Human Mn-superoxide dismutase in pulmonary epithelial cells of transgenic mice confers protection from oxygen injury.
To test directly whether mitochondrial Mn-superoxide dismutase (Mn-SOD) protects the lung epithelium from oxygen-induced injury, transgenic mice were produced in which the expression of human Mn-SOD mRNA was directly by transcriptional elements from the human pulmonary surfactant protein C gene. Human Mn-SOD mRNA was expressed in a lung-specific manner, and increased Mn-SOD protein was detected within mitochondria of alveolar Type II and nonciliated bronchiolar cells of the distal respiratory epithelium of the transgenic mice. The activity of Mn-SOD, but not catalase, CuZn-SOD, or glutathione peroxidase, was increased in lungs of transgenic mice. Transgenic mice were highly protected from lung injury during exposure to 95% oxygen, surviving significantly longer than nontransgenic littermates. Pulmonary pathology demonstrated decreased hemorrhage, hyaline membrane formation, and alveolar and interstitial edema in transgenic animals. The finding that increased Mn-SOD in distal respiratory epithelial cells confers protection from oxygen injury provides a basis for novel therapies to protect lung from injury during oxygen therapy of acute and chronic lung diseases.
Wispé
J R
JR
Children's Hospital Medical Center, Division of Pulmonary Biology, Cincinnati, Ohio 45229.
Warner
B B
BB
Clark
J C
JC
Dey
C R
CR
Neuman
J
J
Glasser
S W
SW
Crapo
J D
JD
Chang
L Y
LY
Whitsett
J A
JA
D000818:Animals; D015152:Blotting, Northern; D002374:Catalase / Q000378:metabolism; D004848:Epithelium / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D005260:Female; D015316:Genetic Therapy; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D008171:Lung Diseases / Q000628:therapy; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010100:Oxygen / Q000633:toxicity*; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D015183:Restriction Mapping; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism*
D007527:Isoenzymes; D012313:RNA; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D010100:Oxygen