Integrins as therapeutic targets for respiratory diseases

Current Molecular Medicine

Volumn 15, Issue 8, 2015, Pages 714-734

  Teoh, C M ^a   Tan, S S L ^a   Tran, T ^a  

^a NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

Author keywords

Asthma; Emphysema; Integrins; Lung cancer; Lung disease; Pulmonary fibrosis; Sarcoidosis

Indexed keywords

ALPHA1 INTEGRIN; ALPHA3 INTEGRIN; ALPHAEBETA7 INTEGRIN; ALPHAVBETA5 INTEGRIN; ALPHAVBETA6 INTEGRIN; BETA INTEGRIN; CILENGITIDE; ETARACIZUMAB; GW 559090X; HMR 1031; INTEGRIN; INTEGRIN LINKED KINASE; INTERCELLULAR ADHESION MOLECULE 1; IV L745; OSTEONECTIN; PHOSPHATIDYLINOSITOL 3 KINASE; TR 14035; TRANSCRIPTION FACTOR RUNX2; TRANSFORMING GROWTH FACTOR BETA; UNCLASSIFIED DRUG; UNINDEXED DRUG; VALATEGRAST; VASCULAR CELL ADHESION MOLECULE 1; VASCULOTROPIN; VERY LATE ACTIVATION ANTIGEN 1; VERY LATE ACTIVATION ANTIGEN 2; VERY LATE ACTIVATION ANTIGEN 4; VERY LATE ACTIVATION ANTIGEN 5; VITRONECTIN RECEPTOR; VOLOCIXIMAB; CARRIER PROTEIN; PROTEIN BINDING;

AIRWAY REMODELING; ANGIOGENESIS; ARTICLE; ASTHMA; BRANCHING MORPHOGENESIS; CELL ADHESION; CELL INTERACTION; CELL MIGRATION; CELL SURVIVAL; CHRONIC OBSTRUCTIVE LUNG DISEASE; EMPHYSEMA; EXTRACELLULAR MATRIX; FETUS LUNG MATURATION; HUMAN; INFLAMMATION; LUNG CANCER; LUNG ENDOTHELIUM; LUNG FIBROSIS; LUNG HYPOPLASIA; NON SMALL CELL LUNG CANCER; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PNEUMONIA; RESPIRATORY TRACT DISEASE; SARCOIDOSIS; ANIMAL; ANTAGONISTS AND INHIBITORS; CELL MOTION; CHEMISTRY; CLINICAL TRIAL (TOPIC); DISEASE MODEL; GENE EXPRESSION REGULATION; GENETICS; KNOCKOUT MOUSE; LUNG; METABOLISM; MOLECULARLY TARGETED THERAPY; MULTIGENE FAMILY; NEOVASCULARIZATION (PATHOLOGY); PATHOLOGY; PHENOTYPE; RESPIRATORY TRACT DISEASES; SIGNAL TRANSDUCTION; TREATMENT OUTCOME;

AIRWAY REMODELING; ANIMALS; CARRIER PROTEINS; CELL ADHESION; CELL MOVEMENT; CELL SURVIVAL; CLINICAL TRIALS AS TOPIC; DISEASE MODELS, ANIMAL; EXTRACELLULAR MATRIX; GENE EXPRESSION REGULATION; HUMANS; INTEGRINS; LUNG; MICE, KNOCKOUT; MOLECULAR TARGETED THERAPY; MULTIGENE FAMILY; NEOVASCULARIZATION, PATHOLOGIC; OSTEONECTIN; PHENOTYPE; PROTEIN BINDING; RESPIRATORY TRACT DISEASES; SIGNAL TRANSDUCTION; TRANSFORMING GROWTH FACTOR BETA; TREATMENT OUTCOME;

EID: 84945971123     PISSN: 15665240     EISSN: 18755666     Source Type: Journal    
DOI: 10.2174/1566524015666150921105339     Document Type: Article

References (195)

1. Minino AM, Heron MP, Murphy SL, et al. Deaths: final data for 2004. Natl Vital Stat Rep 2007; 55(19): 1-119.
2. Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell 1992;69(1):11-25.
3. Hood JD, Cheresh DA. Role of integrins in cell invasion and migration. Nat Rev Cancer 2002; 2(2): 91-100.
4. Humphries MJ. Integrin structure. Biochem Soc Trans 2000; 28(4): 311-39.
5. Giancotti FG, Ruoslahti E. Integrin signaling. Science 1999; 285(5430): 1028-32.
6. Cabodi S, Di Stefano P, Leal MeP, et al. Integrins and signal transduction. Adv Exp Med Biol 2010; 674: 43-54.
7. Bazan-Socha S, Bukiej A, Marcinkiewicz C, et al. Integrins in pulmonary inflammatory diseases. Curr Pharm Des 2005;11(7): 893-901.
8. van der Flier A, Sonnenberg A. Function and interactions of integrins. Cell Tissue Res 2001; 305(3): 285-98.
9. Cox D, Brennan M, Moran N. Integrins as therapeutic targets: lessons and opportunities. Nat Rev Drug Discov 2010; 9(10): 804-20.
10. Minagawa S, Lou J, Seed RI, et al. Selective targeting of TGF-β activation to treat fibroinflammatory airway disease. Sci Transl Med 2014; 6(241): 241ra79.
11. Mu D, Cambier S, Fjellbirkeland L, et al. The integrin alpha(v)beta8 mediates epithelial homeostasis through MT1- MMP-dependent activation of TGF-beta1. J Cell Biol 2002; 157(3): 493-507.
12. Giancotti F, Ruoslahti E. Integrin signaling. Science 1999; 285(5430): 1028-32.
13. Ross R. Molecular and mechanical synergy: cross-talk between integrins and growth factor receptors. Cardiovasc Res 2004; 63(3): 81-90.
14. Zaidel-Bar R, Itzkovitz S, Ma'ayan A, et al. Functional atlas of the integrin adhesome. Nat Cell Biol 2007; 9(8): 858-67.
15. Harburger DS, Calderwood DA. Integrin signalling at a glance. J Cell Sci 2009; 122(Pt 2): 159-63.
16. Legate KR, Wickstrom SA, Fassler R. Genetic and cell biological analysis of integrin outside-in signaling. Genes Dev 2009; 23(4): 397-418.
17. Welsh CF, Assoian RK. A growing role for Rho family GTPases as intermediaries in growth factor- and adhesiondependent cell cycle progression. Biochim Biophys Acta 2000; 1471(1): M21-9.
18. Hanks SK, Calalb MB, Harper MC, et al. Focal adhesion protein-tyrosine kinase phosphorylated in response to cell attachment to fibronectin. Proc Natl Acad Sci U S A 1992; 89(18): 8487-91.
19. Huveneers S, Truong H, Danen HJ. Integrins: signaling, disease, and therapy. Int J Radiat Biol 2007; 83(11-12): 743- 51.
20. Kim SH, Turnbull J, Guimond S. Extracellular matrix and cell signalling: the dynamic cooperation of integrin, proteoglycan and growth factor receptor. J Endocrinol 2011; 209(2): 139- 51.
21. Kim SH. Antagonistic effect of EGF on FAK phosphorylation/dephosphorylation in a cell. Cell Biochem Funct 2008; 26(5): 539-47.
22. Slack-Davis JK, Eblen ST, Zecevic M, et al. PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation. J Cell Biol 2003; 162(2): 281-91.
23. Edin ML, Juliano RL. Raf-1 serine 338 phosphorylation plays a key role in adhesion-dependent activation of extracellular signal-regulated kinase by epidermal growth factor. Mol Cell Biol 2005; 25(11): 4466-75.
24. Sheppard D. Functions of pulmonary epithelial integrins: from development to disease. Physiol Rev 2003; 83(3): 673-86.
25. Coraux C, Delplanque A, Hinnrasky J, et al. Distribution of integrins during human fetal lung development. J Histochem Cytochem 1998; 46(7): 803-10.
26. Wagner TE, Frevert CW, Herzog EL, et al. Expression of the integrin subunit alpha8 in murine lung development. J Histochem Cytochem 2003; 51(10): 1307-15.
27. Wu JE, Santoro SA. Differential expression of integrin alpha subunits supports distinct roles during lung branching morphogenesis. Dev Dyn 1996; 206(2): 169-81.
28. Cambier S, Mu DZ, O'Connell D, et al. A role for the integrin alphavbeta8 in the negative regulation of epithelial cell growth. Cancer Res 2000; 60(24): 7084-93.
29. Damjanovich L, Albelda SM, Mette SA, et al. Distribution of integrin cell adhesion receptors in normal and malignant lung tissue. Am J Respir Cell Mol Biol 1992; 6(2): 197-206.
30. Mette SA, Pilewski J, Buck CA, et al. Distribution of integrin cell adhesion receptors on normal bronchial epithelial cells and lung cancer cells in vitro and in vivo. Am J Respir Cell Mol Biol 1993; 8(5): 562-72.
31. Palmer EL, Ruegg C, Ferrando R, et al. Sequence and tissue distribution of the integrin alpha 9 subunit, a novel partner of beta 1 that is widely distributed in epithelia and muscle. J Cell Biol 1993; 123(5): 1289-97.
32. Pilewski JM, Latoche JD, Arcasoy SM, et al. Expression of integrin cell adhesion receptors during human airway epithelial repair in vivo. Am J Physiol 1997; 273(1 Pt 1): L256-63.
33. Weinacker A, Ferrando R, Elliott M, et al. Distribution of integrins alpha v beta 6 and alpha 9 beta 1 and their known ligands, fibronectin and tenascin, in human airways. Am J Respir Cell Mol Biol 1995; 12(5): 547-56.
34. Korhonen M, Ylanne J, Laitinen L, et al. The alpha 1-alpha 6 subunits of integrins are characteristically expressed in distinct segments of developing and adult human nephron. J Cell Biol 1990; 111(3): 1245-54.
35. Kadoya Y, Kadoya K, Durbeej M, et al. Antibodies against domain E3 of laminin-1 and integrin alpha 6 subunit perturb branching epithelial morphogenesis of submandibular gland, but by different modes. J Cell Biol 1995; 129(2): 521-34.
36. Sorokin L, Sonnenberg A, Aumailley M, et al. Recognition of the laminin E8 cell-binding site by an integrin possessing the alpha 6 subunit is essential for epithelial polarization in developing kidney tubules. J Cell Biol 1990; 111(3): 1265-73.
37. Carter WG, Wayner EA, Bouchard TS, et al. The role of integrins alpha 2 beta 1 and alpha 3 beta 1 in cell-cell and cell-substrate adhesion of human epidermal cells. J Cell Biol 1990; 110(4): 1387-404.
38. Sriramarao P, Steffner P, Gehlsen KR. Biochemical evidence for a homophilic interaction of the alpha 3 beta 1 integrin. J Biol Chem 1993; 268(29): 22036-41.
39. Symington BE, Takada Y, Carter WG. Interaction of integrins alpha 3 beta 1 and alpha 2 beta 1: potential role in keratinocyte intercellular adhesion. J Cell Biol 1993; 120(2): 523-35.
40. Tenchini ML, Adams JC, Gilberty C, et al. Evidence against a major role for integrins in calcium-dependent intercellular adhesion of epidermal keratinocytes. Cell Adhes Commun 1993; 1(1): 55-66.
41. Weitzman JB, Chen A, Hemler ME. Investigation of the role of beta 1 integrins in cell-cell adhesion. J Cell Sci 1995; 108 (Pt 11): 3635-44.
42. Weitzman JB, Pasqualini R, Takada Y, et al. The function and distinctive regulation of the integrin VLA-3 in cell adhesion, spreading, and homotypic cell aggregation. J Biol Chem 1993; 268(12): 8651-7.
43. Georges-Labouesse E, Messaddeq N, Yehia G, et al. Absence of integrin alpha 6 leads to epidermolysis bullosa and neonatal death in mice. Nat Genet 1996; 13(3): 370-3.
44. van der Neut R, Krimpenfort P, Calafat J, et al. Epithelial detachment due to absence of hemidesmosomes in integrin beta 4 null mice. Nat Genet 1996; 13(3): 366-9.
45. Eto K, Huet C, Tarui T, et al. Functional classification of ADAMs based on a conserved motif for binding to integrin alpha 9beta 1: implications for sperm-egg binding and other cell interactions. J Biol Chem 2002; 277(20): 17804-10.
46. Busk M, Pytela R, Sheppard D. Characterization of the integrin alpha v beta 6 as a fibronectin-binding protein. J Biol Chem 1992; 267(9): 5790-6.
47. Roman J, Little CW, McDonald JA. Potential role of RGDbinding integrins in mammalian lung branching morphogenesis. Development 1991; 112(2): 551-8.
48. Singh B, Fu C, Bhattacharya J. Vascular expression of the alpha(v)beta(3)-integrin in lung and other organs. Am J Physiol Lung Cell Mol Physiol 2000; 278(1): L217-26.
49. Berlin M, Lundahl J, Skold CM, et al. The lymphocytic alveolitis in sarcoidosis is associated with increased amounts of soluble and cell-bound adhesion molecules in bronchoalveolar lavage fluid and serum. J Intern Med 1998; 244(4): 333-40.
50. Shigehara K, Shijubo N, Hirasawa M, et al. Immunolocalization of extracellular matrix proteins and integrins in sarcoid lymph nodes. Virchows Arch 1998; 433(1): 55-61.
51. White ES, Thannickal VJ, Carskadon SL, et al. Integrin alpha4beta1 regulates migration across basement membranes by lung fibroblasts: a role for phosphatase and tensin homologue deleted on chromosome 10. Am J Respir Crit Care Med 2003; 168(4): 436-42.
52. Zhu CQ, Popova SN, Brown ER, et al. Integrin alpha 11 regulates IGF2 expression in fibroblasts to enhance tumorigenicity of human non-small-cell lung cancer cells. Proc Natl Acad Sci U S A 2007; 104(28): 11754-9.
53. Freyer A, Johnson S, Hall I. Effects of growth factors and extracellular matrix on survival of human airway smooth muscle cells. Am J Respir Cell Mol Biol 2001; 25(5): 569-76.
54. Tran T, Ens-Blackie K, Rector ES, et al. Laminin-binding integrin alpha7 is required for contractile phenotype expression by human airway myocytes. Am J Respir Cell Mol Biol 2007; 37(6): 668-80.
55. Lohmeyer J, Friedrich J, Grimminger F, et al. Expression of mucosa-related integrin alphaEbeta7 on alveolar T cells in interstitial lung diseases. Clin Exp Immunol 1999; 116(2): 340-6.
56. Tatler AL, John AE, Jolly L, et al. Integrin αvβ5-mediated TGF-β activation by airway smooth muscle cells in asthma. J Immunol 2011; 187(11): 6094-107.
57. Senger DR, Claffey KP, Benes JE, et al. Angiogenesis promoted by vascular endothelial growth factor: regulation through alpha1beta1 and alpha2beta1 integrins. Proc Natl Acad Sci U S A 1997; 94(25): 13612-7.
58. Macias-Perez I, Borza C, Chen X, et al. Loss of integrin alpha1beta1 ameliorates Kras-induced lung cancer. Cancer Res 2008; 68(15): 6127-35.
59. Berlin M, Lundahl J, Skold CM, et al. The lymphocytic alveolitis in sarcoidosis is associated with increased amounts of soluble and cell-bound adhesion molecules in bronchoalveolar lavage fluid and serum. J Intern Med 1998; 244(4): 333-40.
60. Ohashi Y, Motojima S, Fukuda T, et al. Airway hyperresponsiveness, increased intracellular spaces of bronchial epithelium, and increased infiltration of eosinophils and lymphocytes in bronchial mucosa in asthma. Am Rev Respir Dis 1992; 145(6): 1469-76.
61. Nagata M, Yamamoto H, Tabe K, et al. Eosinophil transmigration across VCAM-1-expressing endothelial cells is upregulated by antigen-stimulated mononuclear cells. Int Arch Allergy Immunol 2001; 125 Suppl 1: 7-11.
62. Hocking DC. Fibronectin matrix deposition and cell contractility: implications for airway remodeling in asthma. Chest 2002; 122 (6 Suppl): 275S-8S.
63. Han JY, Kim HS, Lee SH, et al. Immunohistochemical expression of integrins and extracellular matrix proteins in non-small cell lung cancer: correlation with lymph node metastasis. Lung Cancer 2003; 41(1): 65-70.
64. Huang XZ, Wu JF, Cass D, et al. Inactivation of the integrin beta 6 subunit gene reveals a role of epithelial integrins in regulating inflammation in the lung and skin. J Cell Biol 1996; 133(4): 921-8.
65. Morris DG, Huang X, Kaminski N, et al. Loss of integrin alpha(v)beta6-mediated TGF-beta activation causes Mmp12- dependent emphysema. Nature 2003; 422(6928): 169-73.
66. Sheppard D. Roles of alphav integrins in vascular biology and pulmonary pathology. Curr Opin Cell Biol 2004; 16(5): 552-7.
67. Wipff PJ, Rifkin DB, Meister JJ, et al. Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix. J Cell Biol 2007; 179(6): 1311-23.
68. Horan GS, Wood S, Ona V, et al. Partial inhibition of integrin alpha(v)beta6 prevents pulmonary fibrosis without exacerbating inflammation. Am J Respir Crit Care Med 2008; 177(1): 56-65.
69. John AE, Luckett JC, Tatler AL, et al. Preclinical SPECT/CT imaging of αvβ6 integrins for molecular stratification of idiopathic pulmonary fibrosis. J Nucl Med 2013; 54(12): 2146-52.
70. Jenkins RG, Su X, Su G, et al. Ligation of protease-activated receptor 1 enhances alpha(v)beta6 integrin-dependent TGFbeta activation and promotes acute lung injury. J Clin Invest 2006; 116(6): 1606-14.
71. Xu MY, Porte J, Knox AJ, et al. Lysophosphatidic acid induces alphavbeta6 integrin-mediated TGF-beta activation via the LPA2 receptor and the small G protein G alpha(q). Am J Pathol 2009; 174(4): 1264-79.
72. Jolly L, Stavrou A, Vanderstoken G, et al. Influenza promotes collagen deposition via αvβ6 integrin-mediated transforming growth factor β activation. J Biol Chem 2014; 289(51): 35246-63.
73. Konishi K, Gibson KF, Lindell KO, et al. Gene expression profiles of acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2009; 180(2): 167-75.
74. Benayoun L, Druilhe A, Dombret M, et al. Airway structural alterations selectively associated with severe asthma. Am J Respir Crit Care Med 2003; 167(10): 1360-8.
75. Tran T, Teoh CM, Tam JK, et al. Laminin drives survival signals to promote a contractile smooth muscle phenotype and airway hyperreactivity. FASEB J 2013; 27(10): 3991- 4003.
76. Lambert RK, Wiggs BR, Kuwano K, et al. Functional significance of increased airway smooth muscle in asthma and COPD. J Appl Physiol 1993; 74(6): 2771-81.
77. Christie PE, Jonas M, Tsai CH, et al. Increase in laminin expression in allergic airway remodelling and decrease by dexamethasone. Eur Respir J 2004; 24(1): 107-15.
78. Rihs S, Walker C, Virchow JC, Jr, et al. Differential expression of alpha E beta 7 integrins on bronchoalveolar lavage T lymphocyte subsets: regulation by alpha 4 beta 1- integrin crosslinking and TGF-beta. Am J Respir Cell Mol Biol 1996; 15(5): 600-10.
79. Leckie MJ, Jenkins GR, Khan J, et al. Sputum T lymphocytes in asthma, COPD and healthy subjects have the phenotype of activated intraepithelial T cells (CD69+ CD103+). Thorax 2003; 58(1): 23-9.
80. Lawler J. The functions of thrombospondin-1 and-2. Curr Opin Cell Biol 2000; 12(5): 634-40.
81. Lawler J, Sunday M, Thibert V, et al. Thrombospondin-1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia. J Clin Invest 1998; 101(5): 982- 92.
82. Yabkowitz R, Dixit VM, Guo N, et al. Activated T-cell adhesion to thrombospondin is mediated by the alpha 4 beta 1 (VLA-4) and alpha 5 beta 1 (VLA-5) integrins. J Immunol 1993; 151(1): 149-58.
83. Mansfield PJ, Boxer LA, Suchard SJ. Thrombospondin stimulates motility of human neutrophils. J Cell Biol 1990; 111(6 Pt 2): 3077-86.
84. Mansfield PJ, Suchard SJ. Thrombospondin promotes chemotaxis and haptotaxis of human peripheral blood monocytes. J Immunol 1994; 153(9): 4219-29.
85. Huber AR, Ellis S, Johnson KJ, et al. Monocyte diapedesis through an in vitro vessel wall construct: inhibition with monoclonal antibodies to thrombospondin. J Leukoc Biol 1992; 52(5): 524-8.
86. Guo N, Templeton NS, Al-Barazi H, et al. Thrombospondin-1 promotes alpha3beta1 integrin-mediated adhesion and neurite-like outgrowth and inhibits proliferation of small cell lung carcinoma cells. Cancer Res 2000; 60(2): 457-66.
87. Ezzie ME, Piper MG, Montague C, et al. Thrombospondin-1- deficient mice are not protected from bleomycin-induced pulmonary fibrosis Am J Respir Cell Mol Biol 2011; 44(4): 556-61.
88. Sheppard D. Transforming growth factor beta: a central modulator of pulmonary and airway inflammation and fibrosis. Proc Am Thorac Soc 2006; 3(5): 413-7.
89. Munger JS, Huang X, Kawakatsu H, et al. The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 1999; 96(3): 319-28.
90. Clark CJ, Sage EH. A prototypic matricellular protein in the tumor microenvironment--where there's SPARC, there's fire. J Cell Biochem 2008; 104(3): 721-32.
91. Kuhn C, Mason RJ. Immunolocalization of SPARC, tenascin, and thrombospondin in pulmonary fibrosis. Am J Pathol 1995; 147(6): 1759-69.
92. Sage H, Vernon RB, Funk SE, et al. SPARC, a secreted protein associated with cellular proliferation, inhibits cell spreading in vitro and exhibits Ca+2-dependent binding to the extracellular matrix. J Cell Biol 1989; 109(1): 341-56.
93. Francki A, Bradshaw AD, Bassuk JA, et al. SPARC regulates the expression of collagen type I and transforming growth factor-beta1 in mesangial cells. J Biol Chem 1999; 274(45): 32145-52.
94. Gruber HE, Sage EH, Norton HJ, et al. Targeted deletion of the SPARC gene accelerates disc degeneration in the aging mouse. J Histochem Cytochem 2005; 53(9): 1131-8.
95. Bradshaw AD, Puolakkainen P, Dasgupta J, et al. SPARCnull mice display abnormalities in the dermis characterized by decreased collagen fibril diameter and reduced tensile strength. J Invest Dermatol 2003; 120(6): 949-55.
96. Barker TH, Baneyx G, Cardo-Vila M, et al. SPARC regulates extracellular matrix organization through its modulation of integrin-linked kinase activity. J Biol Chem 2005; 280(43): 36483-93.
97. Chang W, Wei K, Jacobs SS, et al. SPARC suppresses apoptosis of idiopathic pulmonary fibrosis fibroblasts through constitutive activation of beta-catenin. J Biol Chem 2010; 285(11): 8196-206.
98. Takayama G, Arima K, Kanaji T, et al. Periostin: a novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals. J Allergy Clin Immunol 2006; 118(1): 98-104.
99. Blanchard C, Mingler MK, McBride M, et al. Periostin facilitates eosinophil tissue infiltration in allergic lung and esophageal responses. Mucosal Immunol 2008; 1(4): 289- 96.
100. Gillan L, Matei D, Fishman DA, et al. Periostin secreted by epithelial ovarian carcinoma is a ligand for alpha(V)beta(3) and alpha(V)beta(5) integrins and promotes cell motility. Cancer Res 2002; 62(18): 5358-64.
101. Sehra S, Yao W, Nguyen ET, et al. Periostin regulates goblet cell metaplasia in a model of allergic airway inflammation. J Immunol 2011; 186(8): 4959-66.
102. Thai P, Loukoianov A, Wachi S, et al. Regulation of airway mucin gene expression. Annu Rev Physiol 2008; 70: 405-29.
103. Ouyang G, Liu M, Ruan K, et al. Upregulated expression of periostin by hypoxia in non-small-cell lung cancer cells promotes cell survival via the Akt/PKB pathway. Cancer Lett 2009; 281(2): 213-9.
104. Bao S, Ouyang G, Bai X, et al. Periostin potently promotes metastatic growth of colon cancer by augmenting cell survival via the Akt/PKB pathway. Cancer Cell 2004; 5(4): 329-39.
105. Naik PK, Bozyk PD, Bentley JK, et al. Periostin promotes fibrosis and predicts progression in patients with idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2012; 303(12): L1046-56.
106. Okamoto M, Hoshino T, Kitasato Y, et al. Periostin, a matrix protein, is a novel biomarker for idiopathic interstitial pneumonias. Eur Respir J 2011; 37(5): 1119-27.
107. Uchida M, Shiraishi H, Ohta S, et al. Periostin, a matricellular protein, plays a role in the induction of chemokines in pulmonary fibrosis. Am J Respir Cell Mol Biol 2012; 46(5): 677-86.
108. Pozzi A, Moberg PE, Miles LA, et al. Elevated matrix metalloprotease and angiostatin levels in integrin alpha 1 knockout mice cause reduced tumor vascularization. Proc Natl Acad Sci U S A 2000; 97(5): 2202-7.
109. Kreidberg JA, Donovan MJ, Goldstein SL, et al. Alpha 3 beta 1 integrin has a crucial role in kidney and lung organogenesis. Development 1996; 122(11): 3537-47.
110. DiPersio CM, Hodivala-Dilke KM, Jaenisch R, et al. alpha3beta1 Integrin is required for normal development of the epidermal basement membrane. J Cell Biol 1997; 137(3): 729-42.
111. Anton ES, Kreidberg JA, Rakic P. Distinct functions of alpha3 and alpha(v) integrin receptors in neuronal migration and laminar organization of the cerebral cortex. Neuron 1999; 22(2): 277-89.
112. Georges-Labouesse E, Mark M, Messaddeq N, et al. Essential role of alpha 6 integrins in cortical and retinal lamination. Curr Biol 1998; 8(17): 983-6.
113. De Arcangelis A, Mark M, Kreidberg J, et al. Synergistic activities of alpha3 and alpha6 integrins are required during apical ectodermal ridge formation and organogenesis in the mouse. Development 1999; 126(17): 3957-68.
114. Huang XZ, Wu JF, Ferrando R, et al. Fatal bilateral chylothorax in mice lacking the integrin alpha9beta1. Mol Cell Biol 2000; 20(14): 5208-15.
115. Su G, Hodnett M, Wu N, et al. Integrin alphavbeta5 regulates lung vascular permeability and pulmonary endothelial barrier function Am J Respir Cell Mol Biol 2007; 36(3): 377-86.
116. Kikuchi M, Tachimoto H, Nutku E, et al. Phorbol esters alter alpha4 and alphad integrin usage during eosinophil adhesion to VCAM-1. Cell Commun Adhes 2003; 10(3): 119-28.
117. Bayless KJ, Meininger GA, Scholtz JM, et al. Osteopontin is a ligand for the alpha4beta1 integrin. J Cell Sci 1998; 111 (Pt 9): 1165-74.
118. Bocchino V, Bertorelli G, D'Ippolito R, et al. The increased number of very late activation antigen-4-positive cells correlates with eosinophils and severity of disease in the induced sputum of asthmatic patients. J Allergy Clin Immunol 2000; 105(1 Pt 1): 65-70.
119. Cox D, Brennan M, Moran N. Integrins as therapeutic targets: lessons and opportunities. Nat Rev Drug Discov 2013; 9(10): 804-20.
120. Norris V, Choong L, Tran D, et al. Effect of IVL745, a VLA-4 antagonist, on allergen-induced bronchoconstriction in patients with asthma. J Allergy Clin Immunol 2005; 116(4): 761-7.
121. Davies DE, Wicks J, Powell RM, et al. Airway remodeling in asthma: new insights. J Allergy Clin Immunol 2003; 111(2): 215-25.
122. McMillan SJ, Xanthou G, Lloyd CM. Manipulation of allergeninduced airway remodeling by treatment with anti-TGF-beta antibody: effect on the Smad signaling pathway. J Immunol 2005; 174(9): 5774-80.
123. Churg A, Zhou S, Wang X, et al. The role of interleukin-1beta in murine cigarette smoke-induced emphysema and small airway remodeling. Am J Respir Cell Mol Biol 2009; 40(4): 482-90.
124. Podowski M, Calvi C, Metzger S, et al. Angiotensin receptor blockade attenuates cigarette smoke-induced lung injury and rescues lung architecture in mice. J Clin Invest 2012; 122(1): 229-40.
125. Kitamura H, Cambier S, Somanath S, et al. Mouse and human lung fibroblasts regulate dendritic cell trafficking, airway inflammation, and fibrosis through integrin αvβ8- mediated activation of TGF-β. J Clin Invest 2011; 121(7): 2863-75.
126. Wang Z, Chui WK, Ho PC. Integrin targeted drug and gene delivery. Expert Opin Drug Deliv 2010; 7(2): 159-71.
127. Ellerby HM, Arap W, Ellerby LM, et al. Anti-cancer activity of targeted pro-apoptotic peptides. Nat Med 1999; 5(9): 1032-8.
128. Reardon DA, Neyns B, Weller M, et al. Cilengitide: an RGD pentapeptide ανβ3 and ανβ5 integrin inhibitor in development for glioblastoma and other malignancies. Future Oncol 2011; 7(3): 339-54.
129. Kuwada SK. Drug evaluation: Volociximab, an angiogenesisinhibiting chimeric monoclonal antibody. Curr Opin Mol Ther 2007; 9(1): 92-8.
130. Francis SE, Goh KL, Hodivala-Dilke K, et al. Central roles of alpha5beta1 integrin and fibronectin in vascular development in mouse embryos and embryoid bodies. Arterioscler Thromb Vasc Biol 2002; 22(6): 927-33.
131. Sudhakar A, Sugimoto H, Yang C, et al. Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by alpha v beta 3 and alpha 5 beta 1 integrins. Proc Natl Acad Sci U S A 2003; 100(8): 4766-71.
132. Pedchenko V, Zent R, Hudson BG. Alpha(v)beta3 and alpha(v)beta5 integrins bind both the proximal RGD site and non-RGD motifs within noncollagenous (NC1) domain of the alpha3 chain of type IV collagen: implication for the mechanism of endothelia cell adhesion. J Biol Chem 2004; 279(4): 2772-80.
133. Marneros AG, Olsen BR. The role of collagen-derived proteolytic fragments in angiogenesis. Matrix Biol 2001; 20(5- 6): 337-45.
134. Marcinkiewicz C, Weinreb PH, Calvete JJ, et al. Obtustatin: a potent selective inhibitor of alpha1beta1 integrin in vitro and angiogenesis in vivo. Cancer Res 2003; 63(9): 2020-3.
135. Nakamura T, Lozano PR, Ikeda Y, et al. Fibulin-5/DANCE is essential for elastogenesis in vivo. Nature 2002; 415(6868): 171-5.
136. White SR, Dorscheid DR, Rabe KF, et al. Role of very late adhesion integrins in mediating repair of human airway epithelial cell monolayers after mechanical injury. Am J Respir Cell Mol Biol 1999; 20(4): 787-96.
137. Adachi M, Taki T, Higashiyama M, et al. Significance of integrin alpha5 gene expression as a prognostic factor in node-negative non-small cell lung cancer. Clin Cancer Res 2000; 6(1): 96-101.
138. Caccavari F, Valdembri D, Sandri C, et al. Integrin signaling and lung cancer. Cell Adh Migr 2010; 4(1): 124-9.
139. Wu H, Zhang Y, Xu Z, et al. The expression of integrin alpha5beta1 and transforming growth factor-beta in pulmonary fibrosis of rat. Zhonghua Bing Li Xue Za Zhi 1999; 28(6): 427-31.
140. Saltini C, Hemler ME, Crystal RG. T lymphocytes compartmentalized on the epithelial surface of the lower respiratory tract express the very late activation antigen complex VLA-1. Clin Immunol Immunopathol 1988; 46(2): 221-33.
141. Gardner H, Kreidberg J, Koteliansky V, et al. Deletion of integrin alpha 1 by homologous recombination permits normal murine development but gives rise to a specific deficit in cell adhesion. Dev Biol 1996; 175(2): 301-13.
142. Pozzi A, Wary KK, Giancotti FG, et al. Integrin alpha1beta1 mediates a unique collagen-dependent proliferation pathway in vivo. J Cell Biol 1998; 142(2): 587-94.
143. Gardner HA. Integrin signaling in fibrosis and scleroderma. Curr Rheumatol Rep 1999; 1(1): 28-33.
144. Holtkotter O, Nieswandt B, Smyth N, et al. Integrin alpha 2- deficient mice develop normally, are fertile, but display partially defective platelet interaction with collagen. J Biol Chem 2002; 277(13): 10789-94.
145. Chen J, Diacovo TG, Grenache DG, et al. The alpha(2) integrin subunit-deficient mouse: a multifaceted phenotype including defects of branching morphogenesis and hemostasis. Am J Pathol 2002; 161(1): 337-44.
146. Edelson BT, Li Z, Pappan LK, et al. Mast cell-mediated inflammatory responses require the alpha 2 beta 1 integrin. Blood 2004; 103(6): 2214-20.
147. McCall-Culbreath KD, Li Z, Zutter MM. Crosstalk between the alpha2beta1 integrin and c-met/HGF-R regulates innate immunity. Blood 2008; 111(7): 3562-70.
148. Menko AS, Kreidberg JA, Ryan TT, et al. Loss of alpha3beta1 integrin function results in an altered differentiation program in the mouse submandibular gland. Dev Dyn 2001; 220(4): 337-49.
149. Yang JT, Rayburn H, Hynes RO. Cell adhesion events mediated by alpha 4 integrins are essential in placental and cardiac development. Development 1995; 121(2): 549-60.
150. Arroyo AG, Yang JT, Rayburn H, et al. Differential requirements for alpha4 integrins during fetal and adult hematopoiesis. Cell 1996; 85(7): 997-1008.
151. Arroyo AG, Taverna D, Whittaker CA, et al. In vivo roles of integrins during leukocyte development and traffic: insights from the analysis of mice chimeric for alpha 5, alpha v, and alpha 4 integrins. J Immunol 2000; 165(8): 4667-75.
152. Yang JT, Rayburn H, Hynes RO. Embryonic mesodermal defects in alpha 5 integrin-deficient mice. Development 1993; 119(4): 1093-105.
153. Yang JT, Bader BL, Kreidberg JA, et al. Overlapping and independent functions of fibronectin receptor integrins in early mesodermal development. Dev Biol 1999; 215(2): 264- 77.
154. Goh KL, Yang JT, Hynes RO. Mesodermal defects and cranial neural crest apoptosis in alpha5 integrin-null embryos. Development 1997; 124(21): 4309-19.
155. Miner JH, Li C. Defective glomerulogenesis in the absence of laminin alpha5 demonstrates a developmental role for the kidney glomerular basement membrane. Dev Biol 2000; 217(2): 278-89.
156. Mayer U, Saher G, Fassler R, et al. Absence of integrin alpha 7 causes a novel form of muscular dystrophy. Nat Genet 1997; 17(3): 318-23.
157. Hayashi YK, Chou FL, Engvall E, et al. Mutations in the integrin alpha7 gene cause congenital myopathy. Nat Genet 1998; 19(1): 94-7.
158. Muller U, Wang D, Denda S, et al. Integrin alpha8beta1 is critically important for epithelial-mesenchymal interactions during kidney morphogenesis. Cell 1997; 88(5): 603-13.
159. Littlewood Evans A, Muller U. Stereocilia defects in the sensory hair cells of the inner ear in mice deficient in integrin alpha8beta1. Nat Genet 2000; 24(4): 424-8.
160. Bader BL, Rayburn H, Crowley D, et al. Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins. Cell 1998; 95(4): 507-19.
161. Henderson NC, Arnold TD, Katamura Y, et al. Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med 2013; 19(12): 1617-24.
162. Schmits R, Kundig TM, Baker DM, et al. LFA-1-deficient mice show normal CTL responses to virus but fail to reject immunogenic tumor. J Exp Med 1996; 183(4): 1415-26.
163. Shier P, Ngo K, Fung-Leung WP. Defective CD8+ T cell activation and cytolytic function in the absence of LFA-1 cannot be restored by increased TCR signaling. J Immunol 1999; 163(9): 4826-32.
164. Berlin-Rufenach C, Otto F, Mathies M, et al. Lymphocyte migration in lymphocyte function-associated antigen (LFA)-1- deficient mice. J Exp Med 1999; 189(9): 1467-78.
165. Coxon A, Rieu P, Barkalow FJ, et al. A novel role for the beta 2 integrin CD11b/CD18 in neutrophil apoptosis: a homeostatic mechanism in inflammation. Immunity 1996; 5(6): 653-66.
166. Rosenkranz AR, Coxon A, Maurer M, et al. Impaired mast cell development and innate immunity in Mac-1 (CD11b/CD18, CR3)-deficient mice. J Immunol 1998; 161(12): 6463-7.
167. Dong ZM, Gutierrez-Ramos JC, Coxon A, et al. A new class of obesity genes encodes leukocyte adhesion receptors. Proc Natl Acad Sci U S A 1997; 94(14): 7526-30.
168. Schon MP, Arya A, Murphy EA, et al. Mucosal T lymphocyte numbers are selectively reduced in integrin alpha E (CD103)- deficient mice. J Immunol 1999; 162(11): 6641-9.
169. Tronik-Le Roux D, Roullot V, Poujol C, et al. Thrombasthenic mice generated by replacement of the integrin alpha(IIb) gene: demonstration that transcriptional activation of this megakaryocytic locus precedes lineage commitment. Blood 2000; 96(4): 1399-408.
170. Fassler R, Meyer M. Consequences of lack of beta 1 integrin gene expression in mice. Genes Dev 1995; 9(15): 1896-908.
171. Stephens LE, Sutherland AE, Klimanskaya IV, et al. Deletion of beta 1 integrins in mice results in inner cell mass failure and peri-implantation lethality. Genes Dev 1995; 9(15): 1883- 95.
172. Hirsch E, Iglesias A, Potocnik AJ, et al. Impaired migration but not differentiation of haematopoietic stem cells in the absence of beta1 integrins. Nature 1996; 380(6570): 171-5.
173. Potocnik AJ, Brakebusch C, Fassler R. Fetal and adult hematopoietic stem cells require beta1 integrin function for colonizing fetal liver, spleen, and bone marrow. Immunity 2000; 12(6): 653-63.
174. Keller RS, Shai SY, Babbitt CJ, et al. Disruption of integrin function in the murine myocardium leads to perinatal lethality, fibrosis, and abnormal cardiac performance. Am J Pathol 2001; 158(3): 1079-90.
175. Scharffetter-Kochanek K, Lu H, Norman K, et al. Spontaneous skin ulceration and defective T cell function in CD18 null mice. J Exp Med 1998; 188(1): 119-31.
176. Mizgerd JP, Kubo H, Kutkoski GJ, et al. Neutrophil emigration in the skin, lungs, and peritoneum: different requirements for CD11/CD18 revealed by CD18-deficient mice. J Exp Med 1997; 186(8): 1357-64.
177. Schneeberger EE, Vu Q, LeBlanc BW, et al. The accumulation of dendritic cells in the lung is impaired in CD18-/- but not in ICAM-1-/- mutant mice. J Immunol 2000; 164(5): 2472-8.
178. Hodivala-Dilke KM, McHugh KP, Tsakiris DA, et al. Beta3- integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival. J Clin Invest 1999; 103(2): 229-38.
179. McHugh KP, Hodivala-Dilke K, Zheng MH, et al. Mice lacking beta3 integrins are osteosclerotic because of dysfunctional osteoclasts. J Clin Invest 2000; 105(4): 433-40.
180. Zimmerman D, Jin F, Leboy P, et al. Impaired bone formation in transgenic mice resulting from altered integrin function in osteoblasts. Dev Biol 2000; 220(1): 2-15.
181. Dowling J, Yu QC, Fuchs E. Beta4 integrin is required for hemidesmosome formation, cell adhesion and cell survival. J Cell Biol 1996; 134(2): 559-72.
182. Huang X, Griffiths M, Wu J, et al. Normal development, wound healing, and adenovirus susceptibility in beta5- deficient mice. Mol Cell Biol 2000; 20(3): 755-9.
183. Wagner N, Lohler J, Kunkel EJ, et al. Critical role for beta7 integrins in formation of the gut-associated lymphoid tissue. Nature 1996; 382(6589): 366-70.
184. Zhu J, Motejlek K, Wang D, et al. beta8 integrins are required for vascular morphogenesis in mouse embryos. Development 2002; 129(12): 2891-903.
185. Ding ZM, Babensee JE, Simon SI, et al. Relative contribution of LFA-1 and Mac-1 to neutrophil adhesion and migration. J Immunol 1999; 163(9): 5029-38.
186. Pulkkinen L, Uitto J. Mutation analysis and molecular genetics of epidermolysis bullosa. Matrix Biol 1999; 18(1): 29-42.
187. Miner JH, Cunningham J, Sanes JR. Roles for laminin in embryogenesis: exencephaly, syndactyly, and placentopathy in mice lacking the laminin alpha5 chain. J Cell Biol 1998; 143(6): 1713-23.
188. Wagner N, Lohler J, Tedder TF, et al. L-selectin and beta7 integrin synergistically mediate lymphocyte migration to mesenteric lymph nodes. Eur J Immunol 1998; 28(11): 3832- 9.
189. Lin K, Ateeq HS, Hsiung SH, et al. Selective, tight-binding inhibitors of integrin alpha4beta1 that inhibit allergic airway responses. J Med Chem 1999; 42(5): 920-34.
190. Abraham WM, Gill A, Ahmed A, et al. A small-molecule, tightbinding inhibitor of the integrin alpha(4)beta(1) blocks antigen-induced airway responses and inflammation in experimental asthma in sheep. Am J Respir Crit Care Med 2000; 162(2 Pt 1): 603-11.
191. Ravensberg AJ, Luijk B, Westers P, et al. The effect of a single inhaled dose of a VLA-4 antagonist on allergeninduced airway responses and airway inflammation in patients with asthma. Allergy 2006; 61(9): 1097-103.
192. Diamant Z, Kuperus J, Baan R, et al. Effect of a very late antigen-4 receptor antagonist on allergen-induced airway responses and inflammation in asthma. Clin Exp Allergy 2005; 35(8): 1080-7.
193. Sircar I, Gudmundsson KS, Martin R, et al. Synthesis and SAR of N-benzoyl-L-biphenylalanine derivatives: discovery of TR-14035, a dual alpha(4)beta(7)/alpha(4)beta(1) integrin antagonist. Bioorg Med Chem 2002; 10(6): 2051-66.
194. Cortijo J, Sanz MJ, Iranzo A, et al. A small molecule, orally active, alpha4beta1/alpha4beta7 dual antagonist reduces leukocyte infiltration and airway hyper-responsiveness in an experimental model of allergic asthma in Brown Norway rats. Br J Pharmacol 2006; 147(6): 661-70.
195. Beekman KW, Colevas AD, Cooney K, et al. Phase II evaluations of cilengitide in asymptomatic patients with androgen-independent prostate cancer: scientific rationale and study design. Clin Genitourin Cancer 2006; 4(4): 299- 302.