title: Adventitial CXCL1/G-CSF expression in response to acute aortic dissection triggers local neutrophil recruitment and activation leading to aortic rupture.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: From the Division of Cardiology, Department of Medicine (A.A., J.E., T.K., Y.K., T.M., T.Y., K.I., X.Y., K.S. K.S., F.F., M.S.), Department of Pathology (M.S., Y.O.), Division of Endocrinology, Metabolism and Nephrology, Department of Medicine (R.S.-H.), and Department of Diagnostic Radiology (Y.Y.), Keio University School of Medicine, Tokyo, Japan; and Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (S.U.).
authors.forename: Atsushi
authors.initials: A
authors.lastname: Anzai
authors.affiliation: From the Division of Cardiology, Department of Medicine (A.A., J.E., T.K., Y.K., T.M., T.Y., K.I., X.Y., K.S. K.S., F.F., M.S.), Department of Pathology (M.S., Y.O.), Division of Endocrinology, Metabolism and Nephrology, Department of Medicine (R.S.-H.), and Department of Diagnostic Radiology (Y.Y.), Keio University School of Medicine, Tokyo, Japan; and Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (S.U.).
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shimoda
authors.affiliation: From the Division of Cardiology, Department of Medicine (A.A., J.E., T.K., Y.K., T.M., T.Y., K.I., X.Y., K.S. K.S., F.F., M.S.), Department of Pathology (M.S., Y.O.), Division of Endocrinology, Metabolism and Nephrology, Department of Medicine (R.S.-H.), and Department of Diagnostic Radiology (Y.Y.), Keio University School of Medicine, Tokyo, Japan; and Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (S.U.).
authors.forename: Jin
authors.initials: J
authors.lastname: Endo
authors.affiliation: From the Division of Cardiology, Department of Medicine (A.A., J.E., T.K., Y.K., T.M., T.Y., K.I., X.Y., K.S. K.S., F.F., M.S.), Department of Pathology (M.S., Y.O.), Division of Endocrinology, Metabolism and Nephrology, Department of Medicine (R.S.-H.), and Department of Diagnostic Radiology (Y.Y.), Keio University School of Medicine, Tokyo, Japan; and Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (S.U.).
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
authors.affiliation: From the Division of Cardiology, Department of Medicine (A.A., J.E., T.K., Y.K., T.M., T.Y., K.I., X.Y., K.S. K.S., F.F., M.S.), Department of Pathology (M.S., Y.O.), Division of Endocrinology, Metabolism and Nephrology, Department of Medicine (R.S.-H.), and Department of Diagnostic Radiology (Y.Y.), Keio University School of Medicine, Tokyo, Japan; and Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (S.U.).
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Katsumata
authors.affiliation: From the Division of Cardiology, Department of Medicine (A.A., J.E., T.K., Y.K., T.M., T.Y., K.I., X.Y., K.S. K.S., F.F., M.S.), Department of Pathology (M.S., Y.O.), Division of Endocrinology, Metabolism and Nephrology, Department of Medicine (R.S.-H.), and Department of Diagnostic Radiology (Y.Y.), Keio University School of Medicine, Tokyo, Japan; and Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (S.U.).
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Matsuhashi
authors.affiliation: From the Division of Cardiology, Department of Medicine (A.A., J.E., T.K., Y.K., T.M., T.Y., K.I., X.Y., K.S. K.S., F.F., M.S.), Department of Pathology (M.S., Y.O.), Division of Endocrinology, Metabolism and Nephrology, Department of Medicine (R.S.-H.), and Department of Diagnostic Radiology (Y.Y.), Keio University School of Medicine, Tokyo, Japan; and Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (S.U.).
authors.forename: Tsunehisa
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: From the Division of Cardiology, Department of Medicine (A.A., J.E., T.K., Y.K., T.M., T.Y., K.I., X.Y., K.S. K.S., F.F., M.S.), Department of Pathology (M.S., Y.O.), Division of Endocrinology, Metabolism and Nephrology, Department of Medicine (R.S.-H.), and Department of Diagnostic Radiology (Y.Y.), Keio University School of Medicine, Tokyo, Japan; and Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (S.U.).
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ito
authors.affiliation: From the Division of Cardiology, Department of Medicine (A.A., J.E., T.K., Y.K., T.M., T.Y., K.I., X.Y., K.S. K.S., F.F., M.S.), Department of Pathology (M.S., Y.O.), Division of Endocrinology, Metabolism and Nephrology, Department of Medicine (R.S.-H.), and Department of Diagnostic Radiology (Y.Y.), Keio University School of Medicine, Tokyo, Japan; and Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (S.U.).
authors.forename: Xiaoxiang
authors.initials: X
authors.lastname: Yan
authors.affiliation: From the Division of Cardiology, Department of Medicine (A.A., J.E., T.K., Y.K., T.M., T.Y., K.I., X.Y., K.S. K.S., F.F., M.S.), Department of Pathology (M.S., Y.O.), Division of Endocrinology, Metabolism and Nephrology, Department of Medicine (R.S.-H.), and Department of Diagnostic Radiology (Y.Y.), Keio University School of Medicine, Tokyo, Japan; and Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (S.U.).
authors.forename: Kosuke
authors.initials: K
authors.lastname: Shirakawa
authors.affiliation: From the Division of Cardiology, Department of Medicine (A.A., J.E., T.K., Y.K., T.M., T.Y., K.I., X.Y., K.S. K.S., F.F., M.S.), Department of Pathology (M.S., Y.O.), Division of Endocrinology, Metabolism and Nephrology, Department of Medicine (R.S.-H.), and Department of Diagnostic Radiology (Y.Y.), Keio University School of Medicine, Tokyo, Japan; and Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (S.U.).
authors.forename: Ryoko
authors.initials: R
authors.lastname: Shimizu-Hirota
authors.affiliation: From the Division of Cardiology, Department of Medicine (A.A., J.E., T.K., Y.K., T.M., T.Y., K.I., X.Y., K.S. K.S., F.F., M.S.), Department of Pathology (M.S., Y.O.), Division of Endocrinology, Metabolism and Nephrology, Department of Medicine (R.S.-H.), and Department of Diagnostic Radiology (Y.Y.), Keio University School of Medicine, Tokyo, Japan; and Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (S.U.).
authors.forename: Yoshitake
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: From the Division of Cardiology, Department of Medicine (A.A., J.E., T.K., Y.K., T.M., T.Y., K.I., X.Y., K.S. K.S., F.F., M.S.), Department of Pathology (M.S., Y.O.), Division of Endocrinology, Metabolism and Nephrology, Department of Medicine (R.S.-H.), and Department of Diagnostic Radiology (Y.Y.), Keio University School of Medicine, Tokyo, Japan; and Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (S.U.).
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ueha
authors.affiliation: From the Division of Cardiology, Department of Medicine (A.A., J.E., T.K., Y.K., T.M., T.Y., K.I., X.Y., K.S. K.S., F.F., M.S.), Department of Pathology (M.S., Y.O.), Division of Endocrinology, Metabolism and Nephrology, Department of Medicine (R.S.-H.), and Department of Diagnostic Radiology (Y.Y.), Keio University School of Medicine, Tokyo, Japan; and Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (S.U.).
authors.forename: Ken
authors.initials: K
authors.lastname: Shinmura
authors.affiliation: From the Division of Cardiology, Department of Medicine (A.A., J.E., T.K., Y.K., T.M., T.Y., K.I., X.Y., K.S. K.S., F.F., M.S.), Department of Pathology (M.S., Y.O.), Division of Endocrinology, Metabolism and Nephrology, Department of Medicine (R.S.-H.), and Department of Diagnostic Radiology (Y.Y.), Keio University School of Medicine, Tokyo, Japan; and Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (S.U.).
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: From the Division of Cardiology, Department of Medicine (A.A., J.E., T.K., Y.K., T.M., T.Y., K.I., X.Y., K.S. K.S., F.F., M.S.), Department of Pathology (M.S., Y.O.), Division of Endocrinology, Metabolism and Nephrology, Department of Medicine (R.S.-H.), and Department of Diagnostic Radiology (Y.Y.), Keio University School of Medicine, Tokyo, Japan; and Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (S.U.).
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
authors.affiliation: From the Division of Cardiology, Department of Medicine (A.A., J.E., T.K., Y.K., T.M., T.Y., K.I., X.Y., K.S. K.S., F.F., M.S.), Department of Pathology (M.S., Y.O.), Division of Endocrinology, Metabolism and Nephrology, Department of Medicine (R.S.-H.), and Department of Diagnostic Radiology (Y.Y.), Keio University School of Medicine, Tokyo, Japan; and Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (S.U.). msano@a8.keio.jp.
authors.forename: Motoaki
authors.initials: M
authors.lastname: Sano
mesh_terms: D000208:Acute Disease; D063194:Adventitia / Q000000981:diagnostic imaging / Q000378:metabolism*; D000368:Aged; D000629:Aminopropionitrile / Q000031:analogs & derivatives; D000784:Aortic Dissection / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D000804:Angiotensin II; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000000981:diagnostic imaging / Q000378:metabolism*; D017545:Aortic Aneurysm, Thoracic / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D001019:Aortic Rupture / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000517:prevention & control; D001027:Aortography; D054360:Chemokine CXCL1 / Q000378:metabolism*; D054377:Chemokine CXCL12 / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D004108:Dilatation, Pathologic; D004195:Disease Models, Animal; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000097:blood; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D018375:Neutrophil Activation / Q000187:drug effects; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism* / Q000637:transplantation; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; C508606:CXCL8 protein, human; D054360:Chemokine CXCL1; D054377:Chemokine CXCL12; C475895:Cxcl1 protein, mouse; C515256:Cxcl12 protein, mouse; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D016209:Interleukin-8; D023063:Receptors, Interleukin-8B; C577686:interleukin-6, mouse; D000804:Angiotensin II; C027243:beta-aminopropionitrile fumarate; D016179:Granulocyte Colony-Stimulating Factor; D000629:Aminopropionitrile
keywords: angiotensin II; aortic dissection; chemokines; inflammation; interleukin-6; neutrophils