A nuclear factor-kappaB inhibitor pyrrolidine dithiocarbamate ameliorates pulmonary hypertension in rats.
BACKGROUND
Pulmonary hypertension (PH) is a fatal disorder that is associated with structural changes and inflammatory responses in the pulmonary vasculature. Nuclear factor (NF)-kappaB is a key transcription factor that is involved in the tissue remodeling mediated by inflammatory and fibroproliferative responses. However, the contribution of NF-kappaB-mediated inflammatory pathways to the development of PH is unknown.


METHODS
We therefore investigated whether NF-kappaB activation and the expression of a downstream product vascular cell adhesion molecule (VCAM)-1 is associated with pulmonary vascular diseases in rats that have been injected with the toxin monocrotaline (MCT), and whether a NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC), ameliorates such diseases in rats.


RESULTS
VCAM-1 expression and the nuclear localization of the p65 subunit of NF-kappaB, as analyzed immunohistochemically, was significantly up-regulated in the endothelium of diseased vessels on the days 8 to 22 (p < 0.05). Next, 39 rats were divided into three groups (rats injected with MCT and treated with saline solution or PDTC, and controls similarly treated with saline solution). Compared to controls, MCT treatment increased the mean (+/- SE) pulmonary artery pressure (31.2 +/- 1.4 mm Hg [p < 0.05] vs 22.8 +/- 0.9 mm Hg, respectively), which was reduced by PDTC treatment (24.3 +/- 1.2 mm Hg; p < 0.05). Indexes of right ventricular hypertrophy and pulmonary vascular diseases induced by MCT were similarly inhibited (p < 0.05), which was associated with the suppression of VCAM-1 expression and macrophage infiltration.


CONCLUSIONS
We concluded that the NF-kappaB nuclear localization and VCAM-1 expression is temporally and spatially associated with the development of MCT-induced PH in rats, which was ameliorated by administering a NF-kappaB inhibitor, PDTC.
Sawada
Hirofumi
H
Department of Pediatric and Developmental Science, Mie University Graduate School of Medicine, Tsu City, Japan.
Mitani
Yoshihide
Y
Maruyama
Junko
J
Jiang
Bao Hua
BH
Ikeyama
Yukiko
Y
Dida
Francis A
FA
Yamamoto
Hatsumi
H
Imanaka-Yoshida
Kyoko
K
Shimpo
Hideto
H
Mizoguchi
Akira
A
Maruyama
Kazuo
K
Komada
Yoshihiro
Y
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D018450:Disease Progression; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology*; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D016686:Monocrotaline / Q000009:adverse effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011759:Pyrrolidines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013859:Thiocarbamates / Q000627:therapeutic use*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D000975:Antioxidants; D016328:NF-kappa B; D011759:Pyrrolidines; D013859:Thiocarbamates; D019010:Vascular Cell Adhesion Molecule-1; C020972:pyrrolidine dithiocarbamic acid; D016686:Monocrotaline