Benjamin L Wisniewski1, Chandra L Shrestha2, Shuzhong Zhang2, Rohan Thompson3, Myron Gross4, Judith A Groner5, Karan Uppal6, Octavio Ramilo7, Asuncion Mejias7, Benjamin T Kopp8. 1. Division of Pulmonary Medicine, Nationwide Children's Hospital, Columbus, OH, USA; Center for Microbial Pathogenesis, The Abigail Wexner Research Institute at Nationwide Children's Hospital, W510, 700 Children's Drive, Columbus, OH 43205, USA. 2. Center for Microbial Pathogenesis, The Abigail Wexner Research Institute at Nationwide Children's Hospital, W510, 700 Children's Drive, Columbus, OH 43205, USA. 3. Division of Pulmonary Medicine, Nationwide Children's Hospital, Columbus, OH, USA. 4. Minnesota CHEAR Exposure Assessment Hub, University of Minnesota Twin Cities, Minneapolis, MN, USA. 5. Section of Ambulatory Pediatrics, Nationwide Children's Hospital, Columbus, OH, USA. 6. National Exposure Assessment Laboratory at Emory, Emory University, Atlanta, GA, USA. 7. Division of Infectious Diseases, Nationwide Children's Hospital, Columbus, OH, USA; Center for Vaccines and Immunity, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA. 8. Division of Pulmonary Medicine, Nationwide Children's Hospital, Columbus, OH, USA; Center for Microbial Pathogenesis, The Abigail Wexner Research Institute at Nationwide Children's Hospital, W510, 700 Children's Drive, Columbus, OH 43205, USA. Electronic address: Benjamin.Kopp@NationwideChildrens.org.
Abstract
BACKGROUND: Inflammation is integral to early disease progression in children with CF. The effect of modifiable environmental factors on infection and inflammation in persons with CF is poorly understood. Our prior studies determined that secondhand smoke exposure (SHSe) is highly prevalent in young children with CF. SHSe is associated with increased inflammation, heightened bacterial burden, and worsened clinical outcomes. However, the specific metabolite and signaling pathways that regulate responses to SHSe in CF are relatively unknown. METHODS: High-resolution metabolomics was performed on plasma samples from infants (n = 25) and children (n = 40) with CF compared to non-CF controls (n = 15). CF groups were stratified according to infant or child age and SHSe status. RESULTS: Global metabolomic profiles segregated by age and SHSe status. SHSe in CF was associated with changes in pathways related to steroid biosynthesis, fatty acid metabolism, cysteine metabolism, and oxidative stress. CF infants with SHSe demonstrated enrichment for altered metabolite localization to the small intestine, liver, and striatum. CF children with SHSe demonstrated metabolite enrichment for organs/tissues associated with oxidative stress including mitochondria, peroxisomes, and the endoplasmic reticulum. In a confirmatory analysis, SHSe was associated with changes in biomarkers of oxidative stress and cellular adhesion including MMP-9, MPO, and ICAM-1. CONCLUSIONS: SHSe in young children and infants with CF is associated with altered global metabolomics profiles and specific biochemical pathways, including enhanced oxidative stress. SHSe remains an important but understudied modifiable variable in early CF disease.
BACKGROUND: Inflammation is integral to early disease progression in children with CF. The effect of modifiable environmental factors on infection and inflammation in persons with CF is poorly understood. Our prior studies determined that secondhand smoke exposure (SHSe) is highly prevalent in young children with CF. SHSe is associated with increased inflammation, heightened bacterial burden, and worsened clinical outcomes. However, the specific metabolite and signaling pathways that regulate responses to SHSe in CF are relatively unknown. METHODS: High-resolution metabolomics was performed on plasma samples from infants (n = 25) and children (n = 40) with CF compared to non-CF controls (n = 15). CF groups were stratified according to infant or child age and SHSe status. RESULTS: Global metabolomic profiles segregated by age and SHSe status. SHSe in CF was associated with changes in pathways related to steroid biosynthesis, fatty acid metabolism, cysteine metabolism, and oxidative stress. CF infants with SHSe demonstrated enrichment for altered metabolite localization to the small intestine, liver, and striatum. CF children with SHSe demonstrated metabolite enrichment for organs/tissues associated with oxidative stress including mitochondria, peroxisomes, and the endoplasmic reticulum. In a confirmatory analysis, SHSe was associated with changes in biomarkers of oxidative stress and cellular adhesion including MMP-9, MPO, and ICAM-1. CONCLUSIONS: SHSe in young children and infants with CF is associated with altered global metabolomics profiles and specific biochemical pathways, including enhanced oxidative stress. SHSe remains an important but understudied modifiable variable in early CF disease.
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