Computational modeling predicts simultaneous targeting of fibroblasts and epithelial cells is necessary for treatment of pulmonary fibrosis

Frontiers in Pharmacology

Volumn 7, Issue JUN, 2016, Pages

  Warsinske, Hayley C ^a   Wheaton, Amanda K ^a   Kim, Kevin K ^a   Linderman, Jennifer J ^b   Moore, Bethany B ^a   Kirschner, Denise E ^a  

^a UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

^b UNIVERSITY OF MICHIGAN   (United States)

Author keywords

Agent based modeling; Epithelial cells; Fibroblasts; IPF; Prostaglandin E2; Pulmonary fibrosis; Therapeutics for fibrosis; Transforming growth factor beta1

Indexed keywords

PROSTAGLANDIN E2; TRANSFORMING GROWTH FACTOR BETA1;

APOPTOSIS; ARTICLE; CELL DIFFERENTIATION; CELL PROLIFERATION; CELL SURVIVAL; CONTROLLED STUDY; EPITHELIUM CELL; FIBROBLAST; HUMAN; HUMAN CELL; LIGAND BINDING; LUNG FIBROSIS; PREDICTION; SIGNAL TRANSDUCTION; TISSUE REPAIR;

EID: 84977622520     PISSN: None     EISSN: 16639812     Source Type: Journal    
DOI: 10.3389/fphar.2016.00183     Document Type: Article

References (114)

1. Adamson, I. Y. (1984). Drug-induced pulmonary fibrosis. Environ. Health Perspect. 55, 25-36. doi: 10.1289/ehp.845525
2. Adamson, I. Y., and Bowden, D. H. (1974). The pathogenesis of bloemycin-induced pulmonary fibrosis in mice. Am. J. Pathol. 77, 185-197.
3. An, G., Mi, Q., Dutta-Moscato, J., and Vodovotz, Y. (2009). Agent-based models in translational systems biology. Wiley Interdiscip. Rev. Syst. Biol. Med. 1, 159-171. doi: 10.1002/wsbm.45
4. Audoly, L. P., Tilley, S. L., Goulet, J., Key, M., Nguyen, M., Stock, J. L., et al. (1999). Identification of specific EP receptors responsible for the hemodynamic effects of PGE2. Am. J. Physiol. 277(3 Pt 2), H924-H930.
5. Bendelac, A., Rivera, M. N., Park, S. H., and Roark, J. H. (1997). Mouse CD1-specific NK1 T cells: development, specificity, and function. Annu. Rev. Immunol. 15, 535-562. doi: 10.1146/annurev.immunol.15.1.535
6. Bohm, M., Dosoki, H., and Kerkhoff, C. (2014). Is Nox4 a key regulator of the activated state of fibroblasts in systemic sclerosis? Exp. Dermatol. 23, 679-681. doi: 10.1111/exd.12497
7. Budihardjo, I., Oliver, H., Lutter, M., Luo, X., and Wang, X. (1999). Biochemical pathways of caspase activation during apoptosis. Annu. Rev. Cell Dev. Biol. 15, 269-290. doi: 10.1146/annurev.cellbio.15.1.269
8. Buzan, M. T., and Pop, C. M. (2015). State of the art in the diagnosis and management of interstitial lung disease. Clujul Med. 88, 116-123. doi: 10.15386/cjmed-457
9. Camelo, A., Dunmore, R., Sleeman, M. A., and Clarke, D. L. (2014). The epithelium in idiopathic pulmonary fibrosis: breaking the barrier. Front. Pharmacol. 4:173. doi: 10.3389/fphar.2013.00173
10. Chang, S. L., Cavnar, S. P., Takayama, S., Luker, G. D., and Linderman, J. J. (2015). Cell, isoform, and environment factors shape gradients and modulate chemotaxis. PLoS ONE 10:e0123450. doi: 10.1371/journal.pone.0123450
11. Chen, D. B., Yang, Z. M., Hilsenrath, R., Le, S. P., and Harper, M. J. (1995). Stimulation of prostaglandin (PG) F2 alpha and PGE2 release by tumour necrosis factor-alpha and interleukin-1 alpha in cultured human luteal phase endometrial cells. Hum. Reprod. 10, 2773-2780.
12. Cilfone, N. A., Ford, C. B., Marino, S., Mattila, J. T., Gideon, H. P., Flynn, J. L., et al. (2015a). Computational modeling predicts IL-10 control of lesion sterilization by balancing early host immunity-mediated antimicrobial responses with caseation during mycobacterium tuberculosis infection. J. Immunol. 194, 664-677. doi: 10.4049/jimmunol.1400734
13. Cilfone, N. A., Kirschner, D. E., and Linderman, J. J. (2015b). Strategies for efficient numerical implementation of hybrid multi-scale agent-based models to describe biological systems. Cell. Mol. Bioeng. 8, 119-136. doi: 10.1007/s12195-014-0363-6
14. Cilfone, N. A., Perry, C. R., Kirschner, D. E., and Linderman, J. J. (2013). Multi-scale modeling predicts a balance of tumor necrosis factor-alpha and interleukin-10 controls the granuloma environment during Mycobacterium tuberculosis infection. PLoS ONE 8:e68680. doi: 10.1371/journal.pone.0068680
15. Cilfone, N. A., Pienaar, E., Thurber, G. M., Kirschner, D. E., and Linderman, J. J. (2015c). Systems pharmacology approach toward the design of inhaled formulations of rifampicin and isoniazid for treatment of tuberculosis. CPT Pharmacometrics Syst. Pharmacol. 4:e00022. doi: 10.1002/psp4.22
16. Coffey, R. J. Jr. Bascom, C. C., Sipes, N. J., Graves-Deal, R., Weissman, B. E., and Moses, H. L. (1988). Selective inhibition of growth-related gene expression in murine keratinocytes by transforming growth factor beta. Mol. Cell. Biol. 8, 3088-3093. doi: 10.1128/MCB.8.8.3088
17. Corti, M., Brody, A. R., and Harrison, J. H. (1996). Isolation and primary culture of murine alveolar type II cells. Am. J. Respir. Cell Mol. Biol. 14, 309-315. doi: 10.1165/ajrcmb.14.4.8600933
18. Costabel, U., Inoue, Y., Richeldi, L., Collard, H. R., Tschoepe, I., Stowasser, S., et al. (2016). Efficacy of nintedanib in idiopathic pulmonary fibrosis across pre-specified subgroups in INPULSIS(R). Am. J. Respir. Crit. Care Med. 193, 178-185. doi: 10.1164/rccm.201503-0562OC
19. Crosas-Molist, E., and Fabregat, I. (2015). Role of NADPH oxidases in the redox biology of liver fibrosis. Redox Biol. 6, 106-111. doi: 10.1016/j.redox.2015.07.005
20. Crosby, L. M., and Waters, C. M. (2010). Epithelial repair mechanisms in the lung. Am. J. Physiol. Lung Cell. Mol. Physiol. 298, L715-L31. doi: 10.1152/ajplung.00361.2009
21. Crystal, R. G., Randell, S. H., Engelhardt, J. F., Voynow, J., and Sunday, M. E. (2008). Airway epithelial cells: current concepts and challenges. Proc. Am. Thorac. Soc. 5, 772-777. doi: 10.1513/pats.200805-041HR
22. Daba, M. H., El-Tahir, K. E., Al-Arifi, M. N., and Gubara, O. A. (2004). Drug-induced pulmonary fibrosis. Saudi Med. J. 25, 700-706.
23. De Vries, J., Kessels, B. L., and Drent, M. (2001). Quality of life of idiopathic pulmonary fibrosis patients. Eur. Respir. J. 17, 954-961. doi: 10.1183/09031936.01.17509540
24. Desmouliere, A., Geinoz, A., Gabbiani, F., and Gabbiani, G. (1993). Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J. Cell Biol. 122, 103-111. doi: 10.1083/jcb.122.1.103
25. Diegelmann, R. F., and Evans, M. C. (2004). Wound healing: an overview of acute, fibrotic and delayed healing. Front. Biosci. 9, 283-289. doi: 10.2741/1184
26. Dosanjh, A., Ikonen, T., Wan, B., and Morris, R. E. (2002). Pirfenidone: A novel anti-fibrotic agent and progressive chronic allograft rejection. Pulm. Pharmacol. Ther. 15, 433-437. doi: 10.1006/pupt.2002.0367
27. Epa, A. P., Thatcher, T. H., Pollock, S. J., Wahl, L. A., Lyda, E., Kottmann, R. M., et al. (2015). Normal human lung epithelial cells inhibit transforming growth factor-beta induced myofibroblast differentiation via prostaglandin E2. PLoS ONE 10:e0135266. doi: 10.1371/journal.pone.0135266
28. Fallahi-Sichani, M., El-Kebir, M., Marino, S., Kirschner, D. E., and Linderman, J. J. (2011). Multiscale computational modeling reveals a critical role for TNF-alpha receptor 1 dynamics in tuberculosis granuloma formation. J. Immunol. 186, 3472-3483. doi: 10.4049/jimmunol.1003299
29. Fine, A., and Goldstein, R. H. (1987). The effect of transforming growth factor-beta on cell proliferation and collagen formation by lung fibroblasts. J. Biol. Chem. 262, 3897-3902.
30. Fine, A., Poliks, C. F., Donahue, L. P., Smith, B. D., and Goldstein, R. H. (1989). The differential effect of prostaglandin E2 on transforming growth factor-beta and insulin-induced collagen formation in lung fibroblasts. J. Biol. Chem. 264, 16988-16991.
31. George, G., Vaid, U., and Summer, R. (2016). Therapeutic advances in idiopathic pulmonary fibrosis. Clin. Pharmacol. Ther. 99, 30-32. doi: 10.1002/cpt.283
32. Guo, S., and Dipietro, L. A. (2010). Factors affecting wound healing. J. Dent. Res. 89, 219-229. doi: 10.1177/0022034509359125
33. Hagimoto, N., Kuwano, K., Inoshima, I., Yoshimi, M., Nakamura, N., Fujita, M., et al. (2002). TGF-beta 1 as an enhancer of Fas-mediated apoptosis of lung epithelial cells. J. Immunol. 168, 6470-6478. doi: 10.4049/jimmunol.168.12.6470
34. Hashimoto, S., Gon, Y., Takeshita, I., Maruoka, S., and Horie, T. (2001). IL-4 and IL-13 induce myofibroblastic phenotype of human lung fibroblasts through c-Jun NH2-terminal kinase-dependent pathway. J. Allergy Clin. Immunol. 107, 1001-1008. doi: 10.1067/mai.2001.114702
35. Hinz, B., Celetta, G., Tomasek, J. J., Gabbiani, G., and Chaponnier, C. (2001). Alpha-smooth muscle actin expression upregulates fibroblast contractile activity. Mol. Biol. Cell 12, 2730-2741. doi: 10.1091/mbc.12.9.2730
36. Hinz, B., Phan, S. H., Thannickal, V. J., Galli, A., Bochaton-Piallat, M. L., and Gabbiani, G. (2007). The myofibroblast: one function, multiple origins. Am. J. Pathol. 170, 1807-1816. doi: 10.2353/ajpath.2007.070112
37. Hinz, B., Phan, S. H., Thannickal, V. J., Prunotto, M., Desmouliere, A., Varga, J., et al. (2012). Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am. J. Pathol. 180, 1340-1355. doi: 10.1016/j.ajpath.2012.02.004
38. Holtzman, M. J., Byers, D. E., Alexander-Brett, J., and Wang, X. (2014). The role of airway epithelial cells and innate immune cells in chronic respiratory disease. Nat. Rev. Immunol. 14, 686-698. doi: 10.1038/nri3739
39. Ibrahim, M. M., Chen, L., Bond, J. E., Medina, M. A., Ren, L., Kokosis, G., et al. (2015). Myofibroblasts contribute to but are not necessary for wound contraction. Lab. Invest. 95, 1429-1438. doi: 10.1038/labinvest.2015.116
40. Jastrzebski, D., Kozielski, J., Banas, A., Cebula, T., Gumola, A., Ziora, D., et al. (2005). Quality of life during one-year observation of patients with idiopathic pulmonary fibrosis awaiting lung transplantation. J. Physiol. Pharmacol. 56(Suppl. 4), 99-105.
41. Kendall, R. T., and Feghali-Bostwick, C. A. (2014). Fibroblasts in fibrosis: novel roles and mediators. Front. Pharmacol. 5:123. doi: 10.3389/fphar.2014.00123
42. King, T. E. Jr. Bradford, W. Z., Castro-Bernardini, S., Fagan, E. A., Glaspole, I., Glassberg, M. K., et al. (2014). A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N. Engl. J. Med. 370, 2083-2092. doi: 10.1056/NEJMoa1402582
43. Kolodsick, J. E., Peters-Golden, M., Larios, J., Toews, G. B., Thannickal, V. J., and Moore, B. B. (2003). Prostaglandin E2 inhibits fibroblast to myofibroblast transition via E. prostanoid receptor 2 signaling and cyclic adenosine monophosphate elevation. Am. J. Respir. Cell Mol. Biol. 29, 537-544. doi: 10.1165/rcmb.2002-0243OC
44. Kraft, M., Lewis, C., Pham, D., and Chu, H. W. (2001). IL-4, IL-13, and dexamethasone augment fibroblast proliferation in asthma. J. Allergy Clin. Immunol. 107, 602-606. doi: 10.1067/mai.2001.113760
45. Kreuter, M. (2014). Pirfenidone: an update on clinical trial data and insights from everyday practice. Eur. Respir. Rev. 23, 111-117. doi: 10.1183/09059180.00008513
46. Krieg, T., Abraham, D., and Lafyatis, R. (2007). Fibrosis in connective tissue disease: the role of the myofibroblast and fibroblast-epithelial cell interactions. Arthritis Res. Ther. 9(Suppl. 2), S4. doi: 10.1186/ar2188
47. Kronenberg, M., and Rudensky, A. (2005). Regulation of immunity by self-reactive T cells. Nature 435, 598-604. doi: 10.1038/nature03725
48. Kuwano, K. (2008). Involvement of epithelial cell apoptosis in interstitial lung diseases. Intern. Med. 47, 345-353. doi: 10.2169/internalmedicine.47.0713
49. Lama, V., Moore, B. B., Christensen, P., Toews, G. B., and Peters-Golden, M. (2002). Prostaglandin E2 synthesis and suppression of fibroblast proliferation by alveolar epithelial cells is cyclooxygenase-2-dependent. Am. J. Respir. Cell Mol. Biol. 27, 752-758. doi: 10.1165/rcmb.4857
50. Lederer, D. J., Bradford, W. Z., Fagan, E. A., Glaspole, I., Glassberg, M. K., Glasscock, K. F., et al. (2015). Sensitivity analyses of the change in FVC in a Phase 3 trial of pirfenidone for idiopathic pulmonary fibrosis. Chest 148, 196-201. doi: 10.1378/chest.14-2817
51. Lehnert, S. A., and Akhurst, R. J. (1988). Embryonic expression pattern of TGF beta type-1 RNA suggests both paracrine and autocrine mechanisms of action. Development 104, 263-273.
52. Letterio, J. J., and Roberts, A. B. (1998). Regulation of immune responses by TGF-beta. Annu. Rev. Immunol. 16, 137-161. doi: 10.1146/annurev.immunol.16.1.137
53. Leveen, P., Carlsen, M., Makowska, A., Oddsson, S., Larsson, J., Goumans, M. J., et al. (2005). TGF-beta type II receptor-deficient thymocytes develop normally but demonstrate increased CD8+ proliferation in vivo. Blood 106, 4234-4240. doi: 10.1182/blood-2005-05-1871
54. Li, M. O., Wan, Y. Y., and Flavell, R. A. (2007). T cell-produced transforming growth factor-beta1 controls T cell tolerance and regulates Th1-and Th17-cell differentiation. Immunity 26, 579-591. doi: 10.1016/j.immuni.2007.03.014
55. Li, M., Ke, H. Z., Qi, H., Healy, D. R., Li, Y., Crawford, D. T., et al. (2003). A novel, non-prostanoid EP2 receptor-selective prostaglandin E2 agonist stimulates local bone formation and enhances fracture healing. J. Bone Miner. Res. 18, 2033-2042. doi: 10.1359/jbmr.2003.18.11.2033
56. Liu, Y., Zhang, P., Li, J., Kulkarni, A. B., Perruche, S., and Chen, W. (2008). A critical function for TGF-beta signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nat. Immunol. 9, 632-640. doi: 10.1038/ni.1607
57. Loomis-King, H., Flaherty, K. R., and Moore, B. B. (2013). Pathogenesis, current treatments and future directions for idiopathic pulmonary fibrosis. Curr. Opin. Pharmacol. 13, 377-385. doi: 10.1016/j.coph.2013.03.015
58. Maher, T. M., Evans, I. C., Bottoms, S. E., Mercer, P. F., Thorley, A. J., Nicholson, A. G., et al. (2010). Diminished prostaglandin E2 contributes to the apoptosis paradox in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 182, 73-82. doi: 10.1164/rccm.200905-0674OC
59. Maher, T. M., Wells, A. U., and Laurent, G. J. (2007). Idiopathic pulmonary fibrosis: multiple causes and multiple mechanisms? Eur. Respir. J. 30, 835-839. doi: 10.1183/09031936.00069307
60. Maini, P. K., McElwain, D. L., and Leavesley, D. I. (2004). Traveling wave model to interpret a wound-healing cell migration assay for human peritoneal mesothelial cells. Tissue Eng. 10, 475-482. doi: 10.1089/107632704323061834
61. Mansury, Y., Kimura, M., Lobo, J., and Deisboeck, T. S. (2002). Emerging patterns in tumor systems: simulating the dynamics of multicellular clusters with an agent-based spatial agglomeration model. J. Theor. Biol. 219, 343-370. doi: 10.1006/jtbi.2002.3131
62. Marie, J. C., Liggitt, D., and Rudensky, A. Y. (2006). Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor. Immunity 25, 441-454. doi: 10.1016/j.immuni.2006.07.012
63. Marino, S., Hogue, I. B., Ray, C. J., and Kirschner, D. E. (2008). A methodology for performing global uncertainty and sensitivity analysis in systems biology. J. Theor. Biol. 254, 178-196. doi: 10.1016/j.jtbi.2008.04.011
64. Mayer, A. K., and Dalpke, A. H. (2007). Regulation of local immunity by airway epithelial cells. Arch. Immunol. Ther. Exp. (Warsz) 55, 353-62. doi: 10.1007/s00005-007-0041-7
65. Mi, Q., Riviere, B., Clermont, G., Steed, D. L., and Vodovotz, Y. (2007). Agent-based model of inflammation and wound healing: insights into diabetic foot ulcer pathology and the role of transforming growth factor-beta1. Wound Repair Regen. 15, 671-682. doi: 10.1111/j.1524-475X.2007.00271.x
66. Midwood, K. S., Williams, L. V., and Schwarzbauer, J. E. (2004). Tissue repair and the dynamics of the extracellular matrix. Int. J. Biochem. Cell Biol. 36, 1031-1037. doi: 10.1016/j.biocel.2003.12.003
67. Moore, B. B., Peters-Golden, M., Christensen, P. J., Lama, V., Kuziel, W. A., Paine, R. III, et al. (2003). Alveolar epithelial cell inhibition of fibroblast proliferation is regulated by MCP-1/CCR2 and mediated by PGE2. Am. J. Physiol. Lung Cell. Mol. Physiol. 284, L342-L349. doi: 10.1152/ajplung.00168.2002
68. Muraoka, R. S., Dumont, N., Ritter, C. A., Dugger, T. C., Brantley, D. M., Chen, J., et al. (2002). Blockade of TGF-beta inhibits mammary tumor cell viability, migration, and metastases. J. Clin. Invest. 109, 1551-1559. doi: 10.1172/JCI0215234
69. Myllarniemi, M., and Kaarteenaho, R. (2015). Pharmacological treatment of idiopathic pulmonary fibrosis-preclinical and clinical studies of pirfenidone, nintedanib, and N-acetylcysteine. Eur Clin Respir. J. doi: 10.3402/ecrj.v2.26385. [Epub ahead of print].
70. Nishiyama, O., Taniguchi, H., Kondoh, Y., Kimura, T., Ogawa, T., Watanabe, F., et al. (2005). Health-related quality of life in patients with idiopathic pulmonary fibrosis. What is the main contributing factor? Respir. Med. 99, 408-414. doi: 10.1016/j.rmed.2004.09.005
71. Overgaard, C. E., Schlingmann, B., Dorsainvil White, S., Ward, C., Fan, X., Swarnakar, S., et al. (2015). The relative balance of GM-CSF and TGF-beta1 regulates lung epithelial barrier function. Am. J. Physiol. Lung Cell. Mol. Physiol. 308, L1212-L1223. doi: 10.1152/ajplung.00042.2014
72. Peyton, S. R., Kim, P. D., Ghajar, C. M., Seliktar, D., and Putnam, A. J. (2008). The effects of matrix stiffness and RhoA on the phenotypic plasticity of smooth muscle cells in a 3-D biosynthetic hydrogel system. Biomaterials 29, 2597-2607. doi: 10.1016/j.biomaterials.2008.02.005
73. Pietenpol, J. A., Stein, R. W., Moran, E., Yaciuk, P., Schlegel, R., Lyons, R. M., et al. (1990). TGF-beta 1 inhibition of c-myc transcription and growth in keratinocytes is abrogated by viral transforming proteins with pRB binding domains. Cell 61, 777-785. doi: 10.1016/0092-8674(90)90188-K
74. Prasad, S., Hogaboam, C. M., and Jarai, G. (2014). Deficient repair response of IPF fibroblasts in a co-culture model of epithelial injury and repair. Fibrogenesis Tissue Repair 7:7. doi: 10.1186/1755-1536-7-7
75. Prasanphanich, A. F., Arencibia, C. A., and Kemp, M. L. (2014). Redox processes inform multivariate transdifferentiation trajectories associated with TGFbeta-induced epithelial-mesenchymal transition. Free Radic. Biol. Med. 76, 1-13. doi: 10.1016/j.freeradbiomed.2014.07.032
76. Puthawala, K., Hadjiangelis, N., Jacoby, S. C., Bayongan, E., Zhao, Z., Yang, Z., et al. (2008). Inhibition of integrin alpha(v)beta6, an activator of latent transforming growth factor-beta, prevents radiation-induced lung fibrosis. Am. J. Respir. Crit. Care Med. 177, 82-90. doi: 10.1164/rccm.200706-806OC
77. Raghu, G., King, T. E. Jr. Behr, J., Brown, K. K., du Bois, R. M., Leconte, I., et al. (2010). Quality of life and dyspnoea in patients treated with bosentan for idiopathic pulmonary fibrosis (BUILD-1). Eur. Respir. J. 35, 118-123. doi: 10.1183/09031936.00188108
78. Raghu, G., Weycker, D., Edelsberg, J., Bradford, W. Z., and Oster, G. (2006). Incidence and prevalence of idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 174, 810-816. doi: 10.1164/rccm.200602-163OC
79. Ray, J. C., Flynn, J. L., and Kirschner, D. E. (2009). Synergy between individual TNF-dependent functions determines granuloma performance for controlling Mycobacterium tuberculosis infection. J. Immunol. 182, 3706-3717. doi: 10.4049/jimmunol.0802297
80. Richeldi, L., du Bois, R. M., Raghu, G., Azuma, A., Brown, K. K., Costabel, U., et al. (2015). Noble PW efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N. Engl. J. Med. 373, 782. doi: 10.1056/NEJMx150012
81. Saha, D., Datta, P. K., Sheng, H., Morrow, J. D., Wada, M., Moses, H. L., et al. (1999). Synergistic induction of cyclooxygenase-2 by transforming growth factor-beta1 and epidermal growth factor inhibits apoptosis in epithelial cells. Neoplasia 1, 508-517. doi: 10.1038/sj.neo.7900051
82. Saito, A., Okazaki, H., Sugawara, I., Yamamoto, K., and Takizawa, H. (2003). Potential action of IL-4 and IL-13 as fibrogenic factors on lung fibroblasts in vitro. Int. Arch. Allergy Immunol. 132, 168-176. doi: 10.1159/000073718
83. Salkind, N., and Abdi, H. (2007). "The bonferonni and sidak corrections for multiple comparisons," in Encyclopedia of Measurement and Statistics, ed N. Salkind (Thousand Oaks, CA: Sage Publications), 103-106.
84. Segovia-Juarez, J. L., Ganguli, S., and Kirschner, D. (2004). Identifying control mechanisms of granuloma formation during M. tuberculosisi infection using an agent-based model. J. Theor. Biol. 231, 357-376. doi: 10.1016/j.jtbi.2004.06.031
85. Selman, M., Thannickal, V. J., Pardo, A., Zisman, D. A., Martinez, F. J., and Lynch, J. P. (2004). Idiopathic pulmonary fibrosis: pathogenesis and therapeutic approaches. Drugs 64, 405-430. doi: 10.2165/00003495-200464040-00005
86. Shi, F., Harman, J., Fujiwara, K., and Sottile, J. (2010). Collagen I matrix turnover is regulated by fibronectin polymerization. Am. J. Physiol. Cell Physiol. 298, C1265-C1275. doi: 10.1152/ajpcell.00341.2009
87. Stern, J. R., Christley, S., Zaborina, O., Alverdy, J. C., and An, G. (2012). Integration of TGF-beta-and EGFR-based signaling pathways using an agent-based model of epithelial restitution. Wound Repair Regen. 20, 862-871. doi: 10.1111/j.1524-475X.2012.00852.x
88. Strieter, R. M. (2008). What differentiates normal lung repair and fibrosis? Inflammation, resolution of repair, and fibrosis. Proc. Am. Thorac. Soc. 5, 305-310. doi: 10.1513/pats.200710-160DR
89. Sugimoto, Y., and Narumiya, S. (2007). Prostaglandin E receptors. J. Biol. Chem. 282, 11613-11617. doi: 10.1074/jbc. R600038200
90. Swigris, J. J., Kuschner, W. G., Jacobs, S. S., Wilson, S. R., and Gould, M. K. (2005). Health-related quality of life in patients with idiopathic pulmonary fibrosis: a systematic review. Thorax 60, 588-594. doi: 10.1136/thx.2004.035220
91. Taniguchi, H., Kondoh, Y., Ebina, M., Azuma, A., Ogura, T., Taguchi, Y., et al. (2011). The clinical significance of 5% change in vital capacity in patients with idiopathic pulmonary fibrosis: extended analysis of the pirfenidone trial. Respir. Res. 12:93. doi: 10.1186/1465-9921-12-93
92. Thannickal, V. J., Lee, D. Y., White, E. S., Cui, Z., Larios, J. M., Chacon, R., et al. (2003). Myofibroblast differentiation by transforming growth factor-beta1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase. J. Biol. Chem. 278, 12384-12389. doi: 10.1074/jbc. M208544200
93. Thomas, P. E., Peters-Golden, M., White, E. S., Thannickal, V. J., and Moore, B. B. (2007). PGE(2) inhibition of TGF-beta1-induced myofibroblast differentiation is Smad-independent but involves cell shape and adhesion-dependent signaling. Am. J. Physiol. Lung Cell. Mol. Physiol. 293, L417-L428. doi: 10.1152/ajplung.00489.2006
94. Thorne, B. C., Bailey, A. M., and Peirce, S. M. (2007). Combining experiments with multi-cell agent-based modeling to study biological tissue patterning. Brief. Bioinformatics 8, 245-257. doi: 10.1093/bib/bbm024
95. Tian, M., and Schiemann, W. P. (2010). PGE2 receptor EP2 mediates the antagonistic effect of COX-2 on TGF-beta signaling during mammary tumorigenesis. FASEB J. 24, 1105-1116. doi: 10.1096/fj.09-141341
96. Tobin, S. W., Douville, K., Benbow, U., Brinckerhoff, C. E., Memoli, V. A., and Arrick, B. A. (2002). Consequences of altered TGF-beta expression and responsiveness in breast cancer: evidence for autocrine and paracrine effects. Oncogene 21, 108-118. doi: 10.1038/sj.onc.1205026
97. Tomioka, H., Imanaka, K., Hashimoto, K., and Iwasaki, H. (2007). Health-related quality of life in patients with idiopathic pulmonary fibrosis-cross-sectional and longitudinal study. Intern. Med. 46, 1533-1542. doi: 10.2169/internalmedicine.46.6218
98. Turley, J. M., Falk, L. A., Ruscetti, F. W., Kasper, J. J., Francomano, T., Fu, T., et al. (1996). Transforming growth factor beta 1 functions in monocytic differentiation of hematopoietic cells through autocrine and paracrine mechanisms. Cell Growth Differ. 7, 1535-1544.
99. Tzanakis, N., Samiou, M., Lambiri, I., Antoniou, K., Siafakas, N., and Bouros, D. (2005). Evaluation of health-related quality-of-life and dyspnea scales in patients with idiopathic pulmonary fibrosis. Correlation with pulmonary function tests. Eur. J. Intern. Med. 16, 105-112. doi: 10.1016/j.ejim.2004.09.013
100. Vanhee, D., Gosset, P., Wallaert, B., Voisin, C., and Tonnel, A. B. (1994). Mechanisms of fibrosis in coal workers' pneumoconiosis. Increased production of platelet-derived growth factor, insulin-like growth factor type I, and transforming growth factor beta and relationship to disease severity. Am. J. Respir. Crit. Care Med. 150, 1049-1055. doi: 10.1164/ajrccm.150.4.7921435
101. Velnar, T., Bailey, T., and Smrkolj, V. (2009). The wound healing process: an overview of the cellular and molecular mechanisms. J. Int. Med. Res. 37, 1528-1542. doi: 10.1177/147323000903700531
102. Verma, G., Marras, T., Chowdhury, N., and Singer, L. (2011). Health-related quality of life and 6 min walk distance in patients with idiopathic pulmonary fibrosis. Can. Respir. J. 18, 283-287. doi: 10.1155/2011/109635
103. Wakefield, L. M., Winokur, T. S., Hollands, R. S., Christopherson, K., Levinson, A. D., and Sporn, M. B. (1990). Recombinant latent transforming growth factor beta 1 has a longer plasma half-life in rats than active transforming growth factor beta 1, and a different tissue distribution. J. Clin. Invest. 86, 1976-1984. doi: 10.1172/JCI114932
104. Walker, D. C., Hill, G., Wood, S. M., Smallwood, R. H., and Southgate, J. (2004). Agent-based computational modeling of wounded epithelial cell monolayers. IEEE Trans. Nanobiosci. 3, 153-163. doi: 10.1109/TNB.2004.833680
105. Wang, J., Yang, Y., Xu, J., Lin, X., Wu, K., and Yu, M. (2013). Pirfenidone inhibits migration, differentiation, and proliferation of human retinal pigment epithelial cells in vitro. Mol. Vis. 19, 2626-2635.
106. Warsinske, H. C., Ashley, S. L., Linderman, J. J., Moore, B. B., and Kirschner, D. E. (2015). Identifying mechanisms of homeostatic signaling in fibroblast differentiation. Bull Math Biol. 77, 1556-1582. doi: 10.1007/s11538-015-0096-2
107. Willis, B. C., and Borok, Z. (2007). TGF-beta-induced EMT: mechanisms and implications for fibrotic lung disease. Am. J. Physiol. Lung Cell. Mol. Physiol. 293, L525-L534. doi: 10.1152/ajplung.00163.2007
108. Witte, M. B., and Barbul, A. (1997). General principles of wound healing. Surg. Clin. North Am. 77, 509-528. doi: 10.1016/S0039-6109(05)70566-1
109. Wootton, S. C., Kim, D. S., Kondoh, Y., Chen, E., Lee, J. S., Song, J. W., et al. (2011). Viral infection in acute exacerbation of idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 183, 1698-1702. doi: 10.1164/rccm.201010-1752OC
110. Xaubet, A., Serrano-Mollar, A., and Ancochea, J. (2014). Pirfenidone for the treatment of idiopathic pulmonary fibrosis. Expert Opin. Pharmacother. 15, 275-281. doi: 10.1517/14656566.2014.867328
111. Yanagisawa, K., Osada, H., Masuda, A., Kondo, M., Saito, T., Yatabe, Y., et al. (1998). Induction of apoptosis by Smad3 and down-regulation of Smad3 expression in response to TGF-beta in human normal lung epithelial cells. Oncogene 17, 1743-1747. doi: 10.1038/sj.onc.1202052
112. Zhang, L., Wang, Z., Sagotsky, J. A., and Deisboeck, T. S. (2009). Multiscale agent-based cancer modeling. J. Math. Biol. 58, 545-559. doi: 10.1007/s00285-008-0211-1
113. Zhou, X., Loomis-King, H., Gurczynski, S. J., Wilke, C. A., Konopka, K. E., Ptaschinski, C., et al. (2015). Bone marrow transplantation alters lung antigen-presenting cells to promote T17 response and the development of pneumonitis and fibrosis following gammaherpesvirus infection. Mucosal Immunol. 9, 610-620. doi: 10.1038/mi.2015.85
114. Zimmermann, C. S., Carvalho, C. R., Silveira, K. R., Yamaguti, W. P., Moderno, E. V., Salge, J. M., et al. (2007). Comparison of two questionnaires which measure the health-related quality of life of idiopathic pulmonary fibrosis patients. Braz. J. Med. Biol. Res. 40, 179-187. doi: 10.1590/S0100-879X2007000200004