceptible individuals and exacerbate the pathogenesis of chronic inflammatory lung diseases including chronic obstructive pulmonary disease (COPD), cystic fibrosis and asthma. Exposure to lipopolysaccharide (LPS) or endotoxin, a constituent of outer cell membrane of gram negative bacteria, induces airway inflammation that is primarily characterized by increased polymorphonuclear neutrophils (PMNs) at early time points. Because LPS is present in variety of occupational and home environments and is an active constituent of cigarette smoke it is a risk factor for increasing prevalence and severity of non-occupational COPD, for adult onset of asthma and for wheezing in children. In airway epithelial cells, LPS stimulation increases mucin gene expression and mucous production. Hypersecretion of mucus overwhelms the ciliary clearance and obstructs airways, causing morbidity and mortality in chronic inflammatory respiratory lung diseases. In addition, acute bacterial infection contributes to the exacerbation of chronic airway diseases, specifically in advanced COPD and CF subjects, leading to increased healthcare burden and higher mortality. Bcl-2, a prosurvival protein that inhibits cell death plays a key role in normal cellular homeostasis and regulates the integrity of the mitochondrial and endoplasmic reticulum membranes. Gain- and loss-of-function studies showed that Bcl-2 expression sustains hyperplastic epithelial cells, and Bcl-2 expression is elevated in airway epithelial cells of subjects with cystic fibrosis and asthma. The present study investigated which inflammatory mediators induce mucous cell metaplasia and Bcl-2 expression following LPS exposure. Microarray analyses of mRNA from airway epithelial cells captured by laser microdissection from rat lungs snap-frozen at day 0 and 2 post LPS exposure were analyzed. Microarray analysis of mRNA from airway epithelial cells captured by laser microdissection from rat lungs snap-frozen at day 0 and day 2 post LPS exposure was performed to identify inflammatory mediators modulated by LPS exposure. Specific pathogen-free F344/NCrR male rats of 8–10 wk of age (from NCI, Frederick, MD) were exposed to LPS (1000 ug in 0.5 ML Saline) and rats were sacrificed on day 0 and day 2 of LPS exposure. Right lungs were snap-frozen in OCT and airway epithelial cells were captured by laser-dissection microsopy to extract RNA. Gene expression data from nonexposed rats (0d) was used a control.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Hitendra Chand

PROVIDER: E-GEOD-36174 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Acute lung inflammation can alter the pulmonary function of susceptible individuals and exacerbate the pathogenesis of chronic inflammatory lung diseases including chronic obstructive pulmonary disease (COPD), cystic fibrosis and asthma. Exposure to lipopolysaccharide (LPS) or endotoxin, a constituent of outer cell membrane of gram negative bacteria, induces airway inflammation that is primarily characterized by increased polymorphonuclear neutrophils (PMNs) at early time points. Because LPS is present in variety of occupational and home environments and is an active constituent of cigarette smoke it is a risk factor for increasing prevalence and severity of non-occupational COPD, for adult onset of asthma and for wheezing in children. In airway epithelial cells, LPS stimulation increases mucin gene expression and mucous production. Hypersecretion of mucus overwhelms the ciliary clearance and obstructs airways, causing morbidity and mortality in chronic inflammatory respiratory lung diseases. In addition, acute bacterial infection contributes to the exacerbation of chronic airway diseases, specifically in advanced COPD and CF subjects, leading to increased healthcare burden and higher mortality. Bcl-2, a prosurvival protein that inhibits cell death plays a key role in normal cellular homeostasis and regulates the integrity of the mitochondrial and endoplasmic reticulum membranes. Gain- and loss-of-function studies showed that Bcl-2 expression sustains hyperplastic epithelial cells, and Bcl-2 expression is elevated in airway epithelial cells of subjects with cystic fibrosis and asthma. The present study investigated which inflammatory mediators induce mucous cell metaplasia and Bcl-2 expression following LPS exposure. Microarray analyses of mRNA from airway epithelial cells captured by laser microdissection from rat lungs snap-frozen at day 0 and 2 post LPS exposure were analyzed. Microarray analysis of mRNA from airway epithelial cells captured by laser microdissection from rat lungs snap-frozen at day 0 and day 2 post LPS exposure was performed to identify inflammatory mediators modulated by LPS exposure.

Project description:The apical junctional complex (AJC), composed of tight junctions and adherens junctions, is essential for maintaining epithelial barrier function. Since cigarette smoking and chronic obstructive pulmonary disease (COPD), the major smoking-induced disease, are both associated with increased lung epithelial permeability, we hypothesized that smoking alters the transcriptional program regulating AJC integrity in the small airway epithelium (SAE), the primary site of pathological changes in COPD. Transcriptome analysis revealed a global down-regulation of physiological AJC gene expression in the SAE of healthy smokers (n=53) compared to healthy nonsmokers (n=59), an observation associated with changes in molecular pathways regulating epithelial differentiation such as PTEN signaling and accompanied by induction of cancer-related AJC genes. Genome-wide co-expression analysis identified a smoking-sensitive AJC transcriptional network. The overall expression of AJC-associated genes was further decreased in COPD smokers (n=23). Exposure of human airway epithelial cells to cigarette smoke extract in vitro resulted in down-regulation of several AJC-related genes, accompanied by decreased transepithelial resistance. Thus, cigarette smoking alters the AJC gene expression architecture in the human airway epithelium, providing a molecular basis for the dysregulation of airway epithelial barrier function during the development of smoking-induced lung disease. The apical junctional complex (AJC), composed of tight junctions and adherens junctions, is essential for maintaining epithelial barrier function. Since cigarette smoking and chronic obstructive pulmonary disease (COPD), the major smoking-induced disease, are both associated with increased lung epithelial permeability, we hypothesized that smoking alters the transcriptional program regulating AJC integrity in the small airway epithelium (SAE), the primary site of pathological changes in COPD. In this study, microarray analysis of the SAE obtained from 53 healthy nonsmokers, 59 healthy smokers, and 23 smokers with COPD was performed to determine physiological AJC gene expression architecture in the SAE and its modification by cigarette smoking and during the development of COPD.

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LPS-induced expression in rat lung epithelial cells

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