Chronic intermittent hypoxia induces lung growth in adult mice.
Obstructive sleep apnea (OSA) increases cardiovascular morbidity and mortality, which have been attributed to intermittent hypoxia (IH). The effects of IH on lung structure and function are unknown. We used a mouse model of chronic IH, which mimics the O(2) profile in patients with OSA. We exposed adult C57BL/6J mice to 3 mo of IH with a fraction of inspired oxygen (F(I)(O(2))) nadir of 5% 60 times/h during the 12-h light phase. Control mice were exposed to room air. Lung volumes were measured by quasistatic pressure-volume (PV) curves under anesthesia and by water displacement postmortem. Lungs were processed for morphometry, and the mean airspace chord length (Lm) and alveolar surface area were determined. Lung tissue was stained for markers of proliferation (proliferating cell nuclear antigen), apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling), and type II alveolar epithelial cells (surfactant protein C). Gene microarrays were performed, and results were validated by real-time PCR. IH increased lung volumes by both PV curves (air vs. IH, 1.16 vs. 1.44 ml, P < 0.0001) and water displacement (P < 0.01) without changes in Lm, suggesting that IH increased the alveolar surface area. IH induced a 60% increase in cellular proliferation, but the number of proliferating type II alveolocytes tripled. There was no increase in apoptosis. IH upregulated pathways of cellular movement and cellular growth and development, including key developmental genes vascular endothelial growth factor A and platelet-derived growth factor B. We conclude that IH increases alveolar surface area by stimulating lung growth in adult mice.
Department of Medicine, Div. of Pulmonary Medicine, Johns Hopkins University, Baltimore, MD, USA. creinke1@jhmi.edu
Christian
C
Reinke
Shannon
S
Bevans-Fonti
Dmitry N
DN
Grigoryev
Luciano F
LF
Drager
Allen C
AC
Myers
Robert A
RA
Wise
Alan R
AR
Schwartz
Wayne
W
Mitzner
Vsevolod Y
VY
Polotsky
D000818:Animals; D001483:Base Sequence; D002908:Chronic Disease; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D000860:Hypoxia / Q000209:etiology / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D008168:Lung / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics; D020181:Sleep Apnea, Obstructive / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D016212:Transforming Growth Factor beta / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D017931:DNA Primers; D010982:Platelet-Derived Growth Factor; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D040262:Receptors, Vascular Endothelial Growth Factor