Overexpression of Stat3C in pulmonary epithelium protects against hyperoxic lung injury.
Acute lung injury is a side effect of therapy with a high concentration of inspired oxygen in patients. The molecular mechanism underlining this effect is poorly understood. In this study, we report that overexpression of Stat3C, a constitutive active form of STAT3, in respiratory epithelial cells of a doxycycline-controlled double-transgenic mouse system protects lung from inflammation and injury caused by hyperoxia. In this mouse line, >50% of transgenic mice survived exposure to 95% oxygen at day 7, compared with 0% survival of wild-type mice. Overexpression of STAT3C delays acute capillary leakage and neutrophil infiltration into the alveolar region. This protection is mediated at least partially through inhibition of hyperoxia-induced synthesis and release of matrix metalloproteinase (MMP)-9 and MMP-12 by neutrophils and alveolar resident cells. In some MMP-9(-/-) mice, prolonged survival was observed under hyperoxic condition. The finding supports a concept that activation of the Stat3 pathway plays a role to prevent hyperoxia-induced inflammation and injury in the lung.
Lian
Xuemei
X
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, OH 45229, USA.
Qin
Yulin
Y
Hossain
Shaikh Abu
SA
Yang
Li
L
White
Amanda
A
Xu
Huan
H
Shipley
J Michael
JM
Li
Tingyu
T
Senior
Robert M
RM
Du
Hong
H
Yan
Cong
C
D000209:Acute-Phase Proteins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D003587:Cytomegalovirus / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D015536:Down-Regulation; D006470:Hemorrhage / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D018496:Hyperoxia / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D008168:Lung / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D053508:Matrix Metalloproteinase 12; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020556:Neutrophil Infiltration / Q000235:genetics; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D037701:Pulmonary Surfactant-Associated Protein B / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D020545:Respiratory Mucosa / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000235:genetics*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D014598:Uteroglobin / Q000235:genetics
D000209:Acute-Phase Proteins; D004268:DNA-Binding Proteins; D061965:Matrix Metalloproteinase Inhibitors; D037701:Pulmonary Surfactant-Associated Protein B; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C556390:Scgb1a1 protein, mouse; C494087:Stat3 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D015534:Trans-Activators; D014598:Uteroglobin; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D053508:Matrix Metalloproteinase 12