Superoxide Dismutase 3 R213G Single-Nucleotide Polymorphism Blocks Murine Bleomycin-Induced Fibrosis and Promotes Resolution of Inflammation.
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.
1 Developmental Lung Biology and Cardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado; and.
Gary C
GC
Mouradian
2 Department of Medicine, National Jewish Health, Denver, Colorado.
Rohit
R
Gaurav
1 Developmental Lung Biology and Cardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado; and.
Steve
S
Pugliese
1 Developmental Lung Biology and Cardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado; and.
Karim
K
El Kasmi
2 Department of Medicine, National Jewish Health, Denver, Colorado.
Brittany
B
Hartman
1 Developmental Lung Biology and Cardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado; and.
Laura
L
Hernandez-Lagunas
1 Developmental Lung Biology and Cardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado; and.
Kurt R
KR
Stenmark
2 Department of Medicine, National Jewish Health, Denver, Colorado.
Russell P
RP
Bowler
1 Developmental Lung Biology and Cardiovascular Pulmonary Research Laboratories, Departments of Pediatrics and Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado; and.
Eva
E
Nozik-Grayck
D056809:Alveolar Epithelial Cells / Q000378:metabolism; D000818:Animals; D001761:Bleomycin; D001992:Bronchoalveolar Lavage Fluid; D006976:Hypertension, Pulmonary / Q000097:blood / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D011014:Pneumonia / Q000097:blood / Q000150:complications* / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011658:Pulmonary Fibrosis / Q000097:blood / Q000150:complications* / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000097:blood / Q000235:genetics*; D066253:Vascular Remodeling
D001761:Bleomycin; C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase
bleomycin; fibrosis; inflammation; pulmonary hypertension; superoxide dismutase 3