Pulmonary mastocytosis and enhanced lung inflammation in mice heterozygous null for the Foxf1 gene.
The Forkhead Box f1 (Foxf1) transcriptional factor (previously known as HFH-8 or Freac-1) is expressed in endothelial and smooth muscle cells in the embryonic and adult lung. To assess effects of Foxf1 during lung injury, we used CCl(4) and butylated hydroxytoluene (BHT) injury models. Foxf1(+/-) mice developed severe airway obstruction and bronchial edema, associated with increased numbers of pulmonary mast cells and increased mast cell degranulation after injury. Pulmonary inflammation in Foxf1(+/-) mice was associated with diminished expression of Foxf1, increased mast cell tryptase, and increased expression of CXCL12, the latter being essential for mast cell migration and chemotaxis. After ovalbumin (OVA) sensitization and OVA challenge, increased lung inflammation, airway hyperresponsiveness to methacholine, and elevated expression of CXCL12 were observed in Foxf1(+/-) mice. During lung development, Foxf1(+/-) embryos displayed a marked increase in pulmonary mast cells before birth, and this was associated with increased CXCL12 levels in the lung. Expression of a doxycycline-inducible Foxf1 dominant-negative transgene in primary cultures of lung endothelial cells increased CXCL12 expression in vitro. Foxf1 haploinsufficiency caused pulmonary mastocytosis and enhanced pulmonary inflammation after chemically induced or allergen-mediated lung injury, indicating an important role for Foxf1 in the pathogenesis of pulmonary inflammatory responses.
Kalin
Tanya V
TV
Division of Pulmonary Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
Meliton
Lucille
L
Meliton
Angelo Y
AY
Zhu
Xiangdong
X
Whitsett
Jeffrey A
JA
Kalinichenko
Vladimir V
VV
D000402:Airway Obstruction / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism; D000818:Animals; D002084:Butylated Hydroxytoluene; D002251:Carbon Tetrachloride; D015550:Cell Degranulation; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000096:biosynthesis; D002633:Chemotaxis; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000196:embryology / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000502:physiology*; D008168:Lung / Q000196:embryology / Q000276:immunology / Q000473:pathology; D008407:Mast Cells / Q000276:immunology* / Q000502:physiology; D008415:Mastocytosis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010047:Ovalbumin; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D053802:Tryptases / Q000096:biosynthesis
D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D051858:Forkhead Transcription Factors; C486293:Foxf1 protein, mouse; D002084:Butylated Hydroxytoluene; D010047:Ovalbumin; D002251:Carbon Tetrachloride; D053802:Tryptases