title: Antenatal imatinib treatment reduces pulmonary vascular remodeling in a rat model of congenital diaphragmatic hernia.
abstract: The pathophysiology of congenital diaphragmatic hernia (CDH) is constituted by pulmonary hypoplasia and pulmonary hypertension (PH). We previously reported successful treatment with imatinib of a patient with CDH. This study examines the effect of antenatal imatinib administration on the pulmonary vasculature in a rat model of CDH. Pregnant rats were given nitrofen to induce CDH. Controls were given olive oil. Half of the CDH fetuses and half of the controls were treated with imatinib antenatally E17-E21, rendering four groups: Control, Control+Imatinib, CDH, and CDH+Imatinib. Lung sections were obtained for morphometry and immunohistochemistry, and protein was purified for Western blot. Effects of nitrofen and imatinib on Ki-67, caspase-3, PDGF-B, and PDGF receptors were analyzed. Imatinib significantly reduced medial wall thickness in pulmonary arteries of rats with CDH. It also normalized lumen area and reduced the proportion of fully muscularized arteries. Imatinib also caused medial thinning in the control group. Cell proliferation was increased in CDH, and this proliferation was significantly reduced by imatinib. PDGF-B and PDGFR-β were upregulated in CDH, and imatinib treatment resulted in a downregulation. PDGFR-α remained unchanged in CDH but was significantly downregulated by imatinib. Antenatal imatinib treatment reduces development of medial wall thickness and restores lumen area in pulmonary arteries in nitrofen-induced CDH. The mechanism is reduced cell proliferation. Imatinib is an interesting candidate for antenatal therapy for PH in CDH, but potential side effects need to be investigated and more specific targeting of PDGF signaling is needed.
authors.affiliation: Division of Pediatrics, Department of Women’s and Children’s Health, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ya-Ting
authors.initials: YT
authors.lastname: Chang
authors.forename: Andreas
authors.initials: A
authors.lastname: Ringman Uggla
authors.forename: Cecilia
authors.initials: C
authors.lastname: Osterholm
authors.forename: Phan-Kiet
authors.initials: PK
authors.lastname: Tran
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Eklöf
authors.forename: Mariette
authors.initials: M
authors.lastname: Lengquist
authors.forename: Ulf
authors.initials: U
authors.lastname: Hedin
authors.forename: Karin
authors.initials: K
authors.lastname: Tran-Lundmark
authors.forename: Björn
authors.initials: B
authors.lastname: Frenckner
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D053148:Caspase 3 / Q000096:biosynthesis; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006548:Hernia, Diaphragmatic / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D065630:Hernias, Diaphragmatic, Congenital; D000068877:Imatinib Mesylate; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008168:Lung / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology*; D010647:Phenyl Ethers / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis; D011247:Pregnancy; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017479:Receptors, Platelet-Derived Growth Factor / Q000096:biosynthesis
chemical_list: D001549:Benzamides; D019394:Ki-67 Antigen; D010647:Phenyl Ethers; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D011743:Pyrimidines; D012333:RNA, Messenger; D000068877:Imatinib Mesylate; D017479:Receptors, Platelet-Derived Growth Factor; D053148:Caspase 3; C007350:nitrofen