Mechanical ventilation uncouples synthesis and assembly of elastin and increases apoptosis in lungs of newborn mice. Prelude to defective alveolar septation during lung development?
Prolonged mechanical ventilation (MV) with O2-rich gas inhibits lung growth and causes excess, disordered accumulation of lung elastin in preterm infants, often resulting in chronic lung disease (CLD). Using newborn mice, in which alveolarization occurs postnatally, we designed studies to determine how MV with either 40% O2 or air might lead to dysregulated elastin production and impaired lung septation. MV of newborn mice for 8 h with either 40% O2 or air increased lung mRNA for tropoelastin and lysyl oxidase, relative to unventilated controls, without increasing lung expression of genes that regulate elastic fiber assembly (lysyl oxidase-like-1, fibrillin-1, fibrillin-2, fibulin-5, emilin-1). Serine elastase activity in lung increased fourfold after MV with 40% O2, but not with air. We then extended MV with 40% O2 to 24 h and found that lung content of tropoelastin protein doubled, whereas lung content of elastin assembly proteins did not change (lysyl oxidases, fibrillins) or decreased (fibulin-5, emilin-1). Quantitative image analysis of lung sections showed that elastic fiber density increased by 50% after MV for 24 h, with elastin distributed throughout the walls of air spaces, rather than at septal tips, as in control lungs. Dysregulation of elastin was associated with a threefold increase in lung cell apoptosis (TUNEL and caspase-3 assays), which might account for the increased air space size previously reported in this model. Our findings of increased elastin synthesis, coupled with increased elastase activity and reduced lung abundance of proteins that regulate elastic fiber assembly, could explain altered lung elastin deposition, increased apoptosis, and defective septation, as observed in CLD.
Bland
Richard D
RD
Ertsey
Robert
R
Mokres
Lucia M
LM
Xu
Liwen
L
Jacobson
Berit E
BE
Jiang
Shu
S
Alvira
Cristina M
CM
Rabinovitch
Marlene
M
Shinwell
Eric S
ES
Dixit
Anjali
A
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D004549:Elastin / Q000378:metabolism*; D007700:Kinetics; D008168:Lung / Q000254:growth & development* / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D010196:Pancreatic Elastase / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011650:Pulmonary Alveoli / Q000502:physiology*; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012121:Respiration, Artificial
D012313:RNA; D004549:Elastin; D010196:Pancreatic Elastase