Allergic lung inflammation promotes atherosclerosis in apolipoprotein E-deficient mice

Abstract

Inflammation drives asthma and atherosclerosis. Clinical studies suggest that asthmatic patients have a high risk of atherosclerosis. Yet this hypothesis remains uncertain, given that Th2 imbalance causes asthma whereas Th1 immunity promotes atherosclerosis. In this study, chronic allergic lung inflammation (ALI) was induced in mice by ovalbumin sensitization and challenge. Acute ALI was induced in mice by ovalbumin and aluminum sensitization and ovalbumin challenge. Atherosclerosis was produced in apolipoprotein E-deficient (Apoe(-/-)) mice with a Western diet. When chronic ALI and atherosclerosis were produced simultaneously, ALI increased atherosclerotic lesion size, lesion inflammatory cell content, elastin fragmentation, smooth muscle cell (SMC) loss, lesion cell proliferation, and apoptosis. Production of acute ALI before atherogenesis did not affect lesion size, but increased atherosclerotic lesion CD4(+) T cells, lesion SMC loss, angiogenesis, and apoptosis. Production of acute ALI after atherogenesis also did not change atherosclerotic lesion area, but increased lesion elastin fragmentation, cell proliferation, and apoptosis. In mice with chronic ALI and diet-induced atherosclerosis, daily inhalation of a mast cell inhibitor or corticosteroid significantly reduced atherosclerotic lesion T-cell and mast cell contents, SMC loss, angiogenesis, and cell proliferation and apoptosis, although these drugs did not affect lesion area, compared with those that received vehicle treatment. In conclusion, both chronic and acute ALI promote atherogenesis or aortic lesion pathology, regardless whether ALI occurred before, after, or at the same time as atherogenesis. Antiasthmatic medication can efficiently mitigate atherosclerotic lesion pathology.

Figure 1

Chronic ALI promotes atherosclerosis in Apoe^−/− mice. A. Experimental protocol. Aortic arch atherosclerotic lesion area (B), Mac-2-positive macrophage contents (C), intima CD4⁺ T cell and lesion CD8⁺ T cell numbers (D), media elastin fragmentation grade (E), media SMC loss grade (F), Ki67⁺ proliferating cell numbers (G), and TUNEL-positive apoptotic cell numbers (H). BALF levels of IL5 (I), MCP-1 (J), total cell numbers (K), and macrophages, lymphocytes, and eosinophils (L). Representative data in panels C, E–H, and K are shown to the right. Scale: 200 μm.

Figure 2

Production of acute ALI promotes subsequent atherogenesis in Apoe^−/− mice. A. Experimental protocol. Aortic arch atherosclerotic lesion area (B), lesion total and intima CD4⁺ T cell numbers (C), media SMC loss grade (D), CD31⁺ microvessel numbers (E), and intimal TUNEL-positive apoptotic cell numbers (F). BALF total cell numbers (G) and macrophages, lymphocytes, and eosinophils (H). Representative data in panels D–G are shown to the right. Scale: 200 μm.

Figure 3

Production of acute ALI enhances pre-established atherosclerosis in Apoe^−/− mice. A. Experimental protocol. B. Aortic arch atherosclerotic lesion area. C. Lesion media elastin fragmentation grade, Ki67⁺ proliferating cell numbers, and TUNEL-positive apoptotic cell numbers. D. Serum IgE levels. E. Serum IL5, IL13, and eotaxin levels. F. BALF total cell numbers. G. BALF macrophages, lymphocytes, and eosinophils. H. BALF TNF-α, IL4, IL5, IL13, MCP-1, and eotaxin levels. Representative data in panel F are shown to the right. Scale: 200 μm.

Figure 4

Anti-allergic ketotifen and budesonide reduce atherosclerotic lesion pathologies in Apoe^−/− mice. A. Experimental protocol. Aortic arch atherosclerotic lesion area (B), lesion Mac-2-positive macrophage numbers, total and adventitia CD4⁺ T cells, total CD8⁺ T cells, and mast cells (C), media SMC loss grade (D), Ki67⁺ proliferating cells (E), lesion CD31⁺ microvessel numbers (F), and TUNEL-positive apoptotic cell numbers (G). Representative data in panels D and F are shown to the right. Scale: 200 μm.