Published Online
on May 20, 2002

A more recent version of this article appeared on June 18, 2002

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Submitted on December 27, 2001
Revised on March 28, 2002
Accepted on March 28, 2002

Systemic Inflammation Induced by Lipopolysaccharide Increases Neointimal Formation After Balloon and Stent Injury in Rabbits

Haim D. Danenberg MD^*, Frederick G.P. Welt MD, Matthew Walker III PhD, Philip Seifert MS, Greg S. Toegel BA, and Elazer R. Edelman MD, PhD

From Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Mass.

^* To whom correspondence should be addressed. E-mail: danen{at}mit.edu.

Background—Emerging data indicate that the inflammatory response after mechanical arterial injury correlates with the severity of neointimal hyperplasia in animal models and postangioplasty restenosis in humans. The present study was designed to examine whether a nonspecific stimulation of the innate immune system, induced in close temporal proximity to the vascular injury, would modulate the results of the procedure.

Methods and Results—Rabbits subjected to iliac artery balloon injury (balloon denudation with or without stent deployment) were injected twice with a bacterial lipopolysaccharide (LPS) (500 ng/rabbit) before and after surgery. The dose was chosen to be sufficient to induce systemic inflammation but not septic shock. A systemic marker of inflammation (serum interleukin-1ß levels measured by ELISA) and monocytic stimulation (CD14 levels on monocytes measured by flow cytometry) were increased after LPS administration. Arterial macrophage infiltration at 7 days after injury was 1.7±1.2% of total cells in controls and 4.2±1.8% in LPS-treated rabbits (n=4, P<0.05). Morphometric analysis of the injured arteries 4 weeks after injury revealed significantly increased luminal stenosis (38±4.2% versus 23±2.6, mean±SEM; n=8, P<0.05) and neointima-to-media ratio (1.26±0.21 versus 0.66±0.09, P<0.05) in LPS-treated animals compared with controls. This effect was abolished by anti-CD14 Ab administration. Serum interleukin-1ß levels and monocyte CD14 expression were significantly increased in correlation with the severity of intimal hyperplasia. LPS treatment increased neointimal area after stenting from 0.57±0.07 to 0.77±0.1 mm² and stenosis from 9±1% to 13±1.7% (n=5, P<0.05).

Conclusions—Nonspecific systemic stimulation of the innate immune system concurrently with arterial vascular injury facilitates neointimal formation, and conditions associated with increased inflammation may increase restenosis.

Key words: balloon • stents • inflammation • leukocytes • restenosis

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