Anti-inflammatory effects of long-lasting locally-delivered human recombinant tissue factor pathway inhibitor after balloon angioplasty.
BACKGROUND
Tissue factor pathway inhibitor (TFPI) has anti-proliferative and anti-migratory effects on cultured smooth muscle cells (SMC) in addition to its anti-thrombotic activity. Here, we assess how long locally delivered recombinant TFPI (rTFPI) remains detectable at the delivery sites and clarify the main mechanism by which rTFPI blocks neointimal growth in vivo.


METHODS
The iliac arteries of 85 Japanese white rabbits were injured using a Cutting Balloon. First, to establish the efficacy of local delivery of rTFPI, 5 groups of 3 rabbits each were examined immediately or 1, 2, 4 or 7 days after delivery. They were treated locally with a total amount of 200 microg of rTFPI given at 40 microg per pulse per minute by means of a Pulse Spray catheter. Thereafter, 34 rabbits which had received 200 microg of rTFPI after cutting angioplasty were compared to the same number of controls regarding thrombosis, inhibition of neointimal proliferation and inflammation.


RESULTS
A total of 2.6+/-1.6 ng rTFPI persisted on the injured vessel 4 days after delivery. rTFPI was still present on 48 % of the cut sites 7 days after delivery, despite its short half-life in plasma. Thrombosis in the rTFPI-treated group was significantly reduced compared to the controls. The number of macrophages present within the media and intima was significantly decreased at day 7 after delivery of rTFPI. Furthermore, the number of Ki-67-positive cells 14 days after rTFPI delivery was significantly lower than in controls although there were no significant differences between them after 2 days.


CONCLUSIONS
Local delivery of rTFPI decreased the degree of neointimal formation 4 weeks after TFPI delivery because of anti-inflammatory and anti-proliferative effects in addition to, or rather than, via anti-thrombosis.
Nakamura
Yoichi
Y
Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine and Dentistry, Japan. ynakamur@mti.biglobe.ne.jp
Nakamura
Kazufumi
K
Ohta
Keiko
K
Matsubara
Hiromi
H
Yutani
Chikao
C
Hamuro
Tsutomu
T
Kato
Hisao
H
Ohe
Tohru
T
D000800:Angioplasty, Balloon; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002404:Catheterization; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004867:Equipment Design; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006801:Humans; D007083:Iliac Artery / Q000187:drug effects / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D011817:Rabbits; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D013927:Thrombosis / Q000517:prevention & control; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000627:therapeutic use*; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology
D000893:Anti-Inflammatory Agents; D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator