Adventitial CXCL1/G-CSF Expression in Response to Acute Aortic Dissection Triggers Local Neutrophil Recruitment and Activation Leading to Aortic Rupture
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 for 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 approximately 70% of the mice died of aortic rupture. AAD triggered CXCL1 and granulocyte-colony stimulating factor (G-CSF) expression in the tunica adventitia of the dissected aorta, leading to elevation of circulating CXCL1/G-CSF 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 (IL)-6 expression. Neutrophils were 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/G-CSF 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.
- Received August 13, 2014.
- Revision received December 14, 2014.
- Accepted January 6, 2015.