Granulocyte colony-stimulating factor enhances alpha-naphthylthiourea-induced pulmonary hypertension.
Physiopathological discrepancies exist between the most widely used models of pulmonary hypertension (PH), namely monocrotaline- and hypoxia-induced PH. The development of a new model could help in the understanding of underlying mechanisms. Repeated alpha-naphthylthiourea (ANTU) injections (5 mg/kg weekly, 3 wk) induced pulmonary vascular remodeling, which was associated with development of PH and right ventricular hypertrophy. ANTU followed by granulocyte colony-stimulating factor (G-CSF; 25 microgram. kg(-1). day(-1) subcutaneously, 3 days/wk) induced higher pulmonary arterial pressures and right ventricular hypertrophy than ANTU alone. Lidocaine, which inhibits neutrophil functions, inhibited PH exacerbation by G-CSF. Endothelial nitric oxide synthase expression, measured to assess ANTU-related endothelial toxicity, decreased significantly in ANTU-treated rats and fell even more sharply when G-CSF was given. This occurred despite a significant increase in vascular endothelial cell growth factor expression in lung and right ventricle in rats given ANTU alone and even more in rats given ANTU plus G-CSF. Repeated ANTU administration induces PH with vascular remodeling that can be further aggravated by the neutrophil activator G-CSF.
Azoulay
Elie
E
Institut National de la Santé et de la Recherche Médicale U492, Faculté de Médecine-Université Paris XII, 75475 Paris, France.
Eddahibi
Saadia
S
Marcos
Elisabeth
E
Levame
Micheline
M
Harf
Alain
A
Schlemmer
Benoit
B
Adnot
Serge
S
Delclaux
Christophe
C
D000818:Animals; D001808:Blood Vessels / Q000473:pathology; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D002908:Chronic Disease; D004357:Drug Synergism; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology*; D006984:Hypertrophy / Q000503:physiopathology; D008168:Lung / Q000473:pathology; D008297:Male; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052250:Nitric Oxide Synthase Type III; D009929:Organ Size / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013890:Thiourea / Q000031:analogs & derivatives*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D042461:Vascular Endothelial Growth Factor A; D016179:Granulocyte Colony-Stimulating Factor; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D013890:Thiourea; C005277:alpha-naphthyl thiourea