Macrophage depletion by clodronate-containing liposomes reduces neointimal formation after balloon injury in rats and rabbits.
BACKGROUND
Inflammation is critical to vascular repair after mechanical injury. Excessive inflammation enhances neointimal formation and restenosis. We examined whether transient systemic inactivation of macrophages at the time of vascular intervention could attenuate the degree of expected restenosis.


RESULTS
Liposomal clodronate (LC) inhibited the growth of cultured macrophages but had no effect on endothelial or smooth muscle cells and suppressed neointimal hyperplasia in hypercholesterolemic rabbits and rats after intravenous administration of LC, with no adverse effects. LC treatment reduced the number of blood monocytes and decreased macrophage infiltration in the injured arteries as well as smooth muscle cell proliferation, interleukin-1beta transcription, and production and matrix metalloproteinase-2 activity.


CONCLUSIONS
Macrophages play a pivotal role in vascular repair after mechanical arterial injury. Systemic inactivation and depletion of monocytes and macrophages by LC reduce neointimal hyperplasia and restenosis.
Danenberg
Haim D
HD
Department of Cardiology, Hadassah-Hebrew University Hospital, Jerusalem, Israel. danen@md2.huji.ac.il
Fishbein
Ilia
I
Gao
Jianchuan
J
Mönkkönen
Jukka
J
Reich
Reuven
R
Gati
Irith
I
Moerman
Evgeny
E
Golomb
Gershon
G
D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016893:Carotid Stenosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002404:Catheterization / Q000009:adverse effects*; D002455:Cell Division / Q000187:drug effects; D004002:Clodronic Acid / Q000008:administration & dosage* / Q000737:chemistry; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000096:biosynthesis; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D008081:Liposomes; D008099:Liver / Q000166:cytology / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D017539:Tunica Intima / Q000187:drug effects* / Q000293:injuries / Q000473:pathology
D007375:Interleukin-1; D018950:Lipopolysaccharide Receptors; D008081:Liposomes; D018809:Proliferating Cell Nuclear Antigen; D004002:Clodronic Acid; D020778:Matrix Metalloproteinase 2