Granulocyte colony-stimulating factor prevents progression of monocrotaline-induced pulmonary arterial hypertension in rats.
BACKGROUND
Regeneration of the lung microvasculature and replacing pulmonary artery lesions with functional endothelial cells could be a novel and effective therapeutic strategy for treating advanced pulmonary arterial hypertension (PAH). In the present study it was postulated that granulocyte colony-stimulating factor (G-CFS), which induces the proliferation of endothelial cells, would stimulate endothelial regeneration in situ at sites of impaired lung vasculature and prevent the development of PAH.


RESULTS
Daily administration of G-CSF for 48 days did not affect the hemodynamism of normal Fischer 344 rats. PAH was induced with monocrotaline (60 mg/kg) and G-CSF was administered daily (100 microg/kg per day). Echocardiographic findings and an invasive catheter study indicated a significant decrease in the progression of PAH in rats given G-CSF. Furthermore, G-CSF increased Ki-67 positivity in the pulmonary arteries of PAH rats but did not accelerate c-kit positive cell recruitment into peripheral blood. Daily doses of G-CSF at both 2 and 100 microg/kg improved the survival and body weight gain of PAH rats.


CONCLUSIONS
G-CSF improved the progression of PAH in a rat model, possibly by stimulating pulmonary endothelial cells to proliferate at sites of impaired lung vasculature. These findings show that cytokine therapy for PAH is valid based on the concept of vascular regeneration.
Maruyama
Hidekazu
H
Department of Cardiovascular Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Japan.
Watanabe
Shigeyuki
S
Kimura
Taizo
T
Liang
Jingyan
J
Nagasawa
Toshiro
T
Onodera
Masafumi
M
Aonuma
Kazutaka
K
Yamaguchi
Iwao
I
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D004730:Endothelium, Vascular / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology / Q000627:therapeutic use*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*; D008297:Male; D016686:Monocrotaline; D011651:Pulmonary Artery / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D011916:Rats, Inbred F344
D016179:Granulocyte Colony-Stimulating Factor; D016686:Monocrotaline