This Article Full Text Full Text (PDF) All Versions of this Article: 105/24/2917    most recent 01.CIR.0000018168.15904.BBv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Danenberg, H. D. Articles by Edelman, E. R. Search for Related Content PubMed PubMed Citation Articles by Danenberg, H. D. Articles by Edelman, E. R. Related Collections Restenosis Animal models of human disease Other Vascular biology

(Circulation. 2002;105:2917.)
© 2002 American Heart Association, Inc.

Basic Science Reports

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; Elazer R. Edelman, MD, PhD

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

Correspondence to Haim D. Danenberg, MD, MIT Building 56-322, 77 Massachusetts Ave, Cambridge, MA 02139. 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

This article has been cited by other articles:

				V. Mollace, S. Ragusa, I. Sacco, C. Muscoli, F. Sculco, V. Visalli, E. Palma, S. Muscoli, L. Mondello, P. Dugo, et al. The Protective Effect of Bergamot Oil Extract on Lecitine-like OxyLDL Receptor-1 Expression in Balloon Injury-related Neointima Formation Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2008; 13(2): 120 - 129. [Abstract] [PDF]

				C. Brasselet, E. Durand, F. Addad, F. Vitry, G. Chatellier, C. Demerens, M. Lemitre, R. Garnotel, D. Urbain, P. Bruneval, et al. Effect of local heating on restenosis and in-stent neointimal hyperplasia in the atherosclerotic rabbit model: a dose-ranging study Eur. Heart J., February 1, 2008; 29(3): 402 - 412. [Abstract] [Full Text] [PDF]

				B. Liu, M. Han, and J.-K. Wen Acetylbritannilactone Inhibits Neointimal Hyperplasia after Balloon Injury of Rat Artery by Suppressing Nuclear Factor-{kappa}B Activation J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 292 - 298. [Abstract] [Full Text] [PDF]

				F.-Y. Lin, Y.-H. Chen, Y.-W. Lin, J.-S. Tsai, J.-W. Chen, H.-J. Wang, Y.-L. Chen, C.-Y. Li, and S.-J. Lin The Role of Human Antigen R, an RNA-binding Protein, in Mediating the Stabilization of Toll-Like Receptor 4 mRNA Induced by Endotoxin: A Novel Mechanism Involved in Vascular Inflammation Arterioscler Thromb Vasc Biol, December 1, 2006; 26(12): 2622 - 2629. [Abstract] [Full Text] [PDF]

				F.-Y. Lin, Y.-H. Chen, J.-S. Tasi, J.-W. Chen, T.-L. Yang, H.-J. Wang, C.-Y. Li, Y.-L. Chen, and S.-J. Lin Endotoxin Induces Toll-Like Receptor 4 Expression in Vascular Smooth Muscle Cells via NADPH Oxidase Activation and Mitogen-Activated Protein Kinase Signaling Pathways Arterioscler Thromb Vasc Biol, December 1, 2006; 26(12): 2630 - 2637. [Abstract] [Full Text] [PDF]

				W. J. Gomes and E. Buffolo Coronary stenting and inflammation: implications for further surgical and medical treatment. Ann. Thorac. Surg., May 1, 2006; 81(5): 1918 - 1925. [Abstract] [Full Text] [PDF]

				J. Tan, Z. Ma, L. Han, R. Du, L. Zhao, X. Wei, D. Hou, B. H. Johnstone, M. R. Farlow, and Y. Du Caffeic acid phenethyl ester possesses potent cardioprotective effects in a rabbit model of acute myocardial ischemia-reperfusion injury Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H2265 - H2271. [Abstract] [Full Text] [PDF]

				H. Gupta, L. Dai, G. Datta, D. W. Garber, H. Grenett, Y. Li, V. Mishra, M. N. Palgunachari, S. Handattu, S. H. Gianturco, et al. Inhibition of Lipopolysaccharide-Induced Inflammatory Responses by an Apolipoprotein AI Mimetic Peptide Circ. Res., August 5, 2005; 97(3): 236 - 243. [Abstract] [Full Text] [PDF]

				J. F. LaDisa Jr., Lars. E. Olson, R. C. Molthen, D. A. Hettrick, P. F. Pratt, M. D. Hardel, J. R. Kersten, D. C. Warltier, and P. S. Pagel Alterations in wall shear stress predict sites of neointimal hyperplasia after stent implantation in rabbit iliac arteries Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2465 - H2475. [Abstract] [Full Text] [PDF]

				J. F. LaDisa Jr., L. E. Olson, I. Guler, D. A. Hettrick, J. R. Kersten, D. C. Warltier, and P. S. Pagel Circumferential vascular deformation after stent implantation alters wall shear stress evaluated with time-dependent 3D computational fluid dynamics models J Appl Physiol, March 1, 2005; 98(3): 947 - 957. [Abstract] [Full Text] [PDF]

				S. Z.H. Rittersma, J. A. Kremer Hovinga, K. T. Koch, S. M. Boekholdt, B. E. van Aken, A. Scheepmaker, M. Bax, C. E. Schotborgh, J. J. Piek, J. G.P. Tijssen, et al. Relationship between In Vitro Lipopolysaccharide-Induced Cytokine Response in Whole Blood, Angiographic In-Stent Restenosis, and Toll-Like Receptor 4 Gene Polymorphisms Clin. Chem., March 1, 2005; 51(3): 516 - 521. [Abstract] [Full Text] [PDF]

				K. Toutouzas, A. Colombo, and C. Stefanadis Inflammation and restenosis after percutaneous coronary interventions Eur. Heart J., October 1, 2004; 25(19): 1679 - 1687. [Abstract] [Full Text] [PDF]

				C. Muscoli, I. Sacco, W. Alecce, E. Palma, R. Nistico, N. Costa, F. Clementi, D. Rotiroti, F. Romeo, D. Salvemini, et al. The Protective Effect of Superoxide Dismutase Mimetic M40401 on Balloon Injury-Related Neointima Formation: Role of the Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 J. Pharmacol. Exp. Ther., October 1, 2004; 311(1): 44 - 50. [Abstract] [Full Text] [PDF]

				K. Edfeldt, A. M Bennet, P. Eriksson, J. Frostegard, B. Wiman, A. Hamsten, G. K Hansson, U. d. Faire, and Z.-q. Yan Association of hypo-responsive toll-like receptor 4 variants with risk of myocardial infarction Eur. Heart J., August 2, 2004; 25(16): 1447 - 1453. [Abstract] [Full Text] [PDF]

				S.-J. Park, H.-S. Kim, H.-M. Yang, K.-W. Park, S.-W. Youn, S.-I. Jeon, D.-H. Kim, B.-K. Koo, I.-H. Chae, D.-J. Choi, et al. Thalidomide as a Potent Inhibitor of Neointimal Hyperplasia After Balloon Injury in Rat Carotid Artery Arterioscler Thromb Vasc Biol, May 1, 2004; 24(5): 885 - 891. [Abstract] [Full Text]

				M. Schillinger, W. Mlekusch, R. M. Wolfram, A. C. Budinsky, M. Exner, H. Rumpold, O. Wagner, B. Pokrajac, R. Potter, and E. Minar Endovascular Brachytherapy: Effect on Acute Inflammatory Response after Percutaneous Femoropopliteal Arterial Interventions Radiology, February 1, 2004; 230(2): 556 - 560. [Abstract] [Full Text] [PDF]

				A. Colombo and G. Sangiorgi The monocyte: the key in the lock to reduce stent hyperplasia? J. Am. Coll. Cardiol., January 7, 2004; 43(1): 24 - 26. [Full Text] [PDF]

				H. D. Danenberg, G. Golomb, A. Groothuis, J. Gao, H. Epstein, R. V. Swaminathan, P. Seifert, and E. R. Edelman Liposomal Alendronate Inhibits Systemic Innate Immunity and Reduces In-Stent Neointimal Hyperplasia in Rabbits Circulation, December 2, 2003; 108(22): 2798 - 2804. [Abstract] [Full Text] [PDF]

				L. Mandinov, A. Mandinova, S. Kyurkchiev, D. Kyurkchiev, I. Kehayov, V. Kolev, R. Soldi, C. Bagala, E. D. de Muinck, V. Lindner, et al. Copper chelation represses the vascular response to injury PNAS, May 27, 2003; 100(11): 6700 - 6705. [Abstract] [Full Text] [PDF]

				P. K. Shah Inflammation, Neointimal Hyperplasia, and Restenosis: As the Leukocytes Roll, the Arteries Thicken Circulation, May 6, 2003; 107(17): 2175 - 2177. [Full Text] [PDF]