Long-term failure of alveologenesis after an early short-term exposure to a PDGF-receptor antagonist.
Survivors of moderate-to-severe bronchopulmonary dysplasia have impaired alveologenesis lasting at least into early adult life. The mechanisms underlying this long-term effect are unknown. We hypothesized that short-term inhibition of growth factor-mediated early alveolar formation would result in a long-term impairment of subsequent alveologenesis. Neonatal rats were injected daily with the platelet-derived growth factor (PDGF) receptor antagonist, imatinib mesylate, from day 1-7 of life, to inhibit the early alveolar formation occurring by in-growth of secondary crests into precursor saccules. The pups were then allowed to recover for 7, 14, 21, or 58 days. In imatinib-treated pups, DNA synthesis in total lung cells, and specifically in cells of secondary crests, was reduced at day 8 of life, had rebounded on day 14 of life but was then again reduced by day 28 of life. At day 8 of life, imatinib-treated pups had impaired alveologenesis as reflected by a decrease in secondary crests, an increase in alveolar size, and an overall decrease in both estimated alveolar number and generations compared with age-matched controls. No meaningful recovery was observed, even after a 21- or 58-day recovery period. The lungs of imatinib-treated pups had increased fibulin-5 content and an abnormal deposition of elastin. We conclude that reduced signaling through the PDGF pathways, at an early stage of alveologenesis, can result in long-lasting changes in lung architecture. A likely mechanism is through impaired formation of the elastin scaffold required for alveolarization.
Lung Biology Programme, Physiology & Experimental Medicine, Hospital for Sick Children Research Institute, Toronto, Canada.
Mandy
M
Lau
Azhar
A
Masood
Man
M
Yi
Rosetta
R
Belcastro
Jun
J
Li
A Keith
AK
Tanswell
D000818:Animals; D000831:Animals, Newborn; D001549:Benzamides; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count; D003720:Densitometry; D004549:Elastin / Q000378:metabolism; D000068877:Imatinib Mesylate; D009929:Organ Size / Q000187:drug effects; D038081:Organogenesis / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000254:growth & development* / Q000473:pathology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D004549:Elastin; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D001973:Bromodeoxyuridine