title: Wild-type levels of the mouse Forkhead Box f1 gene are essential for lung repair.
abstract: 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.
authors: Department of Molecular Genetics, College of Medicine, University of Illinois at Chicago, 60607-7170, USA.
authors: Vladimir V
authors: VV
authors: Kalinichenko
authors: Yan
authors: Y
authors: Zhou
authors: Brian
authors: B
authors: Shin
authors: Donna Beer
authors: DB
authors: Stolz
authors: Simon C
authors: SC
authors: Watkins
authors: Jeffrey A
authors: JA
authors: Whitsett
authors: Robert H
authors: RH
authors: Costa
mesh_terms: 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
chemical_list: 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