Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis

European Respiratory Journal

Volumn 45, Issue 5, 2015, Pages 1434-1445

  Wollin, Lutz ^a   Wex, Eva ^a   Pautsch, Alexander ^a   Schnapp, Gisela ^a   Hostettler, Katrin E ^b   Stowasser, Susanne ^a   Kolb, Martin ^c  

^a BOEHRINGER INGELHEIM PHARMA GMBH AND CO KG   (Germany)

^b UNIVERSITY HOSPITAL BASEL   (Switzerland)

^c MCMASTER UNIVERSITY   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

FIBROBLAST GROWTH FACTOR; FIBROBLAST GROWTH FACTOR RECEPTOR; NINTEDANIB; PLATELET DERIVED GROWTH FACTOR; PLATELET DERIVED GROWTH FACTOR RECEPTOR; VASCULOTROPIN; VASCULOTROPIN RECEPTOR; BLEOMYCIN; ENZYME INHIBITOR; INDOLE DERIVATIVE; SILICON DIOXIDE; TRANSFORMING GROWTH FACTOR BETA;

ANTIANGIOGENIC ACTIVITY; ANTIFIBROTIC ACTIVITY; ANTIINFLAMMATORY ACTIVITY; APOPTOSIS; CELL DIFFERENTIATION; CELL MIGRATION; CELL PROLIFERATION; CELL TRANSFORMATION; DRUG ACTIVITY; DRUG EFFICACY; DRUG MECHANISM; DRUG POTENCY; DRUG SELECTIVITY; EPITHELIAL MESENCHYMAL TRANSITION; FIBROBLAST; FIBROSING ALVEOLITIS; FORCED VITAL CAPACITY; HUMAN; IC50; MYOFIBROBLAST; NONHUMAN; PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; QUALITY OF LIFE; REVIEW; SIGNAL TRANSDUCTION; ANIMAL; CHEMISTRY; CLINICAL TRIAL (TOPIC); CYTOLOGY; EXTRACELLULAR MATRIX; FIBROSIS; IDIOPATHIC PULMONARY FIBROSIS; LUNG; LUNG DISEASES; METABOLISM; PATHOLOGY;

ANIMALS; APOPTOSIS; BLEOMYCIN; CELL DIFFERENTIATION; CELL PROLIFERATION; CLINICAL TRIALS AS TOPIC; ENZYME INHIBITORS; EXTRACELLULAR MATRIX; FIBROBLAST GROWTH FACTORS; FIBROBLASTS; FIBROSIS; HUMANS; IDIOPATHIC PULMONARY FIBROSIS; INDOLES; LUNG; LUNG DISEASES; PLATELET-DERIVED GROWTH FACTOR; SILICON DIOXIDE; TRANSFORMING GROWTH FACTOR BETA;

EID: 84928995543     PISSN: 09031936     EISSN: 13993003     Source Type: Journal    
DOI: 10.1183/09031936.00174914     Document Type: Review

References (85)

1. Vancheri C, Failla M, Crimi N, et al. Idiopathic pulmonary fibrosis: A disease with similarities and links to cancer biology. Eur Respir J 2010; 35: 496-504.
2. Richeldi L, Cottin V, Flaherty KR, et al. Design of the INPULSIS™ trials: Two phase 3 trials of nintedanib in patients with idiopathic pulmonary fibrosis. Respir Med 2014; 108: 1023-1030.
3. Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014; 370: 2071-2082.
4. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: Idiopathic pulmonary fibrosis: Evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011; 183: 788-824.
5. American Thoracic Society, European Respiratory Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med 2002; 165: 277-304.
6. Nalysnyk L, Cid-Ruzafa J, Rotella P, et al. Incidence and prevalence of idiopathic pulmonary fibrosis: review of the literature. Eur Respir Rev 2012; 21: 355-361.
7. Olson AL, Swigris JJ. Idiopathic pulmonary fibrosis: Diagnosis and epidemiology. Clin Chest Med 2012; 33: 41-50.
8. Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): Two randomised trials. Lancet 2011; 377: 1760-1769.
9. King TE Jr, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014; 370: 2083-2092.
10. Borensztajn K, Crestani B, Kolb M. Idiopathic pulmonary fibrosis: from epithelial injury to biomarkers - insights from the bench side. Respiration 2013; 86: 441-452.
11. Selman M, King TE, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001; 134: 136-151.
12. Steele MP, Schwartz DA. Molecular mechanisms in progressive idiopathic pulmonary fibrosis. Annu Rev Med 2013; 64: 265-276.
13. Wuyts WA, Agostini C, Antoniou KM, et al. The pathogenesis of pulmonary fibrosis: A moving target. Eur Respir J 2013; 41: 1207-1218.
14. King TE Jr, Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet 2011; 378: 1949-1961.
15. Bartis D, Mise N, Mahida RY, et al. Epithelial-mesenchymal transition in lung development and disease: Does it exist and is it important? Thorax 2014; 69: 760-765.
16. Willis BC, duBois RM, Borok Z. Epithelial origin of myofibroblasts during fibrosis in the lung. Proc Am Thorac Soc 2006; 3: 377-382.
17. Maharaj S, Shimbori C, Kolb M. Fibrocytes in pulmonary fibrosis: A brief synopsis. Eur Respir Rev 2013; 22: 552-557.
18. Rowley JE, Johnson JR. Pericytes in chronic lung disease. Int Arch Allergy Immunol 2014; 164: 178-188.
19. Mubarak KK, Montes-Worboys A, Regev D, et al. Parenchymal trafficking of pleural mesothelial cells in idiopathic pulmonary fibrosis. Eur Respir J 2012; 39: 133-140.
20. Selman M, Pardo A, Richeldi L, et al. Emerging drugs for idiopathic pulmonary fibrosis. Expert Opin Emerg Drugs 2011; 16: 341-362.
21. Hecker L, Thannickal VJ. Nonresolving fibrotic disorders: Idiopathic pulmonary fibrosis as a paradigm of impaired tissue regeneration. Am J Med Sci 2011; 341: 431-434.
22. Ebina M, Shimizukawa M, Shibata N, et al. Heterogeneous increase in CD34-positive alveolar capillaries in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2004; 169: 1203-1208.
23. Cosgrove GP, Brown KK, Schiemann WP, et al. Pigment epithelium-derived factor in idiopathic pulmonary fibrosis: A role in aberrant angiogenesis. Am J Respir Crit Care Med 2004; 170: 242-251.
24. Farkas L, Gauldie J, Voelkel NF, et al. Pulmonary hypertension and idiopathic pulmonary fibrosis: A tale of angiogenesis, apoptosis, and growth factors. Am J Respir Cell Mol Biol 2011; 45: 1-15.
25. Farkas L, Farkas D, Ask K, et al. VEGF ameliorates pulmonary hypertension through inhibition of endothelial apoptosis in experimental lung fibrosis in rats. J Clin Invest 2009; 119: 1298-1311.
26. Renzoni EA. Neovascularization in idiopathic pulmonary fibrosis: Too much or too little? Am J Respir Crit Care Med 2004; 169: 1179-1180.
27. Kelly M, Kolb M, Bonniaud P, et al. Re-evaluation of fibrogenic cytokines in lung fibrosis. Curr Pharm Des 2003; 9: 39-49.
28. Bonner JC. Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev 2004; 15: 255-273.
29. Vaillant P, Menard O, Vignaud JM, et al. The role of cytokines in human lung fibrosis. Monaldi Arch Chest Dis 1996; 51: 145-152.
30. Adamali HI, Maher TM. Current and novel drug therapies for idiopathic pulmonary fibrosis. Drug Des Devel Ther 2012; 6: 261-272.
31. Clark JG, Madtes DK, Raghu G. Effects of platelet-derived growth factor isoforms on human lung fibroblast proliferation and procollagen gene expression. Exp Lung Res 1993; 19: 327-344.
32. Katzenstein AL, Myers JL. Idiopathic pulmonary fibrosis: Clinical relevance of pathologic classification. Am J Respir Crit Care Med 1998; 157: 1301-1315.
33. Antoniades HN, Bravo MA, Avila RE, et al. Platelet-derived growth factor in idiopathic pulmonary fibrosis. J Clin Invest 1990; 86: 1055-1064.
34. Martinet Y, Rom WN, Grotendorst GR, et al. Exaggerated spontaneous release of platelet-derived growth factor by alveolar macrophages from patients with idiopathic pulmonary fibrosis. N Engl J Med 1987; 317: 202-209.
35. Abdollahi A, Li M, Ping G, et al. Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis. J Exp Med 2005; 201: 925-935.
36. Li M, Abdollahi A, Gröne HJ, et al. Late treatment with imatinib mesylate ameliorates radiation-induced lung fibrosis in a mouse model. Radiat Oncol 2009; 4: 66.
37. Rice AB, Moomaw CR, Morgan DL, et al. Specific inhibitors of platelet-derived growth factor or epidermal growth factor receptor tyrosine kinase reduce pulmonary fibrosis in rats. Am J Pathol 1999; 155: 213-221.
38. Daniels CE, Wilkes MC, Edens M, et al. Imatinib mesylate inhibits the profibrogenic activity of TGF-β and prevents bleomycin-mediated lung fibrosis. J Clin Invest 2004; 114: 1308-1316.
39. Aono Y, Nishioka Y, Inayama M, et al. Imatinib as a novel antifibrotic agent in bleomycin-induced pulmonary fibrosis in mice. Am J Respir Crit Care Med 2005; 171: 1279-1285.
40. Vuorinen K, Gao F, Oury TD, et al. Imatinib mesylate inhibits fibrogenesis in asbestos-induced interstitial pneumonia. Exp Lung Res 2007; 33: 357-373.
41. Daniels CE, Lasky JA, Limper AH, et al. Imatinib treatment for idiopathic pulmonary fibrosis: randomized placebo-controlled trial results. Am J Respir Crit Care Med 2010; 181: 604-610.
42. Olsen SK, Garbi M, Zampieri N, et al. Fibroblast growth factor (FGF) homologous factors share structural but not functional homology with FGFs. J Biol Chem 2003; 278: 34226-34236.
43. Brooks AN, Kilgour E, Smith PD. Molecular pathways: fibroblast growth factor signaling: A new therapeutic opportunity in cancer. Clin Cancer Res 2012; 18: 1855-1862.
44. Boilly B, Vercoutter-Edouart AS, Hondermarck H, et al. FGF signals for cell proliferation and migration through different pathways. Cytokine Growth Factor Rev 2000; 11: 295-302.
45. Dey JH, Bianchi F, Voshol J, et al. Targeting fibroblast growth factor receptors blocks PI3K/AKT signaling, induces apoptosis, and impairs mammary tumor outgrowth and metastasis. Cancer Res 2010; 70: 4151-4162.
46. Chen Y, Zhao M, Fu M, et al. The role of calcineurin in the lung fibroblasts proliferation and collagen synthesis induced by basic fibroblast growth factor. Chin Med J (Engl) 2003; 116: 857-862.
47. Zou H, Nie XH, Zhang Y, et al. Effect of basic fibroblast growth factor on the proliferation, migration and phenotypic modulation of airway smooth muscle cells. Chin Med J (Engl) 2008; 121: 424-429.
48. Melloni B, Lesur O, Bouhadiba T, et al. Effect of exposure to silica on human alveolar macrophages in supporting growth activity in type II epithelial cells. Thorax 1996; 51: 781-786.
49. Inoue Y, King TE Jr, Tinkle SS, et al. Human mast cell basic fibroblast growth factor in pulmonary fibrotic disorders. Am J Pathol 1996; 149: 2037-2054.
50. Henke C, Marineili W, Jessurun J, et al. Macrophage production of basic fibroblast growth factor in the fibroproliferative disorder of alveolar fibrosis after lung injury. Am J Pathol 1993; 143: 1189-1199.
51. Rifkin DB, Moscatelli D. Recent developments in the cell biology of basic fibroblast growth factor. J Cell Biol 1989; 109: 1-6.
52. Blotnick S, Peoples GE, Freeman MR, et al. T lymphocytes synthesize and export heparin-binding epidermal growth factor-like growth factor and basic fibroblast growth factor, mitogens for vascular cells and fibroblasts: Differential production and release by CD4+ and CD8+ T cells. Proc Natl Acad Sci USA 1994; 91: 2890-2894.
53. Inoue Y, King TE Jr, Barker E, et al. Basic fibroblast growth factor and its receptors in idiopathic pulmonary fibrosis and lymphangioleiomyomatosis. Am J Respir Crit Care Med 2002; 166: 765-773.
54. Coffey E, Newman DR, Sannes PL. Expression of fibroblast growth factor 9 in normal human lung and idiopathic pulmonary fibrosis. J Histochem Cytochem 2013; 61: 671-679.
55. Ramos C, Montaño M, Becerril C, et al. Acidic fibroblast growth factor decreases α-smooth muscle actin expression and induces apoptosis in human normal lung fibroblasts. Am J Physiol Lung Cell Mol Physiol 2006; 291: L871-L879.
56. 2-induced alveolar epithelial cell DNA damage: role of MAPK activation and DNA repair. Am J Respir Cell Mol Biol 2004; 31: 107-113.
57. Gupte VV, Ramasamy SK, Reddy R, et al. Overexpression of fibroblast growth factor-10 during both inflammatory and fibrotic phases attenuates bleomycin-induced pulmonary fibrosis in mice. Am J Respir Crit Care Med 2009; 180: 424-436.
58. Thannickal VJ, Aldweib KD, Rajan T, et al. Upregulated expression of fibroblast growth factor (FGF) receptors by transforming growth factor-β1 (TGF-β1) mediates enhanced mitogenic responses to FGFs in cultured human lung fibroblasts. Biochem Biophys Res Commun 1998; 251: 437-441.
59. Khalil N, Xu YD, O'Connor R, et al. Proliferation of pulmonary interstitial fibroblasts is mediated by transforming growth factor-β1-induced release of extracellular fibroblast growth factor-2 and phosphorylation of p38 MAPK and JNK. J Biol Chem 2005; 280: 43000-43009.
60. Barrios R, Pardo A, Ramos C, et al. Upregulation of acidic fibroblast growth factor during development of experimental lung fibrosis. Am J Physiol 1997; 273: L451-L458.
61. Yu ZH, Wang DD, Zhou ZY, et al. Mutant soluble ectodomain of fibroblast growth factor receptor-2 IIIc attenuates bleomycin-induced pulmonary fibrosis in mice. Biol Pharm Bull 2012; 35: 731-736.
62. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003; 9: 669-676.
63. Koch S, Tugues S, Li X, et al. Signal transduction by vascular endothelial growth factor receptors. Biochem J 2011; 437: 169-183.
64. Mura M, dos Santos CC, Stewart D, et al. Vascular endothelial growth factor and related molecules in acute lung injury. J Appl Physiol (1985) 2004; 97: 1605-1617.
65. Tuder RM, Yun JH. Vascular endothelial growth factor of the lung: friend or foe. Curr Opin Pharmacol 2008; 8: 255-260.
66. Ball SG, Shuttleworth CA, Kielty CM. Vascular endothelial growth factor can signal through platelet-derived growth factor receptors. J Cell Biol 2007; 177: 489-500.
67. Simler NR, Brenchley PE, Horrocks AW, et al. Angiogenic cytokines in patients with idiopathic interstitial pneumonia. Thorax 2004; 59: 581-585.
68. Ando M, Miyazaki E, Ito T, et al. Significance of serum vascular endothelial growth factor level in patients with idiopathic pulmonary fibrosis. Lung 2010; 188: 247-252.
69. Koyama S, Sato E, Haniuda M, et al. Decreased level of vascular endothelial growth factor in bronchoalveolar lavage fluid of normal smokers and patients with pulmonary fibrosis. Am J Respir Crit Care Med 2002; 166: 382-385.
70. Meyer KC, Cardoni A, Xiang ZZ. Vascular endothelial growth factor in bronchoalveolar lavage from normal subjects and patients with diffuse parenchymal lung disease. J Lab Clin Med 2000; 135: 332-338.
71. Hamada N, Kuwano K, Yamada M, et al. Anti-vascular endothelial growth factor gene therapy attenuates lung injury and fibrosis in mice. J Immunol 2005; 175: 1224-1231.
72. Hilberg F, Roth GJ, Krssak M, et al. BIBF 1120: Triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 2008; 68: 4774-4782.
73. Markovic A, MacKenzie KL, Lock RB. FLT-3: A new focus in the understanding of acute leukemia. Int J Biochem Cell Biol 2005; 37: 1168-1172.
74. Ding Q, Cai G-Q, Hu M, et al. Therapeutic targeting of Src kinase and myofibroblast activation in pulmonary fibrosis. Am J Respir Crit Care Med 2012; 185: A1944.
75. Nel AE. T-cell activation through the antigen receptor. Part 1: signaling components, signaling pathways, and signal integration at the T-cell antigen receptor synapse. J Allergy Clin Immunol 2002; 109: 758-770.
76. Seddon B, Legname G, Tomlinson P, et al. Long-term survival but impaired homeostatic proliferation of naïve T cells in the absence of p56lck. Science 2000; 290: 127-131.
77. DeFranco AL, Chan VW, Lowell CA. Positive and negative roles of the tyrosine kinase Lyn in B cell function. Semin Immunol 1998; 10: 299-307.
78. Wollin L, Maillet I, Quesniaux V, et al. Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis. J Pharmacol Exp Ther 2014; 349: 209-220.
79. Hostettler KE, Zhong J, Papakonstantinou E, et al. Anti-fibrotic effects of nintedanib in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis. Respir Res 2014; 15: 157.
80. Marmai C, Sutherland RE, Kim KK, et al. Alveolar epithelial cells express mesenchymal proteins in patients with idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2011; 301: L71-L78.
81. Rock JR, Barkauskas CE, Cronce MJ, et al. Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition. Proc Natl Acad Sci USA 2011; 108: E1475-E1483.
82. Thannickal VJ, Horowitz JC. Evolving concepts of apoptosis in idiopathic pulmonary fibrosis. Proc Am Thorac Soc 2006; 3: 350-356.
83. Crinò L, Metro G. Therapeutic options targeting angiogenesis in nonsmall cell lung cancer. Eur Respir Rev 2014; 23: 79-91.
84. Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med 2011; 365: 1079-1087.
85. Costabel U, Richeldi L, Azuma A, et al. Pre-specified subgroup analyses of pooled data from the INPULSIS™ trials of nintedanib in idiopathic pulmonary fibrosis. The International Colloquium on Lung and Airway Fibrosis, 18th International Colloquium On Lung And Airway Fibrosis, 2014. www.iclaf.com/conference/index.php/2014/ICLAF/paper/view/106. Date last accessed: November 3, 2014. Date last updated: August 6, 2014.