Stat-3 is required for pulmonary homeostasis during hyperoxia
Isamu Hokuto, … , Susan E. Wert, Jeffrey A. Whitsett
Isamu Hokuto, … , Susan E. Wert, Jeffrey A. Whitsett
Published January 1, 2004
Citation Information: J Clin Invest. 2004;113(1):28-37. https://doi.org/10.1172/JCI19491.
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Article Pulmonology

Stat-3 is required for pulmonary homeostasis during hyperoxia

Abstract

Acute lung injury syndromes remain common causes of morbidity and mortality in adults and children. Cellular and physiologic mechanisms maintaining pulmonary homeostasis during lung injury remain poorly understood. In the present study, the Stat-3 gene was selectively deleted in respiratory epithelial cells by conditional expression of Cre-recombinase under control of the surfactant protein C gene promoter. Cell-selective deletion of Stat-3 in respiratory epithelial cells did not alter prenatal lung morphogenesis or postnatal lung function. However, exposure of adult Stat-3–deleted mice to 95% oxygen caused a more rapidly progressive lung injury associated with alveolar capillary leak and acute respiratory distress. Epithelial cell injury and inflammatory responses were increased in the Stat-3–deleted mice. Surfactant proteins and lipids were decreased or absent in alveolar lavage material. Intratracheal treatment with exogenous surfactant protein B improved survival and lung histology in Stat-3–deleted mice during hyperoxia. Expression of Stat-3 in respiratory epithelial cells is not required for lung formation, but plays a critical role in maintenance of surfactant homeostasis and lung function during oxygen injury.

Authors

Isamu Hokuto, Machiko Ikegami, Mitsuhiro Yoshida, Kiyoshi Takeda, Shizuo Akira, Anne-Karina T. Perl, William M. Hull, Susan E. Wert, Jeffrey A. Whitsett

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Exogenous SP-B protects Stat-3Δ/Δ mice during hyperoxia. (a) Lung morpho...
Exogenous SP-B protects Stat-3Δ/Δ mice during hyperoxia. (a) Lung morphology of the Stat-3Δ/Δ mice treated with SP-B/DPPC/POPG (a and b) or DPPC/POPG (c and d) during hyperoxia exposure is shown. Lungs were excised 65 hours after exposure to 95% oxygen and stained with H&E. The lungs of SP-B/DPPC/DOPG–treated mice had less inflammatory cell infiltration, and epithelial cell necrosis was not observed (a and b). Alveolar thickening, inflammation, and epithelial cell necrosis was widespread in mice treated with DPPC/DOPG alone (c and d). Photomicrographs are representative of n = 5 from each group. Bars = 100 μm. (e) SP-B enhances survival of Stat-3Δ/Δ mice during hyperoxia. Stat-3Δ/Δ mice were placed in 95% oxygen and treated (intratracheally) with SP-B/DPPC/DOPG or DPPC/DOPG as described in Methods. Survival on day 4 was significantly increased in SP-B/DPPC/DOPG–treated mice; *P < 0.05. On day 5, more SP-B/DPPC/DOPG–treated mice survived, but differences were not statistically significant; n = 8 per group.