Alleviation of monocrotaline-induced pulmonary hypertension by antibodies to monocyte chemotactic and activating factor/monocyte chemoattractant protein-1.
Administration of monocrotaline (MCT) causes pulmonary vascular lesions consisting of monocyte/macrophage infiltration in the early phase and medial thickening in pulmonary arteries and arterioles associated with pulmonary hypertension (PH) in the later phase. However, the molecular mechanism of monocyte/macrophage infiltration and its roles remain elusive. Herein, we have evaluated the role of a potent monocyte chemotactic and activating chemokine/monocyte chemoattractant protein-1 (MCAF/MCP-1) in MCT-induced PH in rats. A single injection of MCT induced PH at Day 21, as evidenced by increases in the ratio of right ventricular to left ventricular and septum weights (RV/LV+S) and right ventricular systolic pressure (RVSP). A significant increase in macrophage number in lungs started at Day 14, reaching a maximum at Day 21. MCAF/MCP-1 levels in bronchoalveolar lavage fluids were elevated significantly at Day 14 and remained high until Day 28, whereas plasma MCAF/MCP-1 levels increased at Day 7, returning to normal levels by Day 21. Immunoreactive MCAF/MCP-1 proteins were mainly detected in macrophages in alveoli and in perivascular regions of pulmonary arterioles and venules. Intravenous administration of anti-MCAF/MCP-1 antibodies with MCT significantly decreased macrophage infiltration and eventually reduced the increases in RV/LV+S and RVSP, as well as medial thickening of pulmonary arterioles. Thus, MCAF/MCP-1 is essentially involved in MCT-induced PH by recruiting and activating macrophages.
Kimura
H
H
Department of Chest Medicine, Chiba University School of Medicine, Chiba City, Japan.
Kasahara
Y
Y
Kurosu
K
K
Sugito
K
K
Takiguchi
Y
Y
Terai
M
M
Mikata
A
A
Natsume
M
M
Mukaida
N
N
Matsushima
K
K
Kuriyama
T
T
D000818:Animals; D000906:Antibodies / Q000276:immunology* / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000276:immunology*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000503:physiopathology*; D007150:Immunohistochemistry; D007279:Injections, Subcutaneous; D008264:Macrophages / Q000502:physiology; D008297:Male; D016686:Monocrotaline / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000906:Antibodies; D018932:Chemokine CCL2; D016686:Monocrotaline