Adventitial CXCL1/G-CSF expression in response to acute aortic dissection triggers local neutrophil recruitment and activation leading to aortic rupture

Atsushi Anzai, Masayuki Shimoda, Jin Endo, Takashi Kohno, Yoshinori Katsumata, Tomohiro Matsuhashi, Tsunehisa Yamamoto, Kentaro Ito, Xiaoxiang Yan, Kosuke Shirakawa, Ryoko Shimizu, Yoshitake Yamada, Satoshi Ueha, Ken Shinmura, Yasunori Okada, Keiichi Fukuda, Motoaki Sano

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Rationale: In-hospital outcomes are generally acceptable in patients with type B dissection; however, some patients present with undesirable complications, such as aortic expansion and rupture. Excessive inflammation is an independent predictor of adverse clinical outcomes. Objective: We have investigated the underlying mechanisms of catastrophic complications after acute aortic dissection (AAD) in mice. Methods and Results: When angiotensin II was administered in lysyl oxidase inhibitor-preconditioned mice, AAD emerged within 24 hours. The dissection was initiated at the proximal site of the descending thoracic aorta and propagated distally into an abdominal site. Dissection of the aorta caused dilatation, and ≈70% of the mice died of aortic rupture. AAD triggered CXCL1 and granulocyte-colony stimulating factor expression in the tunica adventitia of the dissected aorta, leading to elevation of circulating CXCL1/granulocyte-colony stimulating factor levels. Bone marrow CXCL12 was reduced. These chemokine changes facilitated neutrophil egress from bone marrow and infiltration into the aortic adventitia. Interference of CXCL1 function using an anti-CXCR2 antibody reduced neutrophil accumulation and limited aortic rupture post AAD. The tunica adventitia of the expanded dissected aorta demonstrated high levels of interleukin-6 (IL-6) expression. Neutrophils were the major sources of IL-6, and CXCR2 neutralization significantly reduced local and systemic levels of IL-6. Furthermore, disruption of IL-6 effectively suppressed dilatation and rupture of the dissected aorta without any influence on the incidence of AAD and neutrophil mobilization. Conclusions: Adventitial CXCL1/granulocyte-colony stimulating factor expression in response to AAD triggers local neutrophil recruitment and activation. This leads to adventitial inflammation via IL-6 and results in aortic expansion and rupture.

Original languageEnglish
Pages (from-to)612-623
Number of pages12
JournalCirculation Research
Volume116
Issue number4
DOIs
Publication statusPublished - 2015 Feb 13

Fingerprint

Aortic Rupture
Adventitia
Neutrophil Activation
Neutrophil Infiltration
Granulocyte Colony-Stimulating Factor
Dissection
Interleukin-6
Aorta
Neutrophils
Thoracic Aorta
Dilatation
Bone Marrow
Protein-Lysine 6-Oxidase
Inflammation
Chemokines
Angiotensin II
Rupture
Anti-Idiotypic Antibodies

Keywords

  • Angiotensin II
  • Aortic dissection
  • Chemokines
  • Inflammation
  • Interleukin-6
  • Neutrophils

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

Cite this

Adventitial CXCL1/G-CSF expression in response to acute aortic dissection triggers local neutrophil recruitment and activation leading to aortic rupture. / Anzai, Atsushi; Shimoda, Masayuki; Endo, Jin; Kohno, Takashi; Katsumata, Yoshinori; Matsuhashi, Tomohiro; Yamamoto, Tsunehisa; Ito, Kentaro; Yan, Xiaoxiang; Shirakawa, Kosuke; Shimizu, Ryoko; Yamada, Yoshitake; Ueha, Satoshi; Shinmura, Ken; Okada, Yasunori; Fukuda, Keiichi; Sano, Motoaki.

In: Circulation Research, Vol. 116, No. 4, 13.02.2015, p. 612-623.

Research output: Contribution to journalArticle

Anzai, Atsushi ; Shimoda, Masayuki ; Endo, Jin ; Kohno, Takashi ; Katsumata, Yoshinori ; Matsuhashi, Tomohiro ; Yamamoto, Tsunehisa ; Ito, Kentaro ; Yan, Xiaoxiang ; Shirakawa, Kosuke ; Shimizu, Ryoko ; Yamada, Yoshitake ; Ueha, Satoshi ; Shinmura, Ken ; Okada, Yasunori ; Fukuda, Keiichi ; Sano, Motoaki. / Adventitial CXCL1/G-CSF expression in response to acute aortic dissection triggers local neutrophil recruitment and activation leading to aortic rupture. In: Circulation Research. 2015 ; Vol. 116, No. 4. pp. 612-623.
@article{c221d15814f1465aaac4505e6f752681,
title = "Adventitial CXCL1/G-CSF expression in response to acute aortic dissection triggers local neutrophil recruitment and activation leading to aortic rupture",
abstract = "Rationale: In-hospital outcomes are generally acceptable in patients with type B dissection; however, some patients present with undesirable complications, such as aortic expansion and rupture. Excessive inflammation is an independent predictor of adverse clinical outcomes. Objective: We have investigated the underlying mechanisms of catastrophic complications after acute aortic dissection (AAD) in mice. Methods and Results: When angiotensin II was administered in lysyl oxidase inhibitor-preconditioned mice, AAD emerged within 24 hours. The dissection was initiated at the proximal site of the descending thoracic aorta and propagated distally into an abdominal site. Dissection of the aorta caused dilatation, and ≈70{\%} of the mice died of aortic rupture. AAD triggered CXCL1 and granulocyte-colony stimulating factor expression in the tunica adventitia of the dissected aorta, leading to elevation of circulating CXCL1/granulocyte-colony stimulating factor levels. Bone marrow CXCL12 was reduced. These chemokine changes facilitated neutrophil egress from bone marrow and infiltration into the aortic adventitia. Interference of CXCL1 function using an anti-CXCR2 antibody reduced neutrophil accumulation and limited aortic rupture post AAD. The tunica adventitia of the expanded dissected aorta demonstrated high levels of interleukin-6 (IL-6) expression. Neutrophils were the major sources of IL-6, and CXCR2 neutralization significantly reduced local and systemic levels of IL-6. Furthermore, disruption of IL-6 effectively suppressed dilatation and rupture of the dissected aorta without any influence on the incidence of AAD and neutrophil mobilization. Conclusions: Adventitial CXCL1/granulocyte-colony stimulating factor expression in response to AAD triggers local neutrophil recruitment and activation. This leads to adventitial inflammation via IL-6 and results in aortic expansion and rupture.",
keywords = "Angiotensin II, Aortic dissection, Chemokines, Inflammation, Interleukin-6, Neutrophils",
author = "Atsushi Anzai and Masayuki Shimoda and Jin Endo and Takashi Kohno and Yoshinori Katsumata and Tomohiro Matsuhashi and Tsunehisa Yamamoto and Kentaro Ito and Xiaoxiang Yan and Kosuke Shirakawa and Ryoko Shimizu and Yoshitake Yamada and Satoshi Ueha and Ken Shinmura and Yasunori Okada and Keiichi Fukuda and Motoaki Sano",
year = "2015",
month = "2",
day = "13",
doi = "10.1161/CIRCRESAHA.116.304918",
language = "English",
volume = "116",
pages = "612--623",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "4",

}

TY - JOUR

T1 - Adventitial CXCL1/G-CSF expression in response to acute aortic dissection triggers local neutrophil recruitment and activation leading to aortic rupture

AU - Anzai, Atsushi

AU - Shimoda, Masayuki

AU - Endo, Jin

AU - Kohno, Takashi

AU - Katsumata, Yoshinori

AU - Matsuhashi, Tomohiro

AU - Yamamoto, Tsunehisa

AU - Ito, Kentaro

AU - Yan, Xiaoxiang

AU - Shirakawa, Kosuke

AU - Shimizu, Ryoko

AU - Yamada, Yoshitake

AU - Ueha, Satoshi

AU - Shinmura, Ken

AU - Okada, Yasunori

AU - Fukuda, Keiichi

AU - Sano, Motoaki

PY - 2015/2/13

Y1 - 2015/2/13

N2 - Rationale: In-hospital outcomes are generally acceptable in patients with type B dissection; however, some patients present with undesirable complications, such as aortic expansion and rupture. Excessive inflammation is an independent predictor of adverse clinical outcomes. Objective: We have investigated the underlying mechanisms of catastrophic complications after acute aortic dissection (AAD) in mice. Methods and Results: When angiotensin II was administered in lysyl oxidase inhibitor-preconditioned mice, AAD emerged within 24 hours. The dissection was initiated at the proximal site of the descending thoracic aorta and propagated distally into an abdominal site. Dissection of the aorta caused dilatation, and ≈70% of the mice died of aortic rupture. AAD triggered CXCL1 and granulocyte-colony stimulating factor expression in the tunica adventitia of the dissected aorta, leading to elevation of circulating CXCL1/granulocyte-colony stimulating factor levels. Bone marrow CXCL12 was reduced. These chemokine changes facilitated neutrophil egress from bone marrow and infiltration into the aortic adventitia. Interference of CXCL1 function using an anti-CXCR2 antibody reduced neutrophil accumulation and limited aortic rupture post AAD. The tunica adventitia of the expanded dissected aorta demonstrated high levels of interleukin-6 (IL-6) expression. Neutrophils were the major sources of IL-6, and CXCR2 neutralization significantly reduced local and systemic levels of IL-6. Furthermore, disruption of IL-6 effectively suppressed dilatation and rupture of the dissected aorta without any influence on the incidence of AAD and neutrophil mobilization. Conclusions: Adventitial CXCL1/granulocyte-colony stimulating factor expression in response to AAD triggers local neutrophil recruitment and activation. This leads to adventitial inflammation via IL-6 and results in aortic expansion and rupture.

AB - Rationale: In-hospital outcomes are generally acceptable in patients with type B dissection; however, some patients present with undesirable complications, such as aortic expansion and rupture. Excessive inflammation is an independent predictor of adverse clinical outcomes. Objective: We have investigated the underlying mechanisms of catastrophic complications after acute aortic dissection (AAD) in mice. Methods and Results: When angiotensin II was administered in lysyl oxidase inhibitor-preconditioned mice, AAD emerged within 24 hours. The dissection was initiated at the proximal site of the descending thoracic aorta and propagated distally into an abdominal site. Dissection of the aorta caused dilatation, and ≈70% of the mice died of aortic rupture. AAD triggered CXCL1 and granulocyte-colony stimulating factor expression in the tunica adventitia of the dissected aorta, leading to elevation of circulating CXCL1/granulocyte-colony stimulating factor levels. Bone marrow CXCL12 was reduced. These chemokine changes facilitated neutrophil egress from bone marrow and infiltration into the aortic adventitia. Interference of CXCL1 function using an anti-CXCR2 antibody reduced neutrophil accumulation and limited aortic rupture post AAD. The tunica adventitia of the expanded dissected aorta demonstrated high levels of interleukin-6 (IL-6) expression. Neutrophils were the major sources of IL-6, and CXCR2 neutralization significantly reduced local and systemic levels of IL-6. Furthermore, disruption of IL-6 effectively suppressed dilatation and rupture of the dissected aorta without any influence on the incidence of AAD and neutrophil mobilization. Conclusions: Adventitial CXCL1/granulocyte-colony stimulating factor expression in response to AAD triggers local neutrophil recruitment and activation. This leads to adventitial inflammation via IL-6 and results in aortic expansion and rupture.

KW - Angiotensin II

KW - Aortic dissection

KW - Chemokines

KW - Inflammation

KW - Interleukin-6

KW - Neutrophils

UR - http://www.scopus.com/inward/record.url?scp=84924234012&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84924234012&partnerID=8YFLogxK

U2 - 10.1161/CIRCRESAHA.116.304918

DO - 10.1161/CIRCRESAHA.116.304918

M3 - Article

VL - 116

SP - 612

EP - 623

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 4

ER -