Antenatal imatinib treatment reduces pulmonary vascular remodeling in a rat model of congenital diaphragmatic hernia
(2012) In American Journal of Physiology: Lung Cellular and Molecular Physiology 302(11).- 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,... (More)
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-β 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.
(Less)
- author
- Chang, Ya Ting ; Uggla, Andreas Ringman ; Österholm, Cecilia LU ; Tran, Phan Kiet LU ; Eklöf, Ann Christine ; Lengquist, Mariette ; Hedin, Ulf ; Tran-Lundmark, Karin LU and Frenckner, Björn
- publishing date
- 2012-06-01
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- PDGF, Pulmonary hypertension
- in
- American Journal of Physiology: Lung Cellular and Molecular Physiology
- volume
- 302
- issue
- 11
- publisher
- American Physiological Society
- external identifiers
-
- pmid:22447953
- scopus:84861846385
- ISSN
- 1522-1504
- DOI
- 10.1152/ajplung.00325.2010
- language
- English
- LU publication?
- no
- id
- 7f65469a-3d78-4b44-a509-ef3740bea21d
- date added to LUP
- 2019-07-01 22:15:58
- date last changed
- 2024-04-02 12:02:45
@article{7f65469a-3d78-4b44-a509-ef3740bea21d,
abstract = {{<p>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-β 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.</p>}},
author = {{Chang, Ya Ting and Uggla, Andreas Ringman and Österholm, Cecilia and Tran, Phan Kiet and Eklöf, Ann Christine and Lengquist, Mariette and Hedin, Ulf and Tran-Lundmark, Karin and Frenckner, Björn}},
issn = {{1522-1504}},
keywords = {{PDGF; Pulmonary hypertension}},
language = {{eng}},
month = {{06}},
number = {{11}},
publisher = {{American Physiological Society}},
series = {{American Journal of Physiology: Lung Cellular and Molecular Physiology}},
title = {{Antenatal imatinib treatment reduces pulmonary vascular remodeling in a rat model of congenital diaphragmatic hernia}},
url = {{http://dx.doi.org/10.1152/ajplung.00325.2010}},
doi = {{10.1152/ajplung.00325.2010}},
volume = {{302}},
year = {{2012}},
}