Antenatal imatinib treatment reduces pulmonary vascular remodeling in a rat model of congenital diaphragmatic hernia

Research output: Contribution to journalArticle

Standard

Antenatal imatinib treatment reduces pulmonary vascular remodeling in a rat model of congenital diaphragmatic hernia. / Chang, Ya Ting; Uggla, Andreas Ringman; Österholm, Cecilia; Tran, Phan Kiet; Eklöf, Ann Christine; Lengquist, Mariette; Hedin, Ulf; Tran-Lundmark, Karin; Frenckner, Björn.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 302, No. 11, 01.06.2012.

Research output: Contribution to journalArticle

Harvard

APA

CBE

MLA

Vancouver

Author

Chang, Ya Ting ; Uggla, Andreas Ringman ; Österholm, Cecilia ; Tran, Phan Kiet ; Eklöf, Ann Christine ; Lengquist, Mariette ; Hedin, Ulf ; Tran-Lundmark, Karin ; Frenckner, Björn. / Antenatal imatinib treatment reduces pulmonary vascular remodeling in a rat model of congenital diaphragmatic hernia. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2012 ; Vol. 302, No. 11.

RIS

TY - JOUR

T1 - Antenatal imatinib treatment reduces pulmonary vascular remodeling in a rat model of congenital diaphragmatic hernia

AU - Chang, Ya Ting

AU - Uggla, Andreas Ringman

AU - Österholm, Cecilia

AU - Tran, Phan Kiet

AU - Eklöf, Ann Christine

AU - Lengquist, Mariette

AU - Hedin, Ulf

AU - Tran-Lundmark, Karin

AU - Frenckner, Björn

PY - 2012/6/1

Y1 - 2012/6/1

N2 - 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.

AB - 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.

KW - PDGF

KW - Pulmonary hypertension

UR - http://www.scopus.com/inward/record.url?scp=84861846385&partnerID=8YFLogxK

U2 - 10.1152/ajplung.00325.2010

DO - 10.1152/ajplung.00325.2010

M3 - Article

VL - 302

JO - American Journal of Physiology: Lung Cellular and Molecular Physiology

JF - American Journal of Physiology: Lung Cellular and Molecular Physiology

SN - 1522-1504

IS - 11

ER -