Postpneumonectomy lung expansion elicits hypoxia-inducible factor-1alpha signaling.
We (42) previously reported differential regulation of hypoxia-inducible factors (HIF-1alpha, -2alpha, and -3alpha) mRNA in canine lungs during normal maturation and postpneumonectomy (PNX) compensatory growth in the absence of overt hypoxia. To test the hypothesis that lung expansion activates HIF signaling, we replaced the right lung of six adult foxhounds with inflated custom-shaped silicone prosthesis to keep the mediastinum in the midline and minimize lateral expansion of the remaining lung. After 3 wk of recovery and stabilization of perfusion, the prosthesis was acutely deflated in three animals, causing the remaining lung to expand by 114%. In three other animals, the prosthesis remained inflated. Three days following deflation, we observed significant elevation in the mRNA and nuclear protein levels of HIF-1alpha ( approximately 60%) as well as activation of its transcriptional regulator, the serine/threonine protein kinase B (phospho-Akt-to-total Akt ratio, 124%), and the mRNA and protein levels of its downstream targets, erythropoietin receptor (71-183%) as well as VEGF (33-58%) compared with the pre-PNX control lung from the same animal. The mRNA of HIF-2alpha, HIF-3alpha, and VEGF receptors did not change with acute deflation. We conclude that in vivo lung expansion by post-PNX deflation of space-occupying prosthesis elicits coordinated activation of HIF-1alpha signaling in adult lungs. This pathway could play an important role in mediating lung growth and remodeling during maturation and post-PNX compensation.
Zhang
Quiyang
Q
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9034, USA.
Bellotto
Dennis J
DJ
Ravikumar
Priya
P
Moe
Orson W
OW
Hogg
Richard T
RT
Hogg
Deborah C
DC
Estrera
Aaron S
AS
Johnson
Robert L
RL
Hsia
Connie C W
CC
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D004285:Dogs; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000502:physiology* / Q000601:surgery*; D008176:Lung Volume Measurements; D008297:Male; D011013:Pneumonectomy; D019736:Prostheses and Implants; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D012825:Silicon; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D017467:Receptors, Erythropoietin; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; D012825:Silicon