Gadolinium chloride inhibits pulmonary macrophage influx and prevents O(2)-induced pulmonary hypertension in the neonatal rat.
Newborn rats exposed to 60% O(2) for 14 d demonstrated a bronchopulmonary dysplasia-like lung morphology and pulmonary hypertension. A 21-aminosteroid antioxidant, U74389G, attenuated both pulmonary hypertension and macrophage accumulation in the O(2)-exposed lungs. To determine whether macrophage accumulation played an essential role in the development of pulmonary hypertension in this model, pups were treated with gadolinium chloride (GdCl(3)) to reduce lung macrophage content. Treatment of 60% O(2)-exposed animals with GdCl(3) prevented right ventricular hypertrophy (p < 0.05) and smooth muscle hyperplasia around pulmonary vessels, but had no effect on morphologic changes in the lung parenchyma. In addition, GdCl(3) inhibited 60% O(2)-mediated increases in endothelin-1, 8-isoprostane, and nitrotyrosine residues. Organotypic cultures of fetal rat distal lung cells were subjected to cyclical mechanical strain to assess the potential role of GdCl(3)-induced blockade of stretch-mediated cation channels in these effects. Mechanical strain caused a moderate increase of endothelin-1 (p < 0.05), which was unaffected by GdCl(3), but had no effect on 8-isoprostane or nitric oxide synthesis. A critical role for endothelin-1 in O(2)-mediated pulmonary hypertension was confirmed using the combined endothelin receptor antagonist SB217242. We concluded that pulmonary macrophage accumulation, in response to 60% O(2), mediated pulmonary hypertension through up-regulation of endothelin-1.
Jankov
R P
RP
Canadian Institutes of Health Research Groups in Lung Development, Toronto, Ontario, Canada.
Luo
X
X
Belcastro
R
R
Copland
I
I
Frndova
H
H
Lye
S J
SJ
Hoidal
J R
JR
Post
M
M
Tanswell
A K
AK
D000818:Animals; D000831:Animals, Newborn; D001997:Bronchopulmonary Dysplasia / Q000209:etiology / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism; D028441:F2-Isoprostanes; D005682:Gadolinium / Q000494:pharmacology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000473:pathology; D007231:Infant, Newborn; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D010100:Oxygen / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D019332:Endothelin-1; D028441:F2-Isoprostanes; C075750:8-epi-prostaglandin F2alpha; C002744:3-nitrotyrosine; D014443:Tyrosine; D005682:Gadolinium; D015237:Dinoprost; C038958:gadolinium chloride; D010100:Oxygen