Overexpression of Stat3C in pulmonary epithelium protects against hyperoxic lung injury
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.
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Overexpressing STAT3C in respiratory epithelial cells improves animal survival following hyperoxia and protects the lung from inflammation and injury through reducing mRNA levels of MMP9 and MMP12, and levels of adhesion molecules.
“overexpressing of STAT3C (a constitutively active form of STAT3) in respiratory epithelial cells (Lian et al., 2005) improved animal survival following hyperoxia and protected the lung from inflammation and injury through reducing mRNA levels of matrix metalloproteases, e.g., matrix metalloproteinases (MMP)9 and MMP12, and levels of adhesion molecules”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Lian et al., 2005
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Bharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
Bench-to-bedside review: the effects of hyperoxia during critical illness
Helmerhorst, H. J. F., Schultz, M. J., van der Voort, P. H. J., de Jonge, E., & van Westerloo, D. J. (2015) · Critical Care · doi:10.1186/s13054-015-0996-4 · Cited by 187 · see citing works
- Authors
- Lian, X., Qin, Y., Hossain, S. A., Yang, L., White, A., Xu, H., Shipley, J. M., Li, T., Senior, R. M., Du, H., & Yan, C.
- Affiliations
- University of Cincinnati (US)
- Washington University in St. Louis (US)
- Division of Pulmonary Biology, University of Cincinnati College of Medicine , Cincinnati, OH 45229
- Cincinnati Children's Hospital Medical Center (US)
- Chongqing Medical University (CN)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-06-01
- Volume
- 174
- Issue
- 11
- Pages
- 7250-7256
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2105912583
- Cited by
- 75
- References
- 0
- Citations by year
- 2025: 2 · 2023: 3 · 2022: 1 · 2020: 1 · 2019: 2 · 2018: 1 · 2017: 2 · 2016: 1 · 2015: 1 · 2014: 3 · 2013: 4 · 2012: 8
- FWCI
- 5.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL061803, R01HL047328, P01HL029594, HL 29594, HL 47328, HL-067862, R01HL067862, HL-061803)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Respiratory Support and Mechanisms
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Neonatal Respiratory Health Research
- Keywords
- hyperoxic lung injury, acute lung injury, lung epithelium, MMP-9, matrix metalloproteinase-12, neutrophil infiltration, capillary leak syndrome, lung inflammation, oxygen toxicity, transgenic mouse model
- MeSH terms
- Acute-Phase Proteins, Animals, Cytomegalovirus, DNA-Binding Proteins, Hemorrhage, Lung, Metalloendopeptidases, Mice, Transgenic, Pulmonary Alveoli, RNA, Messenger, Uteroglobin, Signal Transduction, Trans-Activators, Down-Regulation, Hyperoxia, Tissue Inhibitor of Metalloproteinase-1, Respiratory Mucosa, Neutrophil Infiltration, Matrix Metalloproteinase 9, Matrix Metalloproteinases, Pulmonary Surfactant-Associated Protein B, STAT3 Transcription Factor, Mice, Matrix Metalloproteinase 12, Matrix Metalloproteinase Inhibitors
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