Association of SNP–SNP Interactions of Surfactant Protein Genes with Pediatric Acute Respiratory Failure

The hallmarks of pediatric acute respiratory failure (ARF) are dysregulated inflammation and surfactant dysfunction. The objective is to study association of surfactant protein (SP) genes’ single nucleotide polymorphisms (SNPs) with ARF and its morbidity: pulmonary dysfunction at discharge (PDAD), employing a single-, two-, and three-SNP interaction model. We enrolled 468 newborn controls and 248 children aged ≤ 24 months with ARF; 86 developed PDAD. Using quantitative genetic principles, we tested the association of SP genes SNPs with ARF and PDAD. We observed a dominant effect of rs4715 of the SFTPC on ARF risk. In a three-SNP model, we found (a) 34 significant interactions among SNPs of SFTPA1, SFTPA2, and SFTPC associated with ARF (p = 0.000000002–0.05); 15 and 19 of those interactions were associated with increased and decreased risk for ARF, respectively; (b) intergenic SNP–SNP interactions of both hydrophobic and hydrophilic SP genes associated with PDAD (p = 0.00002–0.03). The majority of intra- and intergenic interactions associated with ARF involve the SFTPA2 SNPs, whereas most of the intra- and intergenic interactions associated with PDAD are of SFTPA1 SNPs. We also observed a dominant effect of haplotypes GG of SFTPA1 associated with increased and AA of SFTPC associated with decreased ARF risk (p = 0.02). To the best of our knowledge, this is the first study showing an association of complex interactions of SP genes with ARF and PDAD. Our data indicate that SP genes polymorphisms may contribute to ARF pathogenesis and subsequent PDAD and/or may serve as markers for disease susceptibility in healthy children.

The effects of low-moderate dose prenatal ethanol exposure on the fetal and postnatal rat lung

Little is known about whether exposure of the fetus to alcohol alters pulmonary development or function. This study aimed to determine whether low-moderate ethanol (EtOH) exposure throughout gestation alters structural and non-respiratory functional aspects of the fetal and postnatal lung. Sprague–Dawley rats were fed an ad libitum liquid diet ±6% v/v EtOH daily throughout pregnancy, achieving a plasma ethanol (EtOH) concentration of 0.03%. Gene and protein expression was determined in pulmonary tissue collected from fetuses at embryonic day (E) 20 and adult offspring. The percentage of airspace and alveolar size was measured in pulmonary tissue collected at postnatal day (PN) 1. At E20, EtOH-exposed fetuses had decreased aquaporin 5 mRNA levels and a non-significant trend for decreased epithelial sodium channel type α; expression of other pulmonary fluid homeostatic and development genes and surfactant protein genes were not different between groups. At PN1, there was no difference between EtOH-exposed and control offspring in the distal airspace percentage or diameter. At 8 months, collagen type III α1 gene expression was upregulated in EtOH-exposed male offspring; this was associated with increased collagen deposition at 10 months. At 19 months, male EtOH-exposed offspring had a 25% reduction in the protein levels of surfactant protein B. The alterations observed in male EtOH-exposed offspring suggest chronic low-moderate prenatal EtOH-exposure during development may result in increased pulmonary fibrosis. Such an alteration would decrease the respiratory capacity of the lung.