Vol. 94, Issue 5, 2027-2033, May 2003
Granulocyte colony-stimulating factor enhances
alpha-naphthylthiourea-induced pulmonary hypertension
Élie
Azoulay1,
Saadia
Eddahibi1,
Élisabeth
Marcos1,
Micheline
Levame1,
Alain
Harf1,2,
Benoît
Schlemmer3,
Serge
Adnot1,2, and
Christophe
Delclaux1,2
1 Institut National de la Santé et de la
Recherche Médicale U492, Faculté de
Médecine-Université Paris XII, and
2 Services de Physiologie, Explorations Fonctionnelles,
Hôpital Henri Mondor, Assistance Publique Hôpitaux de
Paris, 94010 Créteil; and 3 Service de
Réanimation Médicale, Hôpital
Saint-Louis-Université Paris VII, Assistance Publique
Hôpitaux de Paris, 75475 Paris, France
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 µg · kg
1 · day1
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.
neutrophil; pulmonary hypertension model; lidocaine
