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

Abstract

BackgroundMechanisms 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.MethodsSeventy-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.ResultsHair 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.ConclusionsInfants 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.

Impact of secondhand smoke on cystic fibrosis: is there a link to fatty acid metabolism?

“…At present, the pro-inflammatory and/or anti-inflammatory effects of PGD 2 are difficult to understand. Although the paper of Kopp et al 2 does not provide a definite answer, it is important to note that not only PGD 2 was downregulated. The manuscript’s findings are especially interesting since CFTR itself seems to be involved in the regulation of the PGD synthase-PGD 2 -15d-PGJ 2 pathway 6…”

“…Taken together, Kopp et al 2 showed for the first time that infants and children with CF and SHS exposure biosynthesize significantly lower amounts of AA-derived lipid mediators, have dysregulated inflammatory gene expression and have impaired bacterial clearance. By correlation of PGD 2 levels with clinical outcome, the authors could show the high impact of altered AA-dependent lipid mediator pathways in infants and children with CF, particularly by SHSe.…”

“…This includes an altered lipid constitution with low amounts of linoleic and docosahexaenoic acid and an altered cholesterol and sphingolipid metabolism. However, Kopp et al 2 were able to show that SHSe aggravates these findings and demonstrate why SHSe is especially detrimental to children with CF. In order to examine whether SHSe alters the endogenous biosynthesis of lipid mediators derived from AA, they determined lipid mediator profiles of patients’ serum and found that SHSe decreased AA-derived prostaglandin (PG) D 2 and leukotriene (LT) C 4 lipid mediators as well as their monohydroxy precursors in patients with CF.…”

“…Many clinicians believe that SHSe is a major contributing factor for disease progression, although the mechanisms associated with increased inflammation and infection due to SHSe in infants and young children with CF is not fully elucidated. Kopp et al 2 in this issue are the first who were able to close this important gap. They could clearly demonstrate that SHSe is highly prevalent in young children with CF and results in alterations of arachidonic acid (AA) metabolism and inflammatory gene expression, which in turn impairs bacterial clearance.…”

“…Kopp et al 2 particularly found decreased PGD 2 serum levels which could be associated with impaired clinical outcome, such as hospitalisation for pulmonary exacerbation in infants with CF and children exposed to SHS. Furthermore, they demonstrated a dose-dependent decrease of PGD 2 with increasing concentrations of cigarette smoke extract (CSE) in in vitro experiments with CSE-exposed macrophages.…”