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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

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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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Figure 1

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Conditional deletion of Stat-3 in respiratory epithelium. (a) The human ...
Conditional deletion of Stat-3 in respiratory epithelium. (a) The human SP-C (hSP-C) promoter was used to express the reverse tetracycline transactivator (rtTA). In the presence of doxycycline (Dox), rtTA binds to the (tetO)7 promoter, activating transcription of Cre-recombinase. The loxP sites were inserted in introns 20 and 21 of the Stat-3 gene (Stat-3flx), deleting exon 21 after recombination, to produce the Stat-3Δ locus. (b) STAT-3 RNA was assessed in purified alveolar type II cells. RNA was extracted from primary cultures of alveolar type II cells isolated from Stat-3Δ/Δ and control mice. RNA from control (n = 2) or Stat-3Δ/Δ (n = 2 or 4) were pooled and analyzed by real-time RT-PCR. Data were standardized to β-actin RNA and normalized to control. In the Stat-3Δ/Δ cells, STAT-3 mRNA was less than 10% of control values.

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