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Superoxide Dismutase 3 R213G Single-Nucleotide Polymorphism Blocks Murine Bleomycin-Induced Fibrosis and Promotes Resolution of Inflammation.

ABSTRACT: Loss of extracellular superoxide dismutase 3 (SOD3) contributes to inflammatory and fibrotic lung diseases. The human SOD3 R213G polymorphism decreases matrix binding, redistributing SOD3 from the lung to extracellular fluids, and protects against LPS-induced alveolar inflammation. We used R213G mice expressing a naturally occurring single-nucleotide polymorphism, rs1799895, within the heparin-binding domain of SOD3, which results in an amino acid substitution at position 213 to test the hypothesis that the redistribution of SOD3 into the extracellular fluids would impart protection against bleomycin-induced lung fibrosis and secondary pulmonary hypertension (PH). In R213G mice, SOD3 content and activity was increased in extracellular fluids and decreased in lung at baseline, with greater increases in bronchoalveolar lavage fluid (BALF) SOD3 compared with wild-type mice 3 days after bleomycin. R213G mice developed less fibrosis based on pulmonary mechanics, fibrosis scoring, collagen quantification, and gene expression at 21 days, and less PH by right ventricular systolic pressure and pulmonary arteriole medial wall thickening at 28 days. In wild-type mice, macrophages, lymphocytes, neutrophils, proinflammatory cytokines, and protein increased in BALF on Day 7 and/or 21. In R213G mice, total BALF cell counts increased on Day 7 but resolved by 21 days. At 1 or 3 days, BALF pro- and antiinflammatory cytokines and BALF protein were higher in R213G mice, resolving by 21 days. We conclude that the redistribution of SOD3 as a result of the R213G single-nucleotide polymorphism protects mice from bleomycin-induced fibrosis and secondary PH by improved resolution of alveolar inflammation.

SUBMITTER: Mouradian GC

PROVIDER: S-EPMC5359538 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Publications

Superoxide Dismutase 3 R213G Single-Nucleotide Polymorphism Blocks Murine Bleomycin-Induced Fibrosis and Promotes Resolution of Inflammation.

Mouradian Gary C GC Gaurav Rohit R Pugliese Steve S El Kasmi Karim K Hartman Brittany B Hernandez-Lagunas Laura L Stenmark Kurt R KR Bowler Russell P RP Nozik-Grayck Eva E

American journal of respiratory cell and molecular biology 20170301 3

Loss of extracellular superoxide dismutase 3 (SOD3) contributes to inflammatory and fibrotic lung diseases. The human SOD3 R213G polymorphism decreases matrix binding, redistributing SOD3 from the lung to extracellular fluids, and protects against LPS-induced alveolar inflammation. We used R213G mice expressing a naturally occurring single-nucleotide polymorphism, rs1799895, within the heparin-binding domain of SOD3, which results in an amino acid substitution at position 213 to test the hypothe ...[more]

PMID: 27805412

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Project description:Extracellular superoxide dismutase (ecSOD) protects the extracellular matrix from oxidative stress. We previously reported a new allele for ecSOD, expressed in 129P3/J mice (129), which differs from the wild type (wt), expressed in C57BL/6J and other strains, by two amino acid substitutions and a 10-bp deletion in the 3' UTR of the mRNA (A. Pierce et al., 2003, Arterioscler. Thromb. Vasc. Biol.23:1820-1825). The newly discovered allele is associated with a phenotype of significantly increased circulating and heparin-releasable enzyme activities and levels. To examine the properties of the two forms of ecSOD in an identical environment we generated, by extensive backcrossing of ecSOD heterozygous progeny to C57BL/6J females, a congenic C57 strain with the 129 (or wt) allele of ecSOD. These mice are homozygous for nearly 5000 SNPs across all chromosomes, as determined by the Affymetrix Parallele Mouse 5K SNP panel. This study describes the generation of the congenic mice (genetically >99.8% identical) and their ecSOD phenotype. The congenic mouse plasma ecSOD activity before and after heparin administration recapitulates the differences reported in the founder mice. Tissue enzyme distribution is similar in both congenic groups, although the 129 allele is associated with higher levels of enzyme expression despite lower levels of enzyme mRNA. In these characteristics the phenotype is allele driven, with little impact from the rest of the genome. The congenic mice carrying the 129 allele have mRNA levels that are in between those in the founder 129P3/J and C57BL/6J strains. We conclude that the ecSOD phenotype in most aspects of enzyme expression is allele driven, with the exception of tissue mRNA levels, for which a significant contribution by the surrounding (host) genome is observed. These results also suggest potential allele-specific differences in the regulation of ecSOD synthesis and intracellular processing/secretion of ecSOD, independent of the genotype context. Most importantly, the congenic mice offer an excellent model to examine the regulatory mechanisms of ecSOD expression and the role of ecSOD in various diseases involving oxidative stress.

Dataset Information

Superoxide Dismutase 3 R213G Single-Nucleotide Polymorphism Blocks Murine Bleomycin-Induced Fibrosis and Promotes Resolution of Inflammation.

Publications

Superoxide Dismutase 3 R213G Single-Nucleotide Polymorphism Blocks Murine Bleomycin-Induced Fibrosis and Promotes Resolution of Inflammation.

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