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Interaction between allergic asthma and atherosclerosis

  • Cong-Lin Liu
    Affiliations
    Department of Cardiology, Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass
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  • Jin-Ying Zhang
    Affiliations
    Department of Cardiology, Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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  • Guo-Ping Shi
    Correspondence
    Reprint requests: Guo-Ping Shi, Cardiovascular Medicine, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, NRB-7, Boston, MA 02115
    Affiliations
    Department of Cardiology, Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass
    Search for articles by this author
Published:October 06, 2015DOI:https://doi.org/10.1016/j.trsl.2015.09.009
      Prior studies have established an essential role of mast cells in allergic asthma and atherosclerosis. Mast cell deficiency or inactivation protects mice from allergen-induced airway hyper-responsiveness and diet-induced atherosclerosis, suggesting that mast cells share pathologic activities in both diseases. Allergic asthma and atherosclerosis are inflammatory diseases that contain similar sets of elevated numbers of inflammatory cells in addition to mast cells in the airway and arterial wall, such as macrophages, monocytes, T cells, eosinophils, and smooth muscle cells. Emerging evidence from experimental models and human studies points to a potential interaction between the 2 seemingly unrelated diseases. Patients or mice with allergic asthma have a high risk of developing atherosclerosis or vice versa, despite the fact that asthma is a T-helper (Th)2–oriented disease, whereas Th1 immunity promotes atherosclerosis. In addition to the preferred Th1/Th2 responses that may differentiate the 2 diseases, mast cells and many other inflammatory cells also contribute to their pathogenesis by more than just T cell immunity. Here, we summarize the different roles of airway and arterial wall inflammatory cells and vascular cells in asthma and atherosclerosis and propose an interaction between the 2 diseases, although limited investigations are available to delineate the molecular and cellular mechanisms by which 1 disease increases the risk of the other. Results from mouse allergic asthma and atherosclerosis models and from human population studies lead to the hypothesis that patients with atherosclerosis may benefit from antiasthmatic medications or that the therapeutic regimens targeting atherosclerosis may also alleviate allergic asthma.

      Abbreviations:

      BAL (bronchoalveolar lavage), LDL (low-density lipoprotein), SMC (smooth muscle cell), TNF- (tumor necrosis factor-), LDLr (LDL receptor), Apoe (apolipoprotein E), OVA (ovalbumin), IMT (intima-media thickness), SMCs (smooth muscle cells), CI (confidence interval), OR (odds ratio), SUVmax (maximum standardized uptake value), MHC-I (major histocompatibility complex class-I), CHD (coronary heart disease), HDM (House dust mite), mMCP-6 (Mouse mast cell protease-6), MCP-1 (monocyte chemoattractant protein-1), PLA2 (phospholipase A2), COX-2 (cyclooxygenase-2), NF-B (nuclear factor-B), AP-1 (activator protein-1), RANTES (regulated on activation, normal T cell expressed and secreted), CCR2/CCL2 (chemokine (C-C Motif) Receptor 2/chemokine (C-C motif) ligand 2), PECAM-1 (platelet endothelial cell adhesion molecule-1), MCP-1 (monocyte chemoattractant protein-1), DRA (dust mite (Dermatophagoides farinae), ragweed, and Aspergillus sp.), LPS (lipopolysaccharide), GSK (glycogen synthase kinase), STAT-3 (signal transducer and Activator of transcription-3), CXCL4 (CXC chemokine ligand 4), ACT (asthma control test), SNPs (single nucleotide polymorphisms), GATA3 (GATA binding protein 3), Treg (regulatory T cell), CADs (coronary artery diseases), miRs (MicroRNAs), NOR-1 (neuronderived orphan receptor-1), 5-LO (5-lipoxygenase), LTA4 (leukotriene A4), GM-CSF (granulocyte-macrophage colony-stimulating factor), FLAP (5-LO–activating protein), HDL-C (high-density lipoprotein cholesterol), VLDL (very low-density lipoprotein)
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      References

        • McFadden Jr., E.R.
        • Gilbert I.A.
        Asthma.
        N Engl J Med. 1992; 327: 1928-1937
        • Lloyd C.M.
        • Saglani S.
        T cells in asthma: influences of genetics, environment, and T-cell plasticity.
        J Allergy Clin Immunol. 2013; 131 (quiz 75): 1267-1274
        • Busse W.W.
        • Lemanske Jr., R.F.
        Asthma.
        N Engl J Med. 2001; 344: 350-362
        • Libby P.
        • Ridker P.M.
        • Hansson G.K.
        Progress and challenges in translating the biology of atherosclerosis.
        Nature. 2011; 473: 317-325
        • Hansson G.K.
        Inflammation, atherosclerosis, and coronary artery disease.
        N Engl J Med. 2005; 352: 1685-1695
        • Stary H.C.
        • Chandler A.B.
        • Dinsmore R.E.
        • et al.
        A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association.
        Circulation. 1995; 92: 1355-1374
        • Weber C.
        • Zernecke A.
        • Libby P.
        The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models.
        Nat Rev Immunol. 2008; 8: 802-815
        • Libby P.
        Inflammation in atherosclerosis.
        Nature. 2002; 420: 868-874
        • Pappas K.
        • Papaioannou A.I.
        • Kostikas K.
        • Tzanakis N.
        The role of macrophages in obstructive airways disease: chronic obstructive pulmonary disease and asthma.
        Cytokine. 2013; 64: 613-625
        • Balhara J.
        • Gounni A.S.
        The alveolar macrophages in asthma: a double-edged sword.
        Mucosal Immunol. 2012; 5: 605-609
        • Shi G.P.
        • Bot I.
        • Kovanen P.T.
        Mast cells in human and experimental cardiometabolic diseases.
        Nat Rev Cardiol. 2015; 12: 643-658
        • Moore K.J.
        • Tabas I.
        Macrophages in the pathogenesis of atherosclerosis.
        Cell. 2011; 145: 341-355
        • Ait-Oufella H.
        • Sage A.P.
        • Mallat Z.
        • Tedgui A.
        Adaptive (T and B cells) immunity and control by dendritic cells in atherosclerosis.
        Circ Res. 2014; 114: 1640-1660
        • Lei Y.
        • Gregory J.A.
        • Nilsson G.P.
        • Adner M.
        Insights into mast cell functions in asthma using mouse models.
        Pulm Pharmacol Ther. 2013; 26: 532-539
        • Galli S.J.
        • Tsai M.
        IgE and mast cells in allergic disease.
        Nat Med. 2012; 18: 693-704
        • Aubier M.
        • Neukirch C.
        • Peiffer C.
        • Melac M.
        Effect of cetirizine on bronchial hyperresponsiveness in patients with seasonal allergic rhinitis and asthma.
        Allergy. 2001; 56: 35-42
        • Humbert M.
        • Busse W.
        • Hanania N.A.
        • et al.
        Omalizumab in asthma: an update on recent developments.
        J Allergy Clin Immunol Pract. 2014; 2: 525-536.e1
        • Cairns A.
        • Constantinides P.
        Mast cells in human atherosclerosis.
        Science. 1954; 120: 31-32
        • Kokkonen J.O.
        • Kovanen P.T.
        Low density lipoprotein degradation by rat mast cells. Demonstration of extracellular proteolysis caused by mast cell granules.
        J Biol Chem. 1985; 260: 14756-14763
        • Judstrom I.
        • Jukkola H.
        • Metso J.
        • Jauhiainen M.
        • Kovanen P.T.
        • Lee-Rueckert M.
        Mast cell-dependent proteolytic modification of HDL particles during anaphylactic shock in the mouse reduces their ability to induce cholesterol efflux from macrophage foam cells ex vivo.
        Atherosclerosis. 2010; 208: 148-154
        • Johnson J.L.
        • Jackson C.L.
        • Angelini G.D.
        • George S.J.
        Activation of matrix-degrading metalloproteinases by mast cell proteases in atherosclerotic plaques.
        Arterioscler Thromb Vasc Biol. 1998; 18: 1707-1715
        • Steffel J.
        • Akhmedov A.
        • Greutert H.
        • et al.
        Histamine induces tissue factor expression: implications for acute coronary syndromes.
        Circulation. 2005; 112: 341-349
        • Kunder C.A.
        • St John A.L.
        • Abraham S.N.
        Mast cell modulation of the vascular and lymphatic endothelium.
        Blood. 2011; 118: 5383-5393
        • Bot I.
        • de Jager S.C.
        • Zernecke A.
        • et al.
        Perivascular mast cells promote atherogenesis and induce plaque destabilization in apolipoprotein E-deficient mice.
        Circulation. 2007; 115: 2516-2525
        • Heikkila H.M.
        • Latti S.
        • Leskinen M.J.
        • et al.
        Activated mast cells induce endothelial cell apoptosis by a combined action of chymase and tumor necrosis factor-alpha.
        Arterioscler Thromb Vasc Biol. 2008; 28: 309-314
        • Leskinen M.J.
        • Lindstedt K.A.
        • Wang Y.
        • Kovanen P.T.
        Mast cell chymase induces smooth muscle cell apoptosis by a mechanism involving fibronectin degradation and disruption of focal adhesions.
        Arterioscler Thromb Vasc Biol. 2003; 23: 238-243
        • Sun J.
        • Sukhova G.K.
        • Wolters P.J.
        • et al.
        Mast cells promote atherosclerosis by releasing proinflammatory cytokines.
        Nat Med. 2007; 13: 719-724
        • Wang J.
        • Sjoberg S.
        • Tia V.
        • et al.
        Pharmaceutical stabilization of mast cells attenuates experimental atherogenesis in low-density lipoprotein receptor-deficient mice.
        Atherosclerosis. 2013; 229: 304-309
        • Heikkila H.M.
        • Trosien J.
        • Metso J.
        • et al.
        Mast cells promote atherosclerosis by inducing both an atherogenic lipid profile and vascular inflammation.
        J Cell Biochem. 2010; 109: 615-623
        • Tang Y.L.
        • Yang Y.Z.
        • Wang S.
        • et al.
        Mast cell degranulator compound 48-80 promotes atherosclerotic plaque in apolipoprotein E knockout mice with perivascular common carotid collar placement.
        Chin Med J (Engl). 2009; 122: 319-325
        • Zhi X.
        • Xu C.
        • Zhang H.
        • et al.
        Tryptase promotes atherosclerotic plaque haemorrhage in ApoE-/- mice.
        PLoS One. 2013; 8: e60960
        • Bot I.
        • Bot M.
        • van Heiningen S.H.
        • et al.
        Mast cell chymase inhibition reduces atherosclerotic plaque progression and improves plaque stability in ApoE-/- mice.
        Cardiovasc Res. 2011; 89: 244-252
        • Willems S.
        • Vink A.
        • Bot I.
        • et al.
        Mast cells in human carotid atherosclerotic plaques are associated with intraplaque microvessel density and the occurrence of future cardiovascular events.
        Eur Heart J. 2013; 34: 3699-3706
        • Ramalho L.S.
        • Oliveira L.F.
        • Cavellani C.L.
        • et al.
        Role of mast cell chymase and tryptase in the progression of atherosclerosis: study in 44 autopsied cases.
        Ann Diagn Pathol. 2013; 17: 28-31
        • Pastorello E.A.
        • Morici N.
        • Farioli L.
        • et al.
        Serum tryptase: a new biomarker in patients with acute coronary syndrome?.
        Int Arch Allergy Immunol. 2014; 164: 97-105
        • Wang J.
        • Cheng X.
        • Xiang M.X.
        • et al.
        IgE stimulates human and mouse arterial cell apoptosis and cytokine expression and promotes atherogenesis in Apoe-/- mice.
        J Clin Invest. 2011; 121: 3564-3577
        • Mayr S.I.
        • Zuberi R.I.
        • Zhang M.
        • et al.
        IgE-dependent mast cell activation potentiates airway responses in murine asthma models.
        J Immunol. 2002; 169: 2061-2068
        • Wang L.
        • Gao S.
        • Xu W.
        • et al.
        Allergic asthma accelerates atherosclerosis dependent on Th2 and Th17 in apolipoprotein E deficient mice.
        J Mol Cell Cardiol. 2014; 72: 20-27
        • Onufrak S.
        • Abramson J.
        • Vaccarino V.
        Adult-onset asthma is associated with increased carotid atherosclerosis among women in the Atherosclerosis Risk in Communities (ARIC) study.
        Atherosclerosis. 2007; 195: 129-137
        • Knoflach M.
        • Kiechl S.
        • Mayr A.
        • et al.
        Allergic rhinitis, asthma, and atherosclerosis in the Bruneck and ARMY studies.
        Arch Intern Med. 2005; 165: 2521-2526
        • Iribarren C.
        • Tolstykh I.V.
        • Eisner M.D.
        Are patients with asthma at increased risk of coronary heart disease?.
        Int J Epidemiol. 2004; 33: 743-748
        • Rudd J.H.
        • Myers K.S.
        • Bansilal S.
        • et al.
        Atherosclerosis inflammation imaging with 18F-FDG PET: carotid, iliac, and femoral uptake reproducibility, quantification methods, and recommendations.
        J Nucl Med. 2008; 49: 871-878
        • Vijayakumar J.
        • Subramanian S.
        • Singh P.
        • et al.
        Arterial inflammation in bronchial asthma.
        J Nucl Cardiol. 2013; 20: 385-395
        • Schanen J.G.
        • Iribarren C.
        • Shahar E.
        • et al.
        Asthma and incident cardiovascular disease: the Atherosclerosis Risk in Communities Study.
        Thorax. 2005; 60: 633-638
        • Zahran H.S.
        • Bailey C.
        Factors associated with asthma prevalence among racial and ethnic groups–United States, 2009-2010 behavioral risk factor surveillance system.
        J Asthma. 2013; 50: 583-589
        • Budoff M.J.
        • Yang T.P.
        • Shavelle R.M.
        • et al.
        Ethnic differences in coronary atherosclerosis.
        J Am Coll Cardiol. 2002; 39: 408-412
        • Donohue K.M.
        • Hoffman E.A.
        • Baumhauer H.
        • et al.
        Asthma and lung structure on computed tomography: the Multi-Ethnic Study of Atherosclerosis Lung Study.
        J Allergy Clin Immunol. 2013; 131: 361-368.e1–11
        • Jaakkola U.
        • Kakko T.
        • Juonala M.
        • et al.
        Neuropeptide Y polymorphism increases the risk for asthma in overweight subjects; protection from atherosclerosis in asthmatic subjects–the cardiovascular risk in young Finns study.
        Neuropeptides. 2012; 46: 321-328
        • Otsuki M.
        • Miyatake A.
        • Fujita K.
        • et al.
        Reduced carotid atherosclerosis in asthmatic patients treated with inhaled corticosteroids.
        Eur Respir J. 2010; 36: 503-508
        • Elias J.A.
        • Lee C.G.
        • Zheng T.
        • et al.
        New insights into the pathogenesis of asthma.
        J Clin Invest. 2003; 111: 291-297
        • Galli S.J.
        • Nakae S.
        • Tsai M.
        Mast cells in the development of adaptive immune responses.
        Nat Immunol. 2005; 6: 135-142
        • Li S.
        • Aliyeva M.
        • Daphtary N.
        • et al.
        Antigen-induced mast cell expansion and bronchoconstriction in a mouse model of asthma.
        Am J Physiol Lung Cell Mol Physiol. 2014; 306: L196-L206
        • Hong G.U.
        • Kim N.G.
        • Kim T.J.
        • Ro J.Y.
        CD1d expressed in mast cell surface enhances IgE production in B cells by up-regulating CD40L expression and mediator release in allergic asthma in mice.
        Cell Signal. 2014; 26: 1105-1117
        • Hong G.U.
        • Lim J.Y.
        • Kim N.G.
        • et al.
        IgE and IgA produced by OX40-OX40L or CD40-CD40L interaction in B cells-mast cells re-activate FcepsilonRI or FcalphaRI on mast cells in mouse allergic asthma.
        Eur J Pharmacol. 2015; 754: 199-210
        • Abdelmotelb A.M.
        • Rose-Zerilli M.J.
        • Barton S.J.
        • et al.
        Alpha-tryptase gene variation is associated with levels of circulating IgE and lung function in asthma.
        Clin Exp Allergy. 2014; 44: 822-830
        • Pejler G.
        • Abrink M.
        • Ringvall M.
        • Wernersson S.
        Mast cell proteases.
        Adv Immunol. 2007; 95: 167-255
        • Cui Y.
        • Dahlin J.S.
        • Feinstein R.
        • et al.
        Mouse mast cell protease-6 and MHC are involved in the development of experimental asthma.
        J Immunol. 2014; 193: 4783-4789
        • Maryanoff B.E.
        • de Garavilla L.
        • Greco M.N.
        • et al.
        Dual inhibition of cathepsin G and chymase is effective in animal models of pulmonary inflammation.
        Am J Respir Crit Care Med. 2010; 181: 247-253
        • Smith D.D.
        • Tan X.
        • Raveendran V.V.
        • et al.
        Mast cell deficiency attenuates progression of atherosclerosis and hepatic steatosis in apolipoprotein E-null mice.
        Am J Physiol Heart Circ Physiol. 2012; 302: H2612-H2621
        • El-Haggar S.M.
        • Farrag W.F.
        • Kotkata F.A.
        Effect of ketotifen in obese patients with type 2 diabetes mellitus.
        J Diabetes Complications. 2015; 29: 427-432
        • Murray P.J.
        • Wynn T.A.
        Protective and pathogenic functions of macrophage subsets.
        Nat Rev Immunol. 2011; 11: 723-737
        • Periyalil H.A.
        • Wood L.G.
        • Scott H.A.
        • et al.
        Macrophage activation, age and sex effects of immunometabolism in obese asthma.
        Eur Respir J. 2015; 45: 388-395
        • Lee Y.G.
        • Jeong J.J.
        • Nyenhuis S.
        • et al.
        Recruited alveolar macrophages, in response to airway epithelial-derived MCP-1/CCL2, regulate airway inflammation and remodeling in allergic asthma.
        Am J Respir Cell Mol Biol. 2015; 52: 772-784
        • Olefsky J.M.
        • Glass C.K.
        Macrophages, inflammation, and insulin resistance.
        Annu Rev Physiol. 2010; 72: 219-246
        • Garcia L.N.
        • Leimgruber C.
        • Uribe Echevarria E.M.
        • et al.
        Protective phenotypes of club cells and alveolar macrophages are favored as part of endotoxin-mediated prevention of asthma.
        Exp Biol Med (Maywood). 2015; 240: 904-916
        • Robbe P.
        • Draijer C.
        • Borg T.R.
        • et al.
        Distinct macrophage phenotypes in allergic and nonallergic lung inflammation.
        Am J Physiol Lung Cell Mol Physiol. 2015; 308: L358-L367
        • Zaslona Z.
        • Przybranowski S.
        • Wilke C.
        • et al.
        Resident alveolar macrophages suppress, whereas recruited monocytes promote, allergic lung inflammation in murine models of asthma.
        J Immunol. 2014; 193: 4245-4253
        • McAlpine C.S.
        • Huang A.
        • Emdin A.
        • et al.
        Deletion of myeloid GSK3alpha attenuates atherosclerosis and promotes an M2 macrophage phenotype.
        Arterioscler Thromb Vasc Biol. 2015; 35: 1113-1122
        • Ng H.P.
        • Zhu X.
        • Harmon E.Y.
        • et al.
        Reduced atherosclerosis in apoE-inhibitory FcγRIIb-deficient mice is associated with increased anti-inflammatory responses by T cells and macrophages.
        Arterioscler Thromb Vasc Biol. 2015; 35: 1101-1112
        • Gleissner C.A.
        • Shaked I.
        • Little K.M.
        • Ley K.
        CXC chemokine ligand 4 induces a unique transcriptome in monocyte-derived macrophages.
        J Immunol. 2010; 184: 4810-4818
        • Erbel C.
        • Wolf A.
        • Lasitschka F.
        • et al.
        Prevalence of M4 macrophages within human coronary atherosclerotic plaques is associated with features of plaque instability.
        Int J Cardiol. 2015; 186: 219-225
        • Kay A.B.
        Allergy and allergic diseases. Second of two parts.
        N Engl J Med. 2001; 344: 109-113
        • Frostegard J.
        • Ulfgren A.K.
        • Nyberg P.
        • et al.
        Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines.
        Atherosclerosis. 1999; 145: 33-43
        • Bergqvist A.
        • Andersson C.K.
        • Mori M.
        • et al.
        Alveolar T-helper type-2 immunity in atopic asthma is associated with poor clinical control.
        Clin Sci (Lond). 2015; 128: 47-56
        • Seumois G.
        • Chavez L.
        • Gerasimova A.
        • et al.
        Epigenomic analysis of primary human T cells reveals enhancers associated with TH2 memory cell differentiation and asthma susceptibility.
        Nat Immunol. 2014; 15: 777-788
        • Krug N.
        • Hohlfeld J.M.
        • Kirsten A.M.
        • et al.
        Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme.
        N Engl J Med. 2015; 372: 1987-1995
        • Rastogi D.
        • Fraser S.
        • Oh J.
        • et al.
        Inflammation, metabolic dysregulation, and pulmonary function among obese urban adolescents with asthma.
        Am J Respir Crit Care Med. 2015; 191: 149-160
        • Irvin C.
        • Zafar I.
        • Good J.
        • et al.
        Increased frequency of dual-positive TH2/TH17 cells in bronchoalveolar lavage fluid characterizes a population of patients with severe asthma.
        J Allergy Clin Immunol. 2014; 134: 1175-1186.e7
        • Singh A.
        • Yamamoto M.
        • Ruan J.
        • et al.
        Th17/Treg ratio derived using DNA methylation analysis is associated with the late phase asthmatic response.
        Allergy Asthma Clin Immunol. 2014; 10: 32
        • Lluis A.
        • Depner M.
        • Gaugler B.
        • et al.
        Increased regulatory T-cell numbers are associated with farm milk exposure and lower atopic sensitization and asthma in childhood.
        J Allergy Clin Immunol. 2014; 133: 551-559
        • Bohm L.
        • Maxeiner J.
        • Meyer-Martin H.
        • et al.
        IL-10 and regulatory T cells cooperate in allergen-specific immunotherapy to ameliorate allergic asthma.
        J Immunol. 2015; 194: 887-897
        • Hinks T.S.
        • Zhou X.
        • Staples K.J.
        • et al.
        Innate and adaptive T cells in asthmatic patients: relationship to severity and disease mechanisms.
        J Allergy Clin Immunol. 2015; 136: 323-333
        • Gao Q.
        • Jiang Y.
        • Ma T.
        • et al.
        A critical function of Th17 proinflammatory cells in the development of atherosclerotic plaque in mice.
        J Immunol. 2010; 185: 5820-5827
        • Ng H.P.
        • Burris R.L.
        • Nagarajan S.
        Attenuated atherosclerotic lesions in apoE-Fcγ chain-deficient hyperlipidemic mouse model is associated with inhibition of Th17 cells and promotion of regulatory T cells.
        J Immunol. 2011; 187: 6082-6093
        • Ma T.
        • Gao Q.
        • Zhu F.
        • et al.
        Th17 cells and IL-17 are involved in the disruption of vulnerable plaques triggered by short-term combination stimulation in apolipoprotein E-knockout mice.
        Cell Mol Immunol. 2013; 10: 338-348
        • Dinh T.N.
        • Kyaw T.S.
        • Kanellakis P.
        • et al.
        Cytokine therapy with interleukin-2/anti-interleukin-2 monoclonal antibody complexes expands CD4+CD25+Foxp3+ regulatory T cells and attenuates development and progression of atherosclerosis.
        Circulation. 2012; 126: 1256-1266
        • Pawankar R.
        • Yamagishi S.
        • Takizawa R.
        • Yagi T.
        Mast cell-IgE-and mast cell-structural cell interactions in allergic airway disease.
        Curr Drug Targets Inflamm Allergy. 2003; 2: 303-312
        • Chin J.E.
        • Hatfield C.A.
        • Winterrowd G.E.
        • et al.
        Airway recruitment of leukocytes in mice is dependent on alpha4-integrins and vascular cell adhesion molecule-1.
        Am J Physiol. 1997; 272: L219-L229
        • Abdala-Valencia H.
        • Earwood J.
        • Bansal S.
        • et al.
        Nonhematopoietic NADPH oxidase regulation of lung eosinophilia and airway hyperresponsiveness in experimentally induced asthma.
        Am J Physiol Lung Cell Mol Physiol. 2007; 292: L1111-L1125
        • Barthel S.R.
        • Johansson M.W.
        • McNamee D.M.
        • Mosher D.F.
        Roles of integrin activation in eosinophil function and the eosinophilic inflammation of asthma.
        J Leukoc Biol. 2008; 83: 1-12
        • Mould A.W.
        • Ramsay A.J.
        • Matthaei K.I.
        • et al.
        The effect of IL-5 and eotaxin expression in the lung on eosinophil trafficking and degranulation and the induction of bronchial hyperreactivity.
        J Immunol. 2000; 164: 2142-2150
        • Gudbjartsson D.F.
        • Bjornsdottir U.S.
        • Halapi E.
        • et al.
        Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction.
        Nat Genet. 2009; 41: 342-347
        • Tran T.N.
        • Khatry D.B.
        • Ke X.
        • et al.
        High blood eosinophil count is associated with more frequent asthma attacks in asthma patients.
        Ann Allergy Asthma Immunol. 2014; 113: 19-24
        • Malinovschi A.
        • Fonseca J.A.
        • Jacinto T.
        • et al.
        Exhaled nitric oxide levels and blood eosinophil counts independently associate with wheeze and asthma events in National Health and Nutrition Examination Survey subjects.
        J Allergy Clin Immunol. 2013; 132: 821-827.e1–5
        • Green R.H.
        • Brightling C.E.
        • McKenna S.
        • et al.
        Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial.
        Lancet. 2002; 360: 1715-1721
        • Pavord I.D.
        • Korn S.
        • Howarth P.
        • et al.
        Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial.
        Lancet. 2012; 380: 651-659
        • Castro M.
        • Zangrilli J.
        • Wechsler M.E.
        • et al.
        Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials.
        Lancet Respir Med. 2015; 3: e15
        • Haley K.J.
        • Lilly C.M.
        • Yang J.H.
        • et al.
        Overexpression of eotaxin and the CCR3 receptor in human atherosclerosis: using genomic technology to identify a potential novel pathway of vascular inflammation.
        Circulation. 2000; 102: 2185-2189
        • Hogan S.P.
        • Rosenberg H.F.
        • Moqbel R.
        • et al.
        Eosinophils: biological properties and role in health and disease.
        Clin Exp Allergy. 2008; 38: 709-750
        • Toor I.S.
        • Jaumdally R.
        • Lip G.Y.
        • et al.
        Eosinophil count predicts mortality following percutaneous coronary intervention.
        Thromb Res. 2012; 130: 607-611
        • Matsumura T.
        • Taketa K.
        • Motoshima H.
        • et al.
        Association between circulating leukocyte subtype counts and carotid intima-media thickness in Japanese subjects with type 2 diabetes.
        Cardiovasc Diabetol. 2013; 12: 177
        • Verdoia M.
        • Schaffer A.
        • Cassetti E.
        • et al.
        Absolute eosinophils count and the extent of coronary artery disease: a single centre cohort study.
        J Thromb Thrombolysis. 2015; 39: 459-466
        • Venge P.
        Monitoring the allergic inflammation.
        Allergy. 2004; 59: 26-32
        • Niccoli G.
        • Sgueglia G.A.
        • Conte M.
        • et al.
        Eosinophil cationic protein and clinical outcome after bare metal stent implantation.
        Atherosclerosis. 2011; 215: 166-169
        • Chung K.F.
        Should treatments for asthma be aimed at the airway smooth muscle?.
        Expert Rev Respir Med. 2007; 1: 209-217
        • Hirota N.
        • Martin J.G.
        Mechanisms of airway remodeling.
        Chest. 2013; 144: 1026-1032
        • Lin T.Y.
        • Venkatesan N.
        • Nishioka M.
        • et al.
        Monocyte-derived fibrocytes induce an inflammatory phenotype in airway smooth muscle cells.
        Clin Exp Allergy. 2014; 44: 1347-1360
        • Comer B.S.
        • Camoretti-Mercado B.
        • Kogut P.C.
        • et al.
        MicroRNA-146a and microRNA-146b expression and anti-inflammatory function in human airway smooth muscle.
        Am J Physiol Lung Cell Mol Physiol. 2014; 307: L727-L734
        • Ackers-Johnson M.
        • Talasila A.
        • Sage A.P.
        • et al.
        Myocardin regulates vascular smooth muscle cell inflammatory activation and disease.
        Arterioscler Thromb Vasc Biol. 2015; 35: 817-828
        • Calvayrac O.
        • Rodriguez-Calvo R.
        • Marti-Pamies I.
        • et al.
        NOR-1 modulates the inflammatory response of vascular smooth muscle cells by preventing NFκB activation.
        J Mol Cell Cardiol. 2015; 80: 34-44
        • Choi E.T.
        • Khan M.F.
        • Leidenfrost J.E.
        • et al.
        Beta3-integrin mediates smooth muscle cell accumulation in neointima after carotid ligation in mice.
        Circulation. 2004; 109: 1564-1569
        • Bentley J.K.
        • Hershenson M.B.
        Airway smooth muscle growth in asthma: proliferation, hypertrophy, and migration.
        Proc Am Thorac Soc. 2008; 5: 89-96
        • De Caterina R.
        • Zampolli A.
        From asthma to atherosclerosis–5-lipoxygenase, leukotrienes, and inflammation.
        N Engl J Med. 2004; 350: 4-7
        • Vila L.
        Cyclooxygenase and 5-lipoxygenase pathways in the vessel wall: role in atherosclerosis.
        Med Res Rev. 2004; 24: 399-424
        • Xue L.
        • Fergusson J.
        • Salimi M.
        • et al.
        Prostaglandin D2 and leukotriene E4 synergize to stimulate diverse TH2 functions and TH2 cell/neutrophil crosstalk.
        J Allergy Clin Immunol. 2015; 135: 1358-1366.e1–11
        • Crosslin D.R.
        • Shah S.H.
        • Nelson S.C.
        • et al.
        Genetic effects in the leukotriene biosynthesis pathway and association with atherosclerosis.
        Hum Genet. 2009; 125: 217-229
        • Stanke-Labesque F.
        • Pepin J.L.
        • de Jouvencel T.
        • et al.
        Leukotriene B4 pathway activation and atherosclerosis in obstructive sleep apnea.
        J Lipid Res. 2012; 53: 1944-1951
        • Zhao J.
        • Goldberg J.
        • Vaccarino V.
        Leukotriene A4 hydrolase haplotype, diet and atherosclerosis: a twin study.
        Atherosclerosis. 2013; 226: 238-244
        • Burdon K.P.
        • Rudock M.E.
        • Lehtinen A.B.
        • et al.
        Human lipoxygenase pathway gene variation and association with markers of subclinical atherosclerosis in the diabetes heart study.
        Mediators Inflamm. 2010; 2010: 170153
        • Camacho M.
        • Martinez-Perez A.
        • Buil A.
        • et al.
        Genetic determinants of 5-lipoxygenase pathway in a Spanish population and their relationship with cardiovascular risk.
        Atherosclerosis. 2012; 224: 129-135
        • Tardif J.C.
        • L'Allier P.L.
        • Ibrahim R.
        • et al.
        Treatment with 5-lipoxygenase inhibitor VIA-2291 (Atreleuton) in patients with recent acute coronary syndrome.
        Circ Cardiovasc Imaging. 2010; 3: 298-307
        • Cao R.Y.
        • St Amand T.
        • Grabner R.
        • et al.
        Genetic and pharmacological inhibition of the 5-lipoxygenase/leukotriene pathway in atherosclerotic lesion development in ApoE deficient mice.
        Atherosclerosis. 2009; 203: 395-400
        • Gaztanaga J.
        • Farkouh M.
        • Rudd J.H.
        • et al.
        A phase 2 randomized, double-blind, placebo-controlled study of the effect of VIA-2291, a 5-lipoxygenase inhibitor, on vascular inflammation in patients after an acute coronary syndrome.
        Atherosclerosis. 2015; 240: 53-60
        • Nissen S.E.
        • Tuzcu E.M.
        • Schoenhagen P.
        • et al.
        Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial.
        JAMA. 2004; 291: 1071-1080
        • Cottrell L.
        • Neal W.A.
        • Ice C.
        • et al.
        Metabolic abnormalities in children with asthma.
        Am J Respir Crit Care Med. 2011; 183: 441-448
        • Yiallouros P.K.
        • Savva S.C.
        • Kolokotroni O.
        • et al.
        Low serum high-density lipoprotein cholesterol in childhood is associated with adolescent asthma.
        Clin Exp Allergy. 2012; 42: 423-432
        • Yao X.
        • Fredriksson K.
        • Yu Z.X.
        • et al.
        Apolipoprotein E negatively regulates house dust mite-induced asthma via a low-density lipoprotein receptor-mediated pathway.
        Am J Respir Crit Care Med. 2010; 182: 1228-1238
        • Fredriksson K.
        • Mishra A.
        • Lam J.K.
        • et al.
        The very low density lipoprotein receptor attenuates house dust mite-induced airway inflammation by suppressing dendritic cell-mediated adaptive immune responses.
        J Immunol. 2014; 192: 4497-4509
        • Huang C.C.
        • Chan W.L.
        • Chen Y.C.
        • et al.
        Statin use in patients with asthma: a nationwide population-based study.
        Eur J Clin Invest. 2011; 41: 507-512
        • McKay A.
        • Leung B.P.
        • McInnes I.B.
        • et al.
        A novel anti-inflammatory role of simvastatin in a murine model of allergic asthma.
        J Immunol. 2004; 172: 2903-2908
        • Menzies D.
        • Nair A.
        • Meldrum K.T.
        • et al.
        Simvastatin does not exhibit therapeutic anti-inflammatory effects in asthma.
        J Allergy Clin Immunol. 2007; 119: 328-335
        • Greenwood J.
        • Steinman L.
        • Zamvil S.S.
        Statin therapy and autoimmune disease: from protein prenylation to immunomodulation.
        Nat Rev Immunol. 2006; 6: 358-370
        • Li W.M.
        • Liu W.
        • Gao C.
        • Zhou B.G.
        Immunoregulatory effects of atorvastatin on experimental autoimmune myocarditis in Lewis rats.
        Immunol Cell Biol. 2006; 84: 274-280
        • Sorkness C.A.
        • Lemanske Jr., R.F.
        • Mauger D.T.
        • et al.
        Long-term comparison of 3 controller regimens for mild-moderate persistent childhood asthma: the Pediatric Asthma Controller Trial.
        J Allergy Clin Immunol. 2007; 119: 64-72
        • Varas-Lorenzo C.
        • Rodriguez L.A.
        • Maguire A.
        • et al.
        Use of oral corticosteroids and the risk of acute myocardial infarction.
        Atherosclerosis. 2007; 192: 376-383
        • Suissa S.
        • Assimes T.
        • Brassard P.
        • Ernst P.
        Inhaled corticosteroid use in asthma and the prevention of myocardial infarction.
        Am J Med. 2003; 115: 377-381
        • Kabra S.K.
        • Pandey R.M.
        • Singh R.
        • Seth V.
        Ketotifen for asthma in children aged 5 to 15 years: a randomized placebo-controlled trial.
        Ann Allergy Asthma Immunol. 2000; 85: 46-52
        • Sano Y.
        • Adachi M.
        • Kiuchi T.
        • Miyamoto T.
        Effects of nebulized sodium cromoglycate on adult patients with severe refractory asthma.
        Respir Med. 2006; 100: 420-433
        • Storms W.
        • Kaliner M.A.
        Cromolyn sodium: fitting an old friend into current asthma treatment.
        J Asthma. 2005; 42: 79-89
        • Wang J.
        • Lindholt J.S.
        • Sukhova G.K.
        • et al.
        IgE actions on CD4+ T cells, mast cells, and macrophages participate in the pathogenesis of experimental abdominal aortic aneurysms.
        EMBO Mol Med. 2014; 6: 952-969
        • Lieberman J.A.
        • Chehade M.
        Use of omalizumab in the treatment of food allergy and anaphylaxis.
        Curr Allergy Asthma Rep. 2013; 13: 78-84
        • Normansell R.
        • Walker S.
        • Milan S.J.
        • Walters E.H.
        • Nair P.
        Omalizumab for asthma in adults and children.
        Cochrane Database Syst Rev. 2014; 1: CD003559
        • Liu C.L.
        • Wang Y.
        • Liao M.
        • et al.
        Allergic lung inflammation aggravates angiotensin II-induced abdominal aortic aneurysms in mice.
        Arterioscler Thromb Vasc Biol. 2016; 36: 69-77
        • Ali A.K.
        • Hartzema A.G.
        Assessing the association between omalizumab and arteriothrombotic events through spontaneous adverse event reporting.
        J Asthma Allergy. 2012; 5: 1-9
        • Yalcin A.D.
        • Cilli A.
        • Bisgin A.
        • Strauss L.G.
        • Herth F.
        Omalizumab is effective in treating severe asthma in patients with severe cardiovascular complications and its effects on sCD200, d-dimer, CXCL8, 25-hydroxyvitamin D and IL-1β levels.
        Expert Opin Biol Ther. 2013; 13: 1335-1341
        • Olafsdottir I.S.
        • Gislason T.
        • Thjodleifsson B.
        • et al.
        C reactive protein levels are increased in non-allergic but not allergic asthma: a multicentre epidemiological study.
        Thorax. 2005; 60: 451-454
        • Beeh K.M.
        • Ksoll M.
        • Buhl R.
        Elevation of total serum immunoglobulin E is associated with asthma in nonallergic individuals.
        Eur Respir J. 2000; 16: 609-614
        • Libby P.
        • Ridker P.M.
        Inflammation and atherosclerosis: role of C-reactive protein in risk assessment.
        Am J Med. 2004; 116: 9S-16S