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Secondhand smoke alters arachidonic acid metabolism and inflammation in infants and children with cystic fibrosis.

ABSTRACT: BACKGROUND:Mechanisms that facilitate early infection and inflammation in cystic fibrosis (CF) are unclear. We previously demonstrated that children with CF and parental-reported secondhand smoke exposure (SHSe) have increased susceptibility to bacterial infections. SHSe hinders arachidonic acid (AA) metabolites that mediate immune function in patients without CF, and may influence CF immune dysfunction. We aimed to define SHSe's impact on inflammation mediators and infection in children with CF. METHODS:Seventy-seven children with CF <10 years of age (35 infants <1?year; 42 children 1-10 years) were enrolled and hair nicotine concentrations measured as an objective surrogate of SHSe. AA signalling by serum and macrophage lipidomics, inflammation using blood transcriptional profiles and in vitro macrophage responses to bacterial infection after SHSe were assessed. RESULTS:Hair nicotine concentrations were elevated in 63% of patients. Of the AA metabolites measured by plasma lipidomics, prostaglandin D2 (PGD2) concentrations were decreased in children with CF exposed to SHSe, and associated with more frequent hospitalisations (p=0.007) and worsened weight z scores (p=0.008). Children with CF exposed to SHSe demonstrated decreased expression of the prostaglandin genes PTGES3 and PTGR2 and overexpression of inflammatory pathways. These findings were confirmed using an in vitro model, where SHSe was associated with a dose-dependent decrease in PGD2 and increased methicillin-resistant Staphylococcus aureus survival in human CF macrophages. CONCLUSIONS:Infants and young children with CF and SHSe have altered AA metabolism and dysregulated inflammatory gene expression resulting in impaired bacterial clearance. Our findings identified potential therapeutic targets to halt early disease progression associated with SHSe in the young population with CF.

SUBMITTER: Kopp BT

PROVIDER: S-EPMC7642975 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Secondhand smoke alters arachidonic acid metabolism and inflammation in infants and children with cystic fibrosis.

Kopp Benjamin T BT Thompson Rohan R Kim Jeeho J Konstan Robert R Diaz Alejandro A Smith Bennett B Shrestha Chandra C Rogers Lynette K LK Hayes Don D Tumin Dmitry D Woodley Frederick W FW Ramilo Octavio O Sanders Don B DB Groner Judith A JA Mejias Asuncion A

Thorax 20190119 3

<h4>Background</h4>Mechanisms that facilitate early infection and inflammation in cystic fibrosis (CF) are unclear. We previously demonstrated that children with CF and parental-reported secondhand smoke exposure (SHSe) have increased susceptibility to bacterial infections. SHSe hinders arachidonic acid (AA) metabolites that mediate immune function in patients without CF, and may influence CF immune dysfunction. We aimed to define SHSe's impact on inflammation mediators and infection in children ...[more]

PMID: 30661024

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Project description:Disease variation can be substantial even in conditions with a single gene etiology such as cystic fibrosis (CF). Simultaneously studying the effects of genes and environment may provide insight into the causes of variation.To determine whether secondhand smoke exposure is associated with lung function and other outcomes in individuals with CF, whether socioeconomic status affects the relationship between secondhand smoke exposure and lung disease severity, and whether specific gene-environment interactions influence the effect of secondhand smoke exposure on lung function.Retrospective assessment of lung function, stratified by environmental and genetic factors. Data were collected by the US Cystic Fibrosis Twin and Sibling Study with missing data supplemented by the Cystic Fibrosis Foundation Data Registry. All participants were diagnosed with CF, were recruited between October 2000 and October 2006, and were primarily from the United States.Disease-specific cross-sectional and longitudinal measures of lung function.Of 812 participants with data on secondhand smoke in the home, 188 (23.2%) were exposed. Of 780 participants with data on active maternal smoking during gestation, 129 (16.5%) were exposed. Secondhand smoke exposure in the home was associated with significantly lower cross-sectional (9.8 percentile point decrease; P < .001) and longitudinal lung function (6.1 percentile point decrease; P = .007) compared with those not exposed. Regression analysis demonstrated that socioeconomic status did not confound the adverse effect of secondhand smoke exposure on lung function. Interaction between gene variants and secondhand smoke exposure resulted in significant percentile point decreases in lung function, namely in CFTR non-DeltaF508 homozygotes (12.8 percentile point decrease; P = .001), TGFbeta1-509 TT homozygotes (22.7 percentile point decrease; P = .006), and TGFbeta1 codon 10 CC homozygotes (20.3 percentile point decrease; P = .005).Any exposure to secondhand smoke adversely affects both cross-sectional and longitudinal measures of lung function in individuals with CF. Variations in the gene that causes CF (CFTR) and a CF-modifier gene (TGFbeta1) amplify the negative effects of secondhand smoke exposure.

Dataset Information

Secondhand smoke alters arachidonic acid metabolism and inflammation in infants and children with cystic fibrosis.

Publications

Secondhand smoke alters arachidonic acid metabolism and inflammation in infants and children with cystic fibrosis.

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