Inhibition of transplant vasculopathy in a rat aortic allograft model after infusion of anti-inflammatory viral serpin

Leslie W. Miller, Erbin Dai, Piers Nash, Liying Liu, Carolyn Icton, Dennis Klironomos, Lilly Fan, Patric N. Nation, Robert Zhong, Douglas McFadden, Alexandra Lucas

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Background - Transplant vasculopathy remains a difficult therapeutic problem, resulting in the majority of late cardiac graft losses. This chronic vascular disease is thought to be triggered by alloantigen-dependent and alloantigen-independent inflammatory factors. Despite improved 1-year survival, the incidence of transplant vasculopathy has not improved with current immunosuppressive protocols. Highly effective strategies have evolved in the large DNA viruses that shield infecting viruses from host inflammatory responses. Serp-1 is a secreted myxoma virus anti-inflammatory serine proteinase inhibitor. Serp-1 inhibits plasminogen activators in a manner similar to plasminogen activator inhibitor (PAI-1), a vascular protein that plays a pivotal regulatory role in vascular wound healing. In this study, we tested the ability of purified Serp-1 protein to ameliorate posttransplant vasculopathy after rat aortic allograft surgery. Methods and Results - Serp-1 protein or controls were infused into 98 rats immediately after segmental aortic allograft transplantation. After either late (28 days, 64 rats) or early (12 to 48 hours, 24 rats) follow-up, transplanted aortic segments were harvested for morphological and immunohistochemical analysis. Significant reductions in intimal plaque growth (P<0.002) and mononuclear cell invasion (P<0.033) were detected after Serp-1 infusion at nanogram doses. Serp-1 reduced early macrophage (P<0.0016) and nonspecific lymphocyte (P<0.0179) invasion into medial and adventitial layers and inhibited associated depletion of medial smooth muscle cells (P<0.0006). Conclusions - Infusion of a viral anti-inflammatory serpin, Serp-1, significantly reduces early inflammatory responses and later luminal occlusion in a rat aortic allograft model.

Original languageEnglish (US)
Pages (from-to)1598-1605
Number of pages8
JournalCirculation
Volume101
Issue number13
DOIs
StatePublished - Apr 4 2000
Externally publishedYes

Fingerprint

Serpins
Allografts
Anti-Inflammatory Agents
Transplants
Isoantigens
Plasminogen Activator Inhibitor 1
Blood Vessels
Myxoma virus
Tunica Intima
Adventitia
Proteins
Serine Proteinase Inhibitors
DNA Viruses
Plasminogen Activators
Immunosuppressive Agents
Vascular Diseases
Wound Healing
Smooth Muscle Myocytes
Chronic Disease
Transplantation

Keywords

  • Inflammation
  • Rejection
  • Serpin
  • Transplantation
  • Viruses

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Miller, L. W., Dai, E., Nash, P., Liu, L., Icton, C., Klironomos, D., ... Lucas, A. (2000). Inhibition of transplant vasculopathy in a rat aortic allograft model after infusion of anti-inflammatory viral serpin. Circulation, 101(13), 1598-1605. https://doi.org/10.1161/01.CIR.101.13.1598

Inhibition of transplant vasculopathy in a rat aortic allograft model after infusion of anti-inflammatory viral serpin. / Miller, Leslie W.; Dai, Erbin; Nash, Piers; Liu, Liying; Icton, Carolyn; Klironomos, Dennis; Fan, Lilly; Nation, Patric N.; Zhong, Robert; McFadden, Douglas; Lucas, Alexandra.

In: Circulation, Vol. 101, No. 13, 04.04.2000, p. 1598-1605.

Research output: Contribution to journalArticle

Miller, LW, Dai, E, Nash, P, Liu, L, Icton, C, Klironomos, D, Fan, L, Nation, PN, Zhong, R, McFadden, D & Lucas, A 2000, 'Inhibition of transplant vasculopathy in a rat aortic allograft model after infusion of anti-inflammatory viral serpin', Circulation, vol. 101, no. 13, pp. 1598-1605. https://doi.org/10.1161/01.CIR.101.13.1598
Miller, Leslie W. ; Dai, Erbin ; Nash, Piers ; Liu, Liying ; Icton, Carolyn ; Klironomos, Dennis ; Fan, Lilly ; Nation, Patric N. ; Zhong, Robert ; McFadden, Douglas ; Lucas, Alexandra. / Inhibition of transplant vasculopathy in a rat aortic allograft model after infusion of anti-inflammatory viral serpin. In: Circulation. 2000 ; Vol. 101, No. 13. pp. 1598-1605.
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abstract = "Background - Transplant vasculopathy remains a difficult therapeutic problem, resulting in the majority of late cardiac graft losses. This chronic vascular disease is thought to be triggered by alloantigen-dependent and alloantigen-independent inflammatory factors. Despite improved 1-year survival, the incidence of transplant vasculopathy has not improved with current immunosuppressive protocols. Highly effective strategies have evolved in the large DNA viruses that shield infecting viruses from host inflammatory responses. Serp-1 is a secreted myxoma virus anti-inflammatory serine proteinase inhibitor. Serp-1 inhibits plasminogen activators in a manner similar to plasminogen activator inhibitor (PAI-1), a vascular protein that plays a pivotal regulatory role in vascular wound healing. In this study, we tested the ability of purified Serp-1 protein to ameliorate posttransplant vasculopathy after rat aortic allograft surgery. Methods and Results - Serp-1 protein or controls were infused into 98 rats immediately after segmental aortic allograft transplantation. After either late (28 days, 64 rats) or early (12 to 48 hours, 24 rats) follow-up, transplanted aortic segments were harvested for morphological and immunohistochemical analysis. Significant reductions in intimal plaque growth (P<0.002) and mononuclear cell invasion (P<0.033) were detected after Serp-1 infusion at nanogram doses. Serp-1 reduced early macrophage (P<0.0016) and nonspecific lymphocyte (P<0.0179) invasion into medial and adventitial layers and inhibited associated depletion of medial smooth muscle cells (P<0.0006). Conclusions - Infusion of a viral anti-inflammatory serpin, Serp-1, significantly reduces early inflammatory responses and later luminal occlusion in a rat aortic allograft model.",
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AU - Icton, Carolyn

AU - Klironomos, Dennis

AU - Fan, Lilly

AU - Nation, Patric N.

AU - Zhong, Robert

AU - McFadden, Douglas

AU - Lucas, Alexandra

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N2 - Background - Transplant vasculopathy remains a difficult therapeutic problem, resulting in the majority of late cardiac graft losses. This chronic vascular disease is thought to be triggered by alloantigen-dependent and alloantigen-independent inflammatory factors. Despite improved 1-year survival, the incidence of transplant vasculopathy has not improved with current immunosuppressive protocols. Highly effective strategies have evolved in the large DNA viruses that shield infecting viruses from host inflammatory responses. Serp-1 is a secreted myxoma virus anti-inflammatory serine proteinase inhibitor. Serp-1 inhibits plasminogen activators in a manner similar to plasminogen activator inhibitor (PAI-1), a vascular protein that plays a pivotal regulatory role in vascular wound healing. In this study, we tested the ability of purified Serp-1 protein to ameliorate posttransplant vasculopathy after rat aortic allograft surgery. Methods and Results - Serp-1 protein or controls were infused into 98 rats immediately after segmental aortic allograft transplantation. After either late (28 days, 64 rats) or early (12 to 48 hours, 24 rats) follow-up, transplanted aortic segments were harvested for morphological and immunohistochemical analysis. Significant reductions in intimal plaque growth (P<0.002) and mononuclear cell invasion (P<0.033) were detected after Serp-1 infusion at nanogram doses. Serp-1 reduced early macrophage (P<0.0016) and nonspecific lymphocyte (P<0.0179) invasion into medial and adventitial layers and inhibited associated depletion of medial smooth muscle cells (P<0.0006). Conclusions - Infusion of a viral anti-inflammatory serpin, Serp-1, significantly reduces early inflammatory responses and later luminal occlusion in a rat aortic allograft model.

AB - Background - Transplant vasculopathy remains a difficult therapeutic problem, resulting in the majority of late cardiac graft losses. This chronic vascular disease is thought to be triggered by alloantigen-dependent and alloantigen-independent inflammatory factors. Despite improved 1-year survival, the incidence of transplant vasculopathy has not improved with current immunosuppressive protocols. Highly effective strategies have evolved in the large DNA viruses that shield infecting viruses from host inflammatory responses. Serp-1 is a secreted myxoma virus anti-inflammatory serine proteinase inhibitor. Serp-1 inhibits plasminogen activators in a manner similar to plasminogen activator inhibitor (PAI-1), a vascular protein that plays a pivotal regulatory role in vascular wound healing. In this study, we tested the ability of purified Serp-1 protein to ameliorate posttransplant vasculopathy after rat aortic allograft surgery. Methods and Results - Serp-1 protein or controls were infused into 98 rats immediately after segmental aortic allograft transplantation. After either late (28 days, 64 rats) or early (12 to 48 hours, 24 rats) follow-up, transplanted aortic segments were harvested for morphological and immunohistochemical analysis. Significant reductions in intimal plaque growth (P<0.002) and mononuclear cell invasion (P<0.033) were detected after Serp-1 infusion at nanogram doses. Serp-1 reduced early macrophage (P<0.0016) and nonspecific lymphocyte (P<0.0179) invasion into medial and adventitial layers and inhibited associated depletion of medial smooth muscle cells (P<0.0006). Conclusions - Infusion of a viral anti-inflammatory serpin, Serp-1, significantly reduces early inflammatory responses and later luminal occlusion in a rat aortic allograft model.

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