Adult onset lung disease following transient disruption of fetal stretch-induced differentiation.
One of the mechanisms by which adult disease can arise from a fetal origin is by in utero disruption of organogenesis. These studies were designed to examine respiratory function changes in aging rats following transient disruption of lung growth at 16 days gestation. Fetuses were treated in utero with a replication deficient adenovirus containing the cystic fibrosis conductance transmembrane regulator (CFTR) gene fragment cloned in the anti-sense direction. The in utero-treated rats demonstrated abnormal lung function beginning as early as 30 days of age and the pathology progressed as the animals aged. The pulmonary function abnormalities included decreased static compliance as well as increased conducting airway resistance, tissue damping, and elastance. Pressure volume (PV) curves demonstrated a slower early rise to volume and air trapping at end-expiration. The alterations of pulmonary function correlated with lung structural changes determined by morphometric analysis. These studies demonstrate how transient disruption of lung organogensis by single gene interference can result in progressive change in lung function and structure. They illustrate how an adult onset disease can arise from subtle changes in gene expression during fetal development.
Hudak
Joseph J
JJ
The Brady Laboratory, Section of Neonatology, Department of Pediatrics, Stony Brook University, School of Medicine, Stony Brook, New York, 11794, USA. joseph.hudak@us.army.mil
Killeen
Erin
E
Chandran
Ashok
A
Cohen
J Craig
JC
Larson
Janet E
JE
D000328:Adult; D017668:Age of Onset; D000818:Animals; D002454:Cell Differentiation; D003001:Cloning, Molecular; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D016373:DNA, Antisense / Q000235:genetics; D005260:Female; D005333:Fetus / Q000502:physiology*; D018014:Gene Transfer Techniques; D006801:Humans; D008168:Lung / Q000166:cytology / Q000196:embryology*; D008171:Lung Diseases / Q000196:embryology / Q000503:physiopathology*; D010446:Peptide Fragments / Q000235:genetics; D011247:Pregnancy; D016372:RNA, Antisense / Q000235:genetics; D051381:Rats; D012026:Reflex, Stretch; D012129:Respiratory Function Tests
D016373:DNA, Antisense; D010446:Peptide Fragments; D016372:RNA, Antisense; D019005:Cystic Fibrosis Transmembrane Conductance Regulator