Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in mice

Jiusong Sun, Galina K. Sukhova, Min Yang, Paul J. Wolters, Lindsey A. MacFarlane, Peter Libby, Chongxiu Sun, Yadong Zhang, Jian Liu, Terri L. Ennis, Rebecca Knispel, Wanfen Xiong, Robert W. Thompson, Bernard Timothy Baxter, Guo Ping Shi

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Abstract

Abdominal aortic aneurysm (AAA), an inflammatory disease, involves leukocyte recruitment, immune responses, inflammatory cytokine production, vascular remodeling, neovascularization, and vascular cell apoptosis, all of which contribute to aortic dilatation. This study demonstrates that mast cells, key participants in human allergic immunity, participate in AAA pathogenesis in mice. Mast cells were found to accumulate in murine AAA lesions. Mast cell-deficient KitW-sh/KitW-sh mice failed to develop AAA elicited by elastase perfusion or periaortic chemical injury. Kit W-sh/KitW-sh mice had reduced aortic expansion and internal elastic lamina degradation; decreased numbers of macrophages, CD3 + T lymphocytes, SMCs, apoptotic cells, and CD31+ microvessels; and decreased levels of aortic tissue IL-6 and IFN-γ. Activation of mast cells in WT mice via C48/80 injection resulted in enhanced AAA growth while mast cell stabilization with disodium cromoglycate diminished AAA formation. Mechanistic studies demonstrated that mast cells participated in angiogenesis, aortic SMC apoptosis, and matrix-degrading protease expression. Reconstitution of KitW-sh/KitW-sh mice with bone marrow-derived mast cells from WT or TNF-α-/- mice, but not from IL-6 -/- or IFN-γ-/- mice, caused susceptibility to AAA formation to be regained. These results demonstrate that mast cells participate in AAA pathogenesis in mice by releasing proinflammatory cytokines IL-6 and IFN-γ, which may induce aortic SMC apoptosis, matrix-degrading protease expression, and vascular wall remodeling, important hallmarks of arterial aneurysms.

Original languageEnglish (US)
Pages (from-to)3359-3368
Number of pages10
JournalJournal of Clinical Investigation
Volume117
Issue number11
DOIs
StatePublished - Nov 1 2007

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Pancreatic Elastase
Abdominal Aortic Aneurysm
Mast Cells
Apoptosis
Interleukin-6
Peptide Hydrolases
Cytokines
Cromolyn Sodium
Microvessels
Aneurysm
Blood Vessels
Dilatation
Immunity
Leukocytes
Perfusion
Bone Marrow
Macrophages
T-Lymphocytes
Injections
Wounds and Injuries

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Sun, J., Sukhova, G. K., Yang, M., Wolters, P. J., MacFarlane, L. A., Libby, P., ... Shi, G. P. (2007). Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in mice. Journal of Clinical Investigation, 117(11), 3359-3368. https://doi.org/10.1172/JCI31311

Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in mice. / Sun, Jiusong; Sukhova, Galina K.; Yang, Min; Wolters, Paul J.; MacFarlane, Lindsey A.; Libby, Peter; Sun, Chongxiu; Zhang, Yadong; Liu, Jian; Ennis, Terri L.; Knispel, Rebecca; Xiong, Wanfen; Thompson, Robert W.; Baxter, Bernard Timothy; Shi, Guo Ping.

In: Journal of Clinical Investigation, Vol. 117, No. 11, 01.11.2007, p. 3359-3368.

Research output: Contribution to journalArticle

Sun, J, Sukhova, GK, Yang, M, Wolters, PJ, MacFarlane, LA, Libby, P, Sun, C, Zhang, Y, Liu, J, Ennis, TL, Knispel, R, Xiong, W, Thompson, RW, Baxter, BT & Shi, GP 2007, 'Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in mice', Journal of Clinical Investigation, vol. 117, no. 11, pp. 3359-3368. https://doi.org/10.1172/JCI31311
Sun, Jiusong ; Sukhova, Galina K. ; Yang, Min ; Wolters, Paul J. ; MacFarlane, Lindsey A. ; Libby, Peter ; Sun, Chongxiu ; Zhang, Yadong ; Liu, Jian ; Ennis, Terri L. ; Knispel, Rebecca ; Xiong, Wanfen ; Thompson, Robert W. ; Baxter, Bernard Timothy ; Shi, Guo Ping. / Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in mice. In: Journal of Clinical Investigation. 2007 ; Vol. 117, No. 11. pp. 3359-3368.
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abstract = "Abdominal aortic aneurysm (AAA), an inflammatory disease, involves leukocyte recruitment, immune responses, inflammatory cytokine production, vascular remodeling, neovascularization, and vascular cell apoptosis, all of which contribute to aortic dilatation. This study demonstrates that mast cells, key participants in human allergic immunity, participate in AAA pathogenesis in mice. Mast cells were found to accumulate in murine AAA lesions. Mast cell-deficient KitW-sh/KitW-sh mice failed to develop AAA elicited by elastase perfusion or periaortic chemical injury. Kit W-sh/KitW-sh mice had reduced aortic expansion and internal elastic lamina degradation; decreased numbers of macrophages, CD3 + T lymphocytes, SMCs, apoptotic cells, and CD31+ microvessels; and decreased levels of aortic tissue IL-6 and IFN-γ. Activation of mast cells in WT mice via C48/80 injection resulted in enhanced AAA growth while mast cell stabilization with disodium cromoglycate diminished AAA formation. Mechanistic studies demonstrated that mast cells participated in angiogenesis, aortic SMC apoptosis, and matrix-degrading protease expression. Reconstitution of KitW-sh/KitW-sh mice with bone marrow-derived mast cells from WT or TNF-α-/- mice, but not from IL-6 -/- or IFN-γ-/- mice, caused susceptibility to AAA formation to be regained. These results demonstrate that mast cells participate in AAA pathogenesis in mice by releasing proinflammatory cytokines IL-6 and IFN-γ, which may induce aortic SMC apoptosis, matrix-degrading protease expression, and vascular wall remodeling, important hallmarks of arterial aneurysms.",
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AU - Sun, Jiusong

AU - Sukhova, Galina K.

AU - Yang, Min

AU - Wolters, Paul J.

AU - MacFarlane, Lindsey A.

AU - Libby, Peter

AU - Sun, Chongxiu

AU - Zhang, Yadong

AU - Liu, Jian

AU - Ennis, Terri L.

AU - Knispel, Rebecca

AU - Xiong, Wanfen

AU - Thompson, Robert W.

AU - Baxter, Bernard Timothy

AU - Shi, Guo Ping

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N2 - Abdominal aortic aneurysm (AAA), an inflammatory disease, involves leukocyte recruitment, immune responses, inflammatory cytokine production, vascular remodeling, neovascularization, and vascular cell apoptosis, all of which contribute to aortic dilatation. This study demonstrates that mast cells, key participants in human allergic immunity, participate in AAA pathogenesis in mice. Mast cells were found to accumulate in murine AAA lesions. Mast cell-deficient KitW-sh/KitW-sh mice failed to develop AAA elicited by elastase perfusion or periaortic chemical injury. Kit W-sh/KitW-sh mice had reduced aortic expansion and internal elastic lamina degradation; decreased numbers of macrophages, CD3 + T lymphocytes, SMCs, apoptotic cells, and CD31+ microvessels; and decreased levels of aortic tissue IL-6 and IFN-γ. Activation of mast cells in WT mice via C48/80 injection resulted in enhanced AAA growth while mast cell stabilization with disodium cromoglycate diminished AAA formation. Mechanistic studies demonstrated that mast cells participated in angiogenesis, aortic SMC apoptosis, and matrix-degrading protease expression. Reconstitution of KitW-sh/KitW-sh mice with bone marrow-derived mast cells from WT or TNF-α-/- mice, but not from IL-6 -/- or IFN-γ-/- mice, caused susceptibility to AAA formation to be regained. These results demonstrate that mast cells participate in AAA pathogenesis in mice by releasing proinflammatory cytokines IL-6 and IFN-γ, which may induce aortic SMC apoptosis, matrix-degrading protease expression, and vascular wall remodeling, important hallmarks of arterial aneurysms.

AB - Abdominal aortic aneurysm (AAA), an inflammatory disease, involves leukocyte recruitment, immune responses, inflammatory cytokine production, vascular remodeling, neovascularization, and vascular cell apoptosis, all of which contribute to aortic dilatation. This study demonstrates that mast cells, key participants in human allergic immunity, participate in AAA pathogenesis in mice. Mast cells were found to accumulate in murine AAA lesions. Mast cell-deficient KitW-sh/KitW-sh mice failed to develop AAA elicited by elastase perfusion or periaortic chemical injury. Kit W-sh/KitW-sh mice had reduced aortic expansion and internal elastic lamina degradation; decreased numbers of macrophages, CD3 + T lymphocytes, SMCs, apoptotic cells, and CD31+ microvessels; and decreased levels of aortic tissue IL-6 and IFN-γ. Activation of mast cells in WT mice via C48/80 injection resulted in enhanced AAA growth while mast cell stabilization with disodium cromoglycate diminished AAA formation. Mechanistic studies demonstrated that mast cells participated in angiogenesis, aortic SMC apoptosis, and matrix-degrading protease expression. Reconstitution of KitW-sh/KitW-sh mice with bone marrow-derived mast cells from WT or TNF-α-/- mice, but not from IL-6 -/- or IFN-γ-/- mice, caused susceptibility to AAA formation to be regained. These results demonstrate that mast cells participate in AAA pathogenesis in mice by releasing proinflammatory cytokines IL-6 and IFN-γ, which may induce aortic SMC apoptosis, matrix-degrading protease expression, and vascular wall remodeling, important hallmarks of arterial aneurysms.

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