STAT-3 regulates surfactant phospholipid homeostasis in normal lung and during endotoxin-mediated lung injury.
Acute lung injury associated with surfactant deficiency remains a major cause of pulmonary morbidity and mortality. Since signal transducer and activator of transcription-3 (STAT-3) plays an important role in protecting respiratory epithelial cells during injury, we hypothesized that STAT-3 may regulate gene expression in type II cells that mediate surfactant phospholipid synthesis. Conditional deletion of Stat-3 in respiratory epithelial cells in the lung of transgenic mice (Stat-3(Delta/Delta) mice) decreased surfactant phospholipid synthesis and secretion. Deletion of Stat-3 was associated with decreased expression of Akt2, Srebf-1, and other genes expressed in type II cells that may influence surfactant phospholipid synthesis (Glut-1, Slc34a2, Gpam, Acox2, and Cds2). Stat-3(Delta/Delta) mice were more susceptible to intratracheal lipopolysaccharide (LPS). Saturated phosphatidylcholine and surfactant protein B levels were significantly decreased in bronchoalveolar lavage fluid from LPS-treated Stat-3(Delta/Delta) mice. Alveolar capillary leak, proinflammatory cytokine expression, and perturbations of lung mechanics caused by LPS were exacerbated after deletion of STAT-3. STAT-3 plays a critical role in the regulation of surfactant lipid synthesis in the normal lung and during lung injury caused by LPS.
Ikegami
Machiko
M
Cincinnati Children's Hospital, Div. of Pulmonary Biology, Cincinnati, OH 45229-3039, USA. machiko.Ikegami@cchmc.org
Falcone
Angelica
A
Whitsett
Jeffrey A
JA
D000403:Airway Resistance; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D050356:Lipid Metabolism / Q000235:genetics; D008070:Lipopolysaccharides; D008168:Lung / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008170:Lung Compliance; D008171:Lung Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D010713:Phosphatidylcholines / Q000378:metabolism; D010743:Phospholipids / Q000096:biosynthesis / Q000378:metabolism*; D037701:Pulmonary Surfactant-Associated Protein B / Q000378:metabolism; D011663:Pulmonary Surfactants / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D016207:Cytokines; D008070:Lipopolysaccharides; D010713:Phosphatidylcholines; D010743:Phospholipids; D037701:Pulmonary Surfactant-Associated Protein B; D011663:Pulmonary Surfactants; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse