Neutrophils are responsible for impaired medial smooth muscle cell recovery and exaggerated allograft vasculopathy in aortic allografts exposed to prolonged cold ischemia

Melvin So, Tim D G Lee, Camille L. Hancock Friesen

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background: Ischemia and reperfusion injury is critical in allograft vasculopathy (AV) development. We have shown that neutrophil-mediated medial smooth muscle cell (SMC) loss precedes AV and that prolonged cold ischemia (CI) impairs medial SMC recovery and accelerates AV development. We hypothesize that neutrophils (NØs) are responsible for failed medial SMC recovery that precedes AV. Methods: Aortic transplants were performed between fully disparate C3H/HeJ murine donors and wild-type C57BL/6 (WT B6), B6.129S7-Rag1 (Rag1 -/-; intact innate but no adaptive immunity), and B6.129S-Cybb (NOX2-/-; NØ loss-of-function) recipients under cyclosporine A immunosuppression. Grafts were exposed to 20 or 60 minutes CI before transplant and harvested at 1 day, 2 weeks, and 8 weeks after transplant. Some WT B6 recipients were treated with remote ischemic pre-conditioning (rIPC). Grafts were assessed for medial SMCs, NØs, and lesion area. Results: The 60-minute vs 20-minute CI grafts exhibited reduced SMC recovery at 2 weeks in WT B6 and Rag1-/- recipients (WT B6: p = 0.0009; Rag1-/-: p = 0.0006). NØ influx was greater in Rag1-/- recipients of 60-minute vs 20-minute CI grafts at 1 day (p = 0.0002). The difference in 2-week medial SMC recovery between ischemia groups was abrogated in NOX2-/- recipients. At 8 weeks, NOX2-/- and rIPC recipients of 60-minute CI grafts exhibited smaller neointimal lesions than B6 recipients (NOX2 -/-: p = 0.0009; rIPC: p = 0.0005). Conclusions: Impaired medial SMC recovery in murine aortic allografts at 2 weeks occurs in the absence of adaptive immunity. Enhanced medial SMC recovery and reduced neointimal lesion formation in NOX2-/- and rIPC recipients of 60-minute CI grafts suggest a causal role for NØs in impaired medial SMC repopulation and the development of AV.

Original languageEnglish (US)
Pages (from-to)360-367
Number of pages8
JournalJournal of Heart and Lung Transplantation
Volume32
Issue number3
DOIs
StatePublished - Mar 1 2013

Fingerprint

Cold Ischemia
Smooth Muscle Myocytes
Allografts
Neutrophils
Transplants
Ischemic Preconditioning
Adaptive Immunity
Reperfusion Injury
Immunosuppression
Cyclosporine
Ischemia

Keywords

  • allograft vasculopathy
  • cold ischemia
  • ischemia and reperfusion injury
  • neutrophils
  • smooth muscle cells

ASJC Scopus subject areas

  • Transplantation
  • Cardiology and Cardiovascular Medicine
  • Pulmonary and Respiratory Medicine
  • Surgery

Cite this

@article{4f58c3be5e674650be9c7246f118612a,
title = "Neutrophils are responsible for impaired medial smooth muscle cell recovery and exaggerated allograft vasculopathy in aortic allografts exposed to prolonged cold ischemia",
abstract = "Background: Ischemia and reperfusion injury is critical in allograft vasculopathy (AV) development. We have shown that neutrophil-mediated medial smooth muscle cell (SMC) loss precedes AV and that prolonged cold ischemia (CI) impairs medial SMC recovery and accelerates AV development. We hypothesize that neutrophils (N{\O}s) are responsible for failed medial SMC recovery that precedes AV. Methods: Aortic transplants were performed between fully disparate C3H/HeJ murine donors and wild-type C57BL/6 (WT B6), B6.129S7-Rag1 (Rag1 -/-; intact innate but no adaptive immunity), and B6.129S-Cybb (NOX2-/-; N{\O} loss-of-function) recipients under cyclosporine A immunosuppression. Grafts were exposed to 20 or 60 minutes CI before transplant and harvested at 1 day, 2 weeks, and 8 weeks after transplant. Some WT B6 recipients were treated with remote ischemic pre-conditioning (rIPC). Grafts were assessed for medial SMCs, N{\O}s, and lesion area. Results: The 60-minute vs 20-minute CI grafts exhibited reduced SMC recovery at 2 weeks in WT B6 and Rag1-/- recipients (WT B6: p = 0.0009; Rag1-/-: p = 0.0006). N{\O} influx was greater in Rag1-/- recipients of 60-minute vs 20-minute CI grafts at 1 day (p = 0.0002). The difference in 2-week medial SMC recovery between ischemia groups was abrogated in NOX2-/- recipients. At 8 weeks, NOX2-/- and rIPC recipients of 60-minute CI grafts exhibited smaller neointimal lesions than B6 recipients (NOX2 -/-: p = 0.0009; rIPC: p = 0.0005). Conclusions: Impaired medial SMC recovery in murine aortic allografts at 2 weeks occurs in the absence of adaptive immunity. Enhanced medial SMC recovery and reduced neointimal lesion formation in NOX2-/- and rIPC recipients of 60-minute CI grafts suggest a causal role for N{\O}s in impaired medial SMC repopulation and the development of AV.",
keywords = "allograft vasculopathy, cold ischemia, ischemia and reperfusion injury, neutrophils, smooth muscle cells",
author = "Melvin So and Lee, {Tim D G} and {Hancock Friesen}, {Camille L.}",
year = "2013",
month = "3",
day = "1",
doi = "10.1016/j.healun.2012.11.029",
language = "English (US)",
volume = "32",
pages = "360--367",
journal = "Journal of Heart and Lung Transplantation",
issn = "1053-2498",
publisher = "Elsevier USA",
number = "3",

}

TY - JOUR

T1 - Neutrophils are responsible for impaired medial smooth muscle cell recovery and exaggerated allograft vasculopathy in aortic allografts exposed to prolonged cold ischemia

AU - So, Melvin

AU - Lee, Tim D G

AU - Hancock Friesen, Camille L.

PY - 2013/3/1

Y1 - 2013/3/1

N2 - Background: Ischemia and reperfusion injury is critical in allograft vasculopathy (AV) development. We have shown that neutrophil-mediated medial smooth muscle cell (SMC) loss precedes AV and that prolonged cold ischemia (CI) impairs medial SMC recovery and accelerates AV development. We hypothesize that neutrophils (NØs) are responsible for failed medial SMC recovery that precedes AV. Methods: Aortic transplants were performed between fully disparate C3H/HeJ murine donors and wild-type C57BL/6 (WT B6), B6.129S7-Rag1 (Rag1 -/-; intact innate but no adaptive immunity), and B6.129S-Cybb (NOX2-/-; NØ loss-of-function) recipients under cyclosporine A immunosuppression. Grafts were exposed to 20 or 60 minutes CI before transplant and harvested at 1 day, 2 weeks, and 8 weeks after transplant. Some WT B6 recipients were treated with remote ischemic pre-conditioning (rIPC). Grafts were assessed for medial SMCs, NØs, and lesion area. Results: The 60-minute vs 20-minute CI grafts exhibited reduced SMC recovery at 2 weeks in WT B6 and Rag1-/- recipients (WT B6: p = 0.0009; Rag1-/-: p = 0.0006). NØ influx was greater in Rag1-/- recipients of 60-minute vs 20-minute CI grafts at 1 day (p = 0.0002). The difference in 2-week medial SMC recovery between ischemia groups was abrogated in NOX2-/- recipients. At 8 weeks, NOX2-/- and rIPC recipients of 60-minute CI grafts exhibited smaller neointimal lesions than B6 recipients (NOX2 -/-: p = 0.0009; rIPC: p = 0.0005). Conclusions: Impaired medial SMC recovery in murine aortic allografts at 2 weeks occurs in the absence of adaptive immunity. Enhanced medial SMC recovery and reduced neointimal lesion formation in NOX2-/- and rIPC recipients of 60-minute CI grafts suggest a causal role for NØs in impaired medial SMC repopulation and the development of AV.

AB - Background: Ischemia and reperfusion injury is critical in allograft vasculopathy (AV) development. We have shown that neutrophil-mediated medial smooth muscle cell (SMC) loss precedes AV and that prolonged cold ischemia (CI) impairs medial SMC recovery and accelerates AV development. We hypothesize that neutrophils (NØs) are responsible for failed medial SMC recovery that precedes AV. Methods: Aortic transplants were performed between fully disparate C3H/HeJ murine donors and wild-type C57BL/6 (WT B6), B6.129S7-Rag1 (Rag1 -/-; intact innate but no adaptive immunity), and B6.129S-Cybb (NOX2-/-; NØ loss-of-function) recipients under cyclosporine A immunosuppression. Grafts were exposed to 20 or 60 minutes CI before transplant and harvested at 1 day, 2 weeks, and 8 weeks after transplant. Some WT B6 recipients were treated with remote ischemic pre-conditioning (rIPC). Grafts were assessed for medial SMCs, NØs, and lesion area. Results: The 60-minute vs 20-minute CI grafts exhibited reduced SMC recovery at 2 weeks in WT B6 and Rag1-/- recipients (WT B6: p = 0.0009; Rag1-/-: p = 0.0006). NØ influx was greater in Rag1-/- recipients of 60-minute vs 20-minute CI grafts at 1 day (p = 0.0002). The difference in 2-week medial SMC recovery between ischemia groups was abrogated in NOX2-/- recipients. At 8 weeks, NOX2-/- and rIPC recipients of 60-minute CI grafts exhibited smaller neointimal lesions than B6 recipients (NOX2 -/-: p = 0.0009; rIPC: p = 0.0005). Conclusions: Impaired medial SMC recovery in murine aortic allografts at 2 weeks occurs in the absence of adaptive immunity. Enhanced medial SMC recovery and reduced neointimal lesion formation in NOX2-/- and rIPC recipients of 60-minute CI grafts suggest a causal role for NØs in impaired medial SMC repopulation and the development of AV.

KW - allograft vasculopathy

KW - cold ischemia

KW - ischemia and reperfusion injury

KW - neutrophils

KW - smooth muscle cells

UR - http://www.scopus.com/inward/record.url?scp=84873889667&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84873889667&partnerID=8YFLogxK

U2 - 10.1016/j.healun.2012.11.029

DO - 10.1016/j.healun.2012.11.029

M3 - Article

C2 - 23415317

AN - SCOPUS:84873889667

VL - 32

SP - 360

EP - 367

JO - Journal of Heart and Lung Transplantation

JF - Journal of Heart and Lung Transplantation

SN - 1053-2498

IS - 3

ER -