Wild-type levels of the mouse Forkhead Box f1 gene are essential for lung repair.
The Forkhead Box (Fox) family of transcription factors plays important roles in regulating expression of genes involved in cellular proliferation and differentiation. In a previous study, we showed that newborn foxf1(+/-) mice with diminished Foxf1 levels exhibited abnormal formation of pulmonary alveoli and capillaries and died postnatally. Interestingly, surviving newborn foxf1(+/-) mice exhibited increased pulmonary Foxf1 levels and normal adult lung morphology, suggesting that wild-type Foxf1 levels are required for lung development and function. The present study was conducted to determine whether adult foxf1(+/-) mice were able to undergo lung repair similar to that observed in wild-type mice. We demonstrated that adult foxf1(+/-) mice died from severe lung hemorrhage after butylated hydroxytoluene (BHT) lung injury and that this phenotype was associated with a 10-fold decrease in pulmonary Foxf1 expression and increased alveolar endothelial cell apoptosis that disrupted capillary integrity. Furthermore, BHT-induced lung hemorrhage of adult foxf1(+/-) mice was associated with a drastic reduction in expression of the Flk-1, bone morphogenetic protein-4, surfactant protein B, platelet endothelial cell adhesion molecule, and vascular endothelial cadherin genes, whereas the expression of these genes was either transiently diminished or increased in wild-type lungs after BHT injury. Because these proteins are critical for lung morphogenesis and endothelial homeostasis, their decreased mRNA levels are likely contributing to BHT-induced lung hemorrhage in foxf1(+/-) mice. Collectively, our data suggest that sustained expression of Foxf1 is essential for normal lung repair and endothelial cell survival in response to pulmonary cell injury.
Kalinichenko
Vladimir V
VV
Department of Molecular Genetics, College of Medicine, University of Illinois at Chicago, 60607-7170, USA.
Zhou
Yan
Y
Shin
Brian
B
Stolz
Donna Beer
DB
Watkins
Simon C
SC
Whitsett
Jeffrey A
JA
Costa
Robert H
RH
D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD; D018952:Antigens, CD34 / Q000096:biosynthesis; D017209:Apoptosis; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002084:Butylated Hydroxytoluene; D015820:Cadherins / Q000378:metabolism; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D018450:Disease Progression; D051858:Forkhead Transcription Factors; D006470:Hemorrhage / Q000139:chemically induced / Q000209:etiology / Q000473:pathology; D006579:Heterozygote; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010641:Phenotype; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D011510:Proteolipids / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011663:Pulmonary Surfactants / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000099152:Cadherin 5
D015703:Antigens, CD; D018952:Antigens, CD34; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D002084:Butylated Hydroxytoluene; D015820:Cadherins; D051858:Forkhead Transcription Factors; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011510:Proteolipids; D011663:Pulmonary Surfactants; D012333:RNA, Messenger; D020794:Receptor Protein-Tyrosine Kinases; D017978:Receptors, Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor; D014157:Transcription Factors; D000099152:Cadherin 5; C525810:Bmp4 protein, mouse; C486293:Foxf1 protein, mouse