Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acute-Phase Proteins / biosynthesis
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Acute-Phase Proteins / genetics
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Animals
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Cytomegalovirus / genetics
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DNA-Binding Proteins / biosynthesis*
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / physiology
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Down-Regulation
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Hemorrhage / genetics
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Hemorrhage / metabolism
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Hemorrhage / prevention & control
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Hyperoxia / genetics
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Hyperoxia / metabolism*
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Hyperoxia / mortality
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Hyperoxia / pathology*
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Lung / enzymology
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Lung / metabolism
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Lung / pathology*
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Matrix Metalloproteinase 12
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Matrix Metalloproteinase 9
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Matrix Metalloproteinase Inhibitors
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Matrix Metalloproteinases / genetics
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Matrix Metalloproteinases / metabolism
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Metalloendopeptidases / antagonists & inhibitors
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Metalloendopeptidases / genetics
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Metalloendopeptidases / metabolism
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Mice
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Mice, Transgenic
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Neutrophil Infiltration / genetics
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Pulmonary Alveoli / enzymology
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Pulmonary Alveoli / metabolism
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Pulmonary Alveoli / pathology
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Pulmonary Surfactant-Associated Protein B / biosynthesis
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Pulmonary Surfactant-Associated Protein B / genetics
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RNA, Messenger / antagonists & inhibitors
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RNA, Messenger / biosynthesis
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RNA, Messenger / metabolism
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Respiratory Mucosa / enzymology
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Respiratory Mucosa / metabolism*
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Respiratory Mucosa / pathology*
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STAT3 Transcription Factor
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Signal Transduction / genetics*
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Tissue Inhibitor of Metalloproteinase-1 / antagonists & inhibitors
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Tissue Inhibitor of Metalloproteinase-1 / biosynthesis
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Tissue Inhibitor of Metalloproteinase-1 / genetics
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Trans-Activators / biosynthesis*
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Trans-Activators / genetics*
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Trans-Activators / physiology
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Uteroglobin / genetics
Substances
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Acute-Phase Proteins
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DNA-Binding Proteins
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Matrix Metalloproteinase Inhibitors
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Pulmonary Surfactant-Associated Protein B
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RNA, Messenger
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STAT3 Transcription Factor
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Scgb1a1 protein, mouse
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Stat3 protein, mouse
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Tissue Inhibitor of Metalloproteinase-1
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Trans-Activators
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Uteroglobin
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Matrix Metalloproteinases
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Metalloendopeptidases
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Matrix Metalloproteinase 9
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Mmp9 protein, mouse
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Matrix Metalloproteinase 12