The Eosinophil: The Cell and Its Weapons, the Cytokines, Its Locations

ABSTRACT

Although the functional role of eosinophils is primarily considered to be host defense against parasitic infection, current studies indicate that this complex cell is ideally adapted for other roles that may involve immune modulation and tissue repair. The eosinophil is an important source of basic proteins, lipid mediators, cytokines, and growth factors. In disease states, eosinophil mobilization from the marrow and circulation can be very rapid yet highly organized and cell selective, particularly in response to interleukin (IL) 5 and eotaxin. Such elaborate recruitment is regulated by a series of interactions by eosinophil receptors and the endothelium and extracellular matrix ligands. Several priming mechanisms activate the eosinophils during this recruitment process so that the cell arrives at its tissue destination prepared for immediate action and prolonged tissue survival. Degranulation is strictly controlled and allows the cell to differentially release its contents in an ordered manner. This is essential to prevent injury to tissue during migration. Therapy is still limited for eosinophil-driven diseases, but intervention at the key events that govern eosinophil recruitment and effector function may be the way forward.

KEYWORDS

Eosinophils - host defense - immunomodulation

REFERENCES

• 1 Steinbach K H, Schick P, Trepel F et al.. Estimation of kinetic parameters of neutrophilic, eosinophilic, and basophilic granulocytes in human blood.  Blut. 1979;  39(1) 27-38
• 2 Sokol R J, James N T, Wales J, Hudson G. Morphometry of eosinophils in human blood.  Acta Anat (Basel). 1987;  129(3) 211-213
• 3 Ackerman S J, Liu L, Kwatia M A et al.. Charcot-Leyden crystal protein (galectin-10) is not a dual function galactin with lysophospholipase activity but binds a lysophospholipase inhibitor in a novel structural fashion.  J Biol Chem. 2002;  277(17) 14859-14868
• 4 Dvorak A M, Letourneau L, Login G R, Weller P F, Ackerman S J. Ultrastructural localization of the Charcot-Leyden crystal protein (lysophospholipase) to a distinct crystalloid-free granule population in mature human eosinophils.  Blood. 1988;  72(1) 150-158
• 5 Menzies-Gow A, Flood-Page P, Sehmi R et al.. Anti-IL-5 (mepolizumab) therapy induces bone marrow eosinophil maturational arrest and decreases eosinophil progenitors in the bronchial mucosa of atopic asthmatics.  J Allergy Clin Immunol. 2003;  111(4) 714-719
• 6 Kopf M, Brombacher F, Hodgkin P D et al.. IL-5-deficient mice have a developmental defect in CD5+ B-1 cells and lack eosinophilia but have normal antibody and cytotoxic T cell responses.  Immunity. 1996;  4(1) 15-24
• 7 Takamoto M, Ovington K S, Behm C A, Sugane K, Young I G, Matthaei K I. Eosinophilia, parasite burden and lung damage in Toxocara canis infection in C57Bl/6 mice genetically deficient in IL-5.  Immunology. 1997;  90(4) 511-517
• 8 Dent L A, Strath M, Mellor A L, Sanderson C J. Eosinophilia in transgenic mice expressing interleukin 5.  J Exp Med. 1990;  172(5) 1425-1431
• 9 Sehmi R, Wood L J, Watson R et al.. Allergen-induced increases in IL-5 receptor alpha-subunit expression on bone marrow-derived CD34+ cells from asthmatic subjects. A novel marker of progenitor cell commitment towards eosinophilic differentiation.  J Clin Invest. 1997;  100(10) 2466-2475
• 10 Dorman S C, Sehmi R, Gauvreau G M et al.. Kinetics of bone marrow eosinophilopoiesis and associated cytokines after allergen inhalation.  Am J Respir Crit Care Med. 2004;  169(5) 565-572
• 11 Tavernier J, Van der H J, Verhee A et al.. Interleukin 5 regulates the isoform expression of its own receptor alpha-subunit.  Blood. 2000;  95(5) 1600-1607
• 12 Leckie M J, ten Brinke A, Khan J et al.. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response.  Lancet. 2000;  356(9248) 2144-2148
• 13 Flood-Page P T, Menzies-Gow A N, Kay A B, Robinson D S. Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway.  Am J Respir Crit Care Med. 2003;  167(2) 199-204
• 14 Gregory B, Kirchem A, Phipps S et al.. Differential regulation of human eosinophil IL-3, IL-5, and GM-CSF receptor alpha-chain expression by cytokines: IL-3, IL-5, and GM-CSF down-regulate IL-5 receptor alpha expression with loss of IL-5 responsiveness, but up-regulate IL-3 receptor alpha expression.  J Immunol. 2003;  170(11) 5359-5366
• 15 Klion A D, Law M A, Noel P, Kim Y J, Haverty T P, Nutman T B. Safety and efficacy of the monoclonal anti-interleukin-5 antibody SCH55700 in the treatment of patients with hypereosinophilic syndrome.  Blood. 2004;  103(8) 2939-2941
• 16 Garrett J K, Jameson S C, Thomson B et al.. Anti-interleukin-5 (mepolizumab) therapy for hypereosinophilic syndromes.  J Allergy Clin Immunol. 2004;  113(1) 115-119
• 17 Pardanani A, Reeder T, Porrata L F et al.. Imatinib therapy for hypereosinophilic syndrome and other eosinophilic disorders.  Blood. 2003;  101(9) 3391-3397
• 18 Gleich G J, Leiferman K M, Pardanani A, Tefferi A, Butterfield J H. Treatment of hypereosinophilic syndrome with imatinib mesilate.  Lancet. 2002;  359(9317) 1577-1578
• 19 Sehmi R, Dorman S, Baatjes A et al.. Allergen-induced fluctuation in CC chemokine receptor 3 expression on bone marrow CD34+ cells from asthmatic subjects: significance for mobilization of haemopoietic progenitor cells in allergic inflammation.  Immunology. 2003;  109(4) 536-546
• 20 Dorman S C, Efthimiadis A, Babirad I et al.. Sputum CD34+IL-5Ralpha+ cells increase after allergen: evidence for in situ eosinophilopoiesis.  Am J Respir Crit Care Med. 2004;  169(5) 573-577
• 21 Hakansson L, Carlson M, Stalenheim G, Venge P. Migratory responses of eosinophil and neutrophil granulocytes from patients with asthma.  J Allergy Clin Immunol. 1990;  85(4) 743-750
• 22 Luijk B, Lindemans C A, Kanters D et al.. Gradual increase in priming of human eosinophils during extravasation from peripheral blood to the airways in response to allergen challenge.  J Allergy Clin Immunol. 2005;  115(5) 997-1003
• 23 Warringa R A, Mengelers H J, Kuijper P H, Raaijmakers J A, Bruijnzeel P L, Koenderman L. In vivo priming of platelet-activating factor-induced eosinophil chemotaxis in allergic asthmatic individuals.  Blood. 1992;  79(7) 1836-1841
• 24 Hakansson L, Venge P. Priming of eosinophil and neutrophil migratory responses by interleukin 3 and interleukin 5.  APMIS. 1994;  102(4) 308-316
• 25 Sehmi R, Wardlaw A J, Cromwell O, Kurihara K, Waltmann P, Kay A B. Interleukin-5 selectively enhances the chemotactic response of eosinophils obtained from normal but not eosinophilic subjects.  Blood. 1992;  79(11) 2952-2959
• 26 Hakansson L, Hoglund M, Jonsson U B, Torsteinsdottir I, Xu X, Venge P. Effects of in vivo administration of G-CSF on neutrophil and eosinophil adhesion.  Br J Haematol. 1997;  98(3) 603-611
• 27 Carlson M, Peterson C, Venge P. The influence of IL-3, IL-5, and GM-CSF on normal human eosinophil and neutrophil C3b-induced degranulation.  Allergy. 1993;  48(6) 437-442
• 28 Burke-Gaffney A, Hellewell P G. Eotaxin stimulates eosinophil adhesion to human lung microvascular endothelial cells.  Biochem Biophys Res Commun. 1996;  227(1) 35-40
• 29 Gordon J R, Swystun V A, Li F et al.. Regular salbutamol use increases CXCL8 responses in asthma: relationship to the eosinophil response.  Eur Respir J. 2003;  22(1) 118-126
• 30 Carlson M, Peterson C, Venge P. The influence of IL-3, IL-5, and GM-CSF on normal human eosinophil and neutrophil C3b-induced degranulation.  Allergy. 1993;  48(6) 437-442
• 31 Phillips R M, Stubbs V E, Henson M R, Williams T J, Pease J E, Sabroe I. Variations in eosinophil chemokine responses: an investigation of CCR1 and CCR3 function, expression in atopy, and identification of a functional CCR1 promoter.  J Immunol. 2003;  170(12) 6190-6201
• 32 Schweizer R C, Welmers B A, Raaijmakers J A, Zanen P, Lammers J W, Koenderman L RA. RANTES- and interleukin-8 induced responses in normal human eosinophils: effects of priming with interleukin-5.  Blood. 1994;  83(12) 3697-3704
• 33 Symon F A, Walsh G M, Watson S R, Wardlaw A J. Eosinophil adhesion to nasal polyp endothelium is P-selectin-dependent.  J Exp Med. 1994;  180(1) 371-376
• 34 del Pozo M A, Sanchez-Mateos P, Nieto M, Sanchez-Madrid F. Chemokines regulate cellular polarization and adhesion receptor redistribution during lymphocyte interaction with endothelium and extracellular matrix. Involvement of cAMP signaling pathway.  J Cell Biol. 1995;  131(2) 495-508
• 35 Finger E B, Bruehl R E, Bainton D F, Springer T A. A differential role for cell shape in neutrophil tethering and rolling on endothelial selectins under flow.  J Immunol. 1996;  157(11) 5085-5096
• 36 Klion A D, Nutman T B. The role of eosinophils in host defense against helminth parasites.  J Allergy Clin Immunol. 2004;  113(1) 30-37
• 37 Kephart G M, Andrade Z A, Gleich G J. Localization of eosinophil major basic protein onto eggs of Schistosoma mansoni in human pathologic tissue.  Am J Pathol. 1988;  133(2) 389-396
• 38 Glauert A M, Butterworth A E, Sturrock R F, Houba V. The mechanism of antibody-dependent, eosinophil-mediated damage to schistosomula of Schistosoma mansoni in vitro: a study by phase-contrast and electron microscopy.  J Cell Sci. 1978;  34 173-192
• 39 Butterworth A E, Vadas M A, Wassom D L et al.. Interactions between human eosinophils and schistosomula of Schistosoma mansoni. II. The mechanism of irreversible eosinophil adherence.  J Exp Med. 1979;  150(6) 1456-1471
• 40 Abu-Ghazaleh R I, Gleich G J, Prendergast F G. Interaction of eosinophil granule major basic protein with synthetic lipid bilayers: a mechanism for toxicity.  J Membr Biol. 1992;  128(2) 153-164
• 41 Kroegel C, Costabel U, Matthys H. Mechanism of membrane damage mediated by eosinophil major basic protein.  Lancet. 1987;  1(8546) 1380-1381
• 42 Gleich G J, Frigas E, Loegering D A, Wassom D L, Steinmuller D. Cytotoxic properties of the eosinophil major basic protein.  J Immunol. 1979;  123(6) 2925-2927
• 43 Arinaga S, Karimine N, Takamuku K et al.. Correlation of eosinophilia with clinical response in patients with advanced carcinoma treated with low-dose recombinant interleukin-2 and mitomycin C.  Cancer Immunol Immunother. 1992;  35(4) 246-250
• 44 O'Donnell M C, Ackerman S J, Gleich G J, Thomas L L. Activation of basophil and mast cell histamine release by eosinophil granule major basic protein.  J Exp Med. 1983;  157(6) 1981-1991
• 45 Moy J N, Gleich G J, Thomas L L. Noncytotoxic activation of neutrophils by eosinophil granule major basic protein. Effect on superoxide anion generation and lysosomal enzyme release.  J Immunol. 1990;  145(8) 2626-2632
• 46 Fryer A D, Costello R W, Yost B L et al.. Antibody to VLA-4, but not to L-selectin, protects neuronal M2 muscarinic receptors in antigen-challenged guinea pig airways.  J Clin Invest. 1997;  99(8) 2036-2044
• 47 Rosenberg H F. The eosinophil ribonucleases.  Cell Mol Life Sci. 1998;  54(8) 795-803
• 48 Durack D T, Sumi S M, Klebanoff S J. Neurotoxicity of human eosinophils.  Proc Natl Acad Sci USA. 1979;  76(3) 1443-1447
• 49 Durack D T, Ackerman S J, Loegering D A, Gleich G J. Purification of human eosinophil-derived neurotoxin.  Proc Natl Acad Sci USA. 1981;  78(8) 5165-5169
• 50 Rosenberg H F, Domachowske J B. Eosinophils, eosinophil ribonucleases, and their role in host defense against respiratory virus pathogens.  J Leukoc Biol. 2001;  70(5) 691-698
• 51 Newton D L, Rybak S M. Unique recombinant human ribonuclease and inhibition of Kaposi's sarcoma cell growth.  J Natl Cancer Inst. 1998;  90(23) 1787-1791
• 52 Harrison A M, Bonville C A, Rosenberg H F, Domachowske J B. Respiratory syncytial virus-induced chemokine expression in the lower airways: eosinophil recruitment and degranulation.  Am J Respir Crit Care Med. 1999;  159(6) 1918-1924
• 53 Garofalo R, Kimpen J L, Welliver R C, Ogra P L. Eosinophil degranulation in the respiratory tract during naturally acquired respiratory syncytial virus infection.  J Pediatr. 1992;  120(1) 28-32
• 54 Domachowske J B, Dyer K D, Bonville C A, Rosenberg H F. Recombinant human eosinophil-derived neurotoxin/RNase 2 functions as an effective antiviral agent against respiratory syncytial virus.  J Infect Dis. 1998;  177(6) 1458-1464
• 55 Domachowske J B, Dyer K D, Adams A G, Leto T L, Rosenberg H F. Eosinophil cationic protein/RNase 3 is another RNase A-family ribonuclease with direct antiviral activity.  Nucleic Acids Res. 1998;  26(14) 3358-3363
• 56 Domachowske J B, Dyer K D, Adams A G, Leto T L, Rosenberg H F. Eosinophil cationic protein/RNase 3 is another RNase A-family ribonuclease with direct antiviral activity.  Nucleic Acids Res. 1998;  26(14) 3358-3363
• 57 Lacy P, Abdel-Latif D, Steward M, Musat-Marcu S, Man S F, Moqbel R. Divergence of mechanisms regulating respiratory burst in blood and sputum eosinophils and neutrophils from atopic subjects.  J Immunol. 2003;  170(5) 2670-2679
• 58 Shult P A, Graziano F M, Wallow I H, Busse W W. Comparison of superoxide generation and luminol-dependent chemiluminescence with eosinophils and neutrophils from normal individuals.  J Lab Clin Med. 1985;  106(6) 638-645
• 59 Schauer U, Leinhaas C, Jager R, Rieger C H. Enhanced superoxide generation by eosinophils from asthmatic children.  Int Arch Allergy Appl Immunol. 1991;  96(4) 317-321
• 60 Jarjour N N, Busse W W, Calhoun W J. Enhanced production of oxygen radicals in nocturnal asthma.  Am Rev Respir Dis. 1992;  146(4) 905-911
• 61 Antczak A, Nowak D, Shariati B, Krol M, Piasecka G, Kurmanowska Z. Increased hydrogen peroxide and thiobarbituric acid-reactive products in expired breath condensate of asthmatic patients.  Eur Respir J. 1997;  10(6) 1235-1241
• 62 Wedi B, Straede J, Wieland B, Kapp A. Eosinophil apoptosis is mediated by stimulators of cellular oxidative metabolisms and inhibited by antioxidants: involvement of a thiol-sensitive redox regulation in eosinophil cell death.  Blood. 1999;  94(7) 2365-2373
• 63 Bandeira-Melo C, Weller P F. Eosinophils and cysteinyl leukotrienes.  Prostaglandins Leukot Essent Fatty Acids. 2003;  69(2-3) 135-143
• 64 Wenzel S E. The role of leukotrienes in asthma.  Prostaglandins Leukot Essent Fatty Acids. 2003;  69(2-3) 145-155
• 65 Cowburn A S, Sladek K, Soja J et al.. Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma.  J Clin Invest. 1998;  101(4) 834-846
• 66 Marom Z, Shelhamer J H, Bach M K, Morton D R, Kaliner M. Slow-reacting substances, leukotrienes C4 and D4, increase the release of mucus from human airways in vitro.  Am Rev Respir Dis. 1982;  126(3) 449-451
• 67 Joris I, Majno G, Corey E J, Lewis R A. The mechanism of vascular leakage induced by leukotriene E4. Endothelial contraction.  Am J Pathol. 1987;  126(1) 19-24
• 68 Adelroth E, Morris M M, Hargreave F E, O'Byrne P M. Airway responsiveness to leukotrienes C4 and D4 and to methacholine in patients with asthma and normal controls.  N Engl J Med. 1986;  315(8) 480-484
• 69 Lee E, Robertson T, Smith J, Kilfeather S. Leukotriene receptor antagonists and synthesis inhibitors reverse survival in eosinophils of asthmatic individuals.  Am J Respir Crit Care Med. 2000;  161(6) 1881-1886
• 70 Bandeira-Melo C, Sugiyama K, Woods L J, Weller P F. Cutting edge: eotaxin elicits rapid vesicular transport-mediated release of preformed IL-4 from human eosinophils.  J Immunol. 2001;  166(8) 4813-4817
• 71 Bandeira-Melo C, Sugiyama K, Woods L J et al.. IL-16 promotes leukotriene C(4) and IL-4 release from human eosinophils via CD4- and autocrine CCR3-chemokine-mediated signaling.  J Immunol. 2002;  168(9) 4756-4763
• 72 Bandeira-Melo C, Bozza P T, Weller P F. The cellular biology of eosinophil eicosanoid formation and function.  J Allergy Clin Immunol. 2002;  109(3) 393-400
• 73 Grewe M, Czech W, Morita A et al.. Human eosinophils produce biologically active IL-12: implications for control of T cell responses.  J Immunol. 1998;  161(1) 415-420
• 74 Lamkhioued B, Gounni A S, Aldebert D et al.. Synthesis of type 1 (IFN gamma) and type 2 (IL-4, IL-5, and IL-10) cytokines by human eosinophils.  Ann NY Acad Sci. 1996;  796 203-208
• 75 Moller G M, de Jong T A, van der Kwast T H et al.. Immunolocalization of interleukin-4 in eosinophils in the bronchial mucosa of atopic asthmatics.  Am J Respir Cell Mol Biol. 1996;  14(5) 439-443
• 76 Moller G M, de Jong T A, Overbeek S E, van der Kwast T H, Postma D S, Hoogsteden H C. Ultrastructural immunogold localization of interleukin 5 to the crystalloid core compartment of eosinophil secondary granules in patients with atopic asthma.  J Histochem Cytochem. 1996;  44(1) 67-69
• 77 Dubucquoi S, Desreumaux P, Janin A et al.. Interleukin 5 synthesis by eosinophils: association with granules and immunoglobulin-dependent secretion.  J Exp Med. 1994;  179(2) 703-708
• 78 Woerly G, Lacy P, Younes A B et al.. Human eosinophils express and release IL-13 following CD28-dependent activation.  J Leukoc Biol. 2002;  72(4) 769-779
• 79 Schmid-Grendelmeier P, Altznauer F, Fischer B et al.. Eosinophils express functional IL-13 in eosinophilic inflammatory diseases.  J Immunol. 2002;  169(2) 1021-1027
• 80 Moqbel R, Ying S, Barkans J et al.. Identification of messenger RNA for IL-4 in human eosinophils with granule localization and release of the translated product.  J Immunol. 1995;  155(10) 4939-4947
• 81 Nakajima H, Gleich G J, Kita H. Constitutive production of IL-4 and IL-10 and stimulated production of IL-8 by normal peripheral blood eosinophils.  J Immunol. 1996;  156(12) 4859-4866
• 82 Kita H, Ohnishi T, Okubo Y, Weiler D, Abrams J S, Gleich G J. Granulocyte/macrophage colony-stimulating factor and interleukin 3 release from human peripheral blood eosinophils and neutrophils.  J Exp Med. 1991;  174(3) 745-748
• 83 Hamid Q, Barkans J, Meng Q et al.. Human eosinophils synthesize and secrete interleukin-6, in vitro.  Blood. 1992;  80(6) 1496-1501
• 84 Braun R K, Franchini M, Erard F et al.. Human peripheral blood eosinophils produce and release interleukin-8 on stimulation with calcium ionophore.  Eur J Immunol. 1993;  23(4) 956-960
• 85 Costa J J, Matossian K, Resnick M B et al.. Human eosinophils can express the cytokines tumor necrosis factor-alpha and macrophage inflammatory protein-1 alpha.  J Clin Invest. 1993;  91(6) 2673-2684
• 86 Lacy P, Mahmudi-Azer S, Bablitz B et al.. Rapid mobilization of intracellularly stored RANTES in response to interferon-gamma in human eosinophils.  Blood. 1999;  94(1) 23-32
• 87 Nakajima T, Yamada H, Iikura M et al.. Intracellular localization and release of eotaxin from normal eosinophils.  FEBS Lett. 1998;  434(3) 226-230
• 88 Hartman M, Piliponsky A M, Temkin V, Levi-Schaffer F. Human peripheral blood eosinophils express stem cell factor.  Blood. 2001;  97(4) 1086-1091
• 89 Levi-Schaffer F, Temkin V, Malamud V, Feld S, Zilberman Y. Mast cells enhance eosinophil survival in vitro: role of TNF-alpha and granulocyte-macrophage colony-stimulating factor.  J Immunol. 1998;  160(11) 5554-5562
• 90 Smith S J, Levi-Schaffer F. Mast cell-eosinophil-fibroblast crosstalk in allergic inflammation.  Chem Immunol. 2000;  78 81-92
• 91 Levi-Schaffer F, Temkin V, Malamud V, Feld S, Zilberman Y. Mast cells enhance eosinophil survival in vitro: role of TNF-alpha and granulocyte-macrophage colony-stimulating factor.  J Immunol. 1998;  160(11) 5554-5562
• 92 Shi H Z. Eosinophils function as antigen-presenting cells.  J Leukoc Biol. 2004;  76(3) 520-527
• 93 Noguchi H, Kephart G M, Colby T V, Gleich G J. Tissue eosinophilia and eosinophil degranulation in syndromes associated with fibrosis.  Am J Pathol. 1992;  140(2) 521-528
• 94 Cho J Y, Miller M, Baek K J et al.. Inhibition of airway remodeling in IL-5-deficient mice.  J Clin Invest. 2004;  113(4) 551-560
• 95 Flood-Page P, Menzies-Gow A, Phipps S et al.. Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics.  J Clin Invest. 2003;  112(7) 1029-1036
• 96 Hernnas J, Sarnstrand B, Lindroth P, Peterson C G, Venge P, Malmstrom A. Eosinophil cationic protein alters proteoglycan metabolism in human lung fibroblast cultures.  Eur J Cell Biol. 1992;  59(2) 352-363
• 97 Powell P P, Klagsbrun M, Abraham J A, Jones R C. Eosinophils expressing heparin-binding EGF-like growth factor mRNA localize around lung microvessels in pulmonary hypertension.  Am J Pathol. 1993;  143(3) 784-793
• 98 Solomon A, Aloe L, Pe'er J et al.. Nerve growth factor is preformed in and activates human peripheral blood eosinophils.  J Allergy Clin Immunol. 1998;  102(3) 454-460
• 99 Wong D T, Elovic A, Matossian K et al.. Eosinophils from patients with blood eosinophilia express transforming growth factor beta 1.  Blood. 1991;  78(10) 2702-2707
• 100 Wong D T, Weller P F, Galli S J et al.. Human eosinophils express transforming growth factor alpha.  J Exp Med. 1990;  172(3) 673-681
• 101 Moqbel R, Ying S, Barkans J et al.. Identification of messenger RNA for IL-4 in human eosinophils with granule localization and release of the translated product.  J Immunol. 1995;  155(10) 4939-4947
• 102 Hogan S P, Matthaei K I, Young J M, Koskinen A, Young I G, Foster P S. A novel T cell-regulated mechanism modulating allergen-induced airways hyperreactivity in BALB/c mice independently of IL-4 and IL-5.  J Immunol. 1998;  161(3) 1501-1509
• 103 Cohn L, Tepper J S, Bottomly K. IL-4-independent induction of airway hyperresponsiveness by Th2, but not Th1, cells.  J Immunol. 1998;  161(8) 3813-3816
• 104 Wills-Karp M, Luyimbazi J, Xu X et al.. Interleukin-13: central mediator of allergic asthma.  Science. 1998;  282(5397) 2258-2261
• 105 Grunig G, Warnock M, Wakil A E et al.. Requirement for IL-13 independently of IL-4 in experimental asthma.  Science. 1998;  282(5397) 2261-2263
• 106 Zhu Z, Homer R J, Wang Z et al.. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production.  J Clin Invest. 1999;  103(6) 779-788
• 107 Chiaramonte M G, Donaldson D D, Cheever A W, Wynn T A. An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2-dominated inflammatory response.  J Clin Invest. 1999;  104(6) 777-785
• 108 Temkin V, Aingorn H, Puxeddu I et al.. Eosinophil major basic protein: first identified natural heparinase-inhibiting protein.  J Allergy Clin Immunol. 2004;  113(4) 703-709
• 109 McDonald D M. Angiogenesis and remodeling of airway vasculature in chronic inflammation.  Am J Respir Crit Care Med. 2001;  164(10 Pt 2) S39-S45
• 110 Lee C G, Link H, Baluk P et al.. Vascular endothelial growth factor (VEGF) induces remodeling and enhances TH2-mediated sensitization and inflammation in the lung.  Nat Med. 2004;  10(10) 1095-1103
• 111 Hoshino M, Takahashi M, Aoike N. Expression of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin immunoreactivity in asthmatic airways and its relationship to angiogenesis.  J Allergy Clin Immunol. 2001;  107(2) 295-301
• 112 Karawajczyk M, Seveus L, Garcia R et al.. Piecemeal degranulation of peripheral blood eosinophils: a study of allergic subjects during and out of the pollen season.  Am J Respir Cell Mol Biol. 2000;  23(4) 521-529
• 113 Sutton R B, Fasshauer D, Jahn R, Brunger A T. Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 A resolution.  Nature. 1998;  395(6700) 347-353
• 114 Hoffmann H J, Bjerke T, Karawajczyk M, Dahl R, Knepper M A, Nielsen S. SNARE proteins are critical for regulated exocytosis of ECP from human eosinophils.  Biochem Biophys Res Commun. 2001;  282(1) 194-199
• 115 Moqbel R, Lacy P. Exocytotic events in eosinophils and mast cells.  Clin Exp Allergy. 1999;  29(8) 1017-1022
• 116 Filley W V, Holley K E, Kephart G M, Gleich G J. Identification by immunofluorescence of eosinophil granule major basic protein in lung tissues of patients with bronchial asthma.  Lancet. 1982;  2(8288) 11-16
• 117 Woolley K L, Gibson P G, Carty K, Wilson A J, Twaddell S H, Woolley M J. Eosinophil apoptosis and the resolution of airway inflammation in asthma.  Am J Respir Crit Care Med. 1996;  154(1) 237-243
• 118 Kankaanranta H, Lindsay M A, Giembycz M A, Zhang X, Moilanen E, Barnes P J. Delayed eosinophil apoptosis in asthma.  J Allergy Clin Immunol. 2000;  106(1 Pt 1) 77-83
• 119 Woolley K L, Gibson P G, Carty K, Wilson A J, Twaddell S H, Woolley M J. Eosinophil apoptosis and the resolution of airway inflammation in asthma.  Am J Respir Crit Care Med. 1996;  154(1) 237-243
• 120 Sexton D W, Blaylock M G, Walsh G M. Human alveolar epithelial cells engulf apoptotic eosinophils by means of integrin- and phosphatidylserine receptor-dependent mechanisms: a process upregulated by dexamethasone.  J Allergy Clin Immunol. 2001;  108(6) 962-969
• 121 Uller L, Persson C G, Kallstrom L, Erjefalt J S. Lung tissue eosinophils may be cleared through luminal entry rather than apoptosis: effects of steroid treatment.  Am J Respir Crit Care Med. 2001;  164(10 Pt 1) 1948-1956
• 122 Yamaguchi Y, Suda T, Ohta S, Tominaga K, Miura Y, Kasahara T. Analysis of the survival of mature human eosinophils: interleukin-5 prevents apoptosis in mature human eosinophils.  Blood. 1991;  78(10) 2542-2547
• 123 Dewson G, Cohen G M, Wardlaw A J. Interleukin-5 inhibits translocation of Bax to the mitochondria, cytochrome c release, and activation of caspases in human eosinophils.  Blood. 2001;  98(7) 2239-2247
• 124 Nutku E, Aizawa H, Hudson S A, Bochner B S. Ligation of Siglec-8: a selective mechanism for induction of human eosinophil apoptosis.  Blood. 2003;  101(12) 5014-5020