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

Warsinske, Hayley C.; Wheaton, Amanda K.; Kim, Kevin K.; Linderman, Jennifer J.; Moore, Bethany B.; Kirschner, Denise E.

doi:10.3389/fphar.2016.00183

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

Journal Article · Thu Jun 23 00:00:00 EDT 2016 · Frontiers in Pharmacology

DOI:https://doi.org/10.3389/fphar.2016.00183· OSTI ID:1285867

Warsinske, Hayley C. ^[1]; Wheaton, Amanda K. ^[2]; Kim, Kevin K. ^[2]; Linderman, Jennifer J. ^[3]; Moore, Bethany B. ^[4]; Kirschner, Denise E. ^[1]

Univ. of Michigan Medical School, Ann Arbor, MI (United States). Dept. of Microbiology and Immunology
Univ. of Michigan Medical School, Ann Arbor, MI (United States). Dept. of Internal Medicine
Univ. of Michigan, Ann Arbor, MI (United States). Dept. of Chemical Engineering
Univ. of Michigan Medical School, Ann Arbor, MI (United States). Dept. of Microbiology and Immunology, Dept. of Internal Medicine

Pulmonary fibrosis is pathologic remodeling of lung tissue that can result in difficulty breathing, reduced quality of life, and a poor prognosis for patients. Fibrosis occurs as a result of insult to lung tissue, though mechanisms of this response are not well-characterized. The disease is driven in part by dysregulation of fibroblast proliferation and differentiation into myofibroblast cells, as well as pro-fibrotic mediator-driven epithelial cell apoptosis. The most well-characterized pro-fibrotic mediator associated with pulmonary fibrosis is TGF-β1. Excessive synthesis of, and sensitivity to, pro-fibrotic mediators as well as insufficient production of and sensitivity to anti-fibrotic mediators has been credited with enabling fibroblast accumulation. Available treatments neither halt nor reverse lung damage. In this study we have two aims: to identify molecular and cellular scale mechanisms driving fibroblast proliferation and differentiation as well as epithelial cell survival in the context of fibrosis, and to predict therapeutic targets and strategies. We combine in vitro studies with a multi-scale hybrid agent-based computational model that describes fibroblasts and epithelial cells in co-culture. Within this model TGF-β1 represents a pro-fibrotic mediator and we include detailed dynamics of TGFβ1 receptor ligand signaling in fibroblasts. PGE₂ represents an anti-fibrotic mediator. Using uncertainty and sensitivity analysis we identify TGF-β1 synthesis, TGF-β1 activation, and PGE₂ synthesis among the key mechanisms contributing to fibrotic outcomes. We further demonstrate that intervention strategies combining potential therapeutics targeting both fibroblast regulation and epithelial cell survival can promote healthy tissue repair better than individual strategies. Combinations of existing drugs and compounds may provide significant improvements to the current standard of care for pulmonary fibrosis. In conclusion, a two-hit therapeutic intervention strategy may prove necessary to halt and reverse disease dynamics.

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Research Organization:: Univ. of Michigan Medical School, Ann Arbor, MI (United States)

Sponsoring Organization:: USDOE Office of Science (SC), National Energy Research Scientific Computing Center

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1285867

Journal Information:: Frontiers in Pharmacology, Vol. 7; ISSN 1663-9812

Publisher:: Frontiers Research FoundationCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 23 works

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References (111)

Therapeutic advances in idiopathic pulmonary fibrosis George, G.; Vaid, U.; Summer, R. Clinical Pharmacology & Therapeutics, Vol. 99, Issue 1 https://doi.org/10.1002/cpt.283	journal	November 2015
A methodology for performing global uncertainty and sensitivity analysis in systems biology Marino, Simeone; Hogue, Ian B.; Ray, Christian J. Journal of Theoretical Biology, Vol. 254, Issue 1 https://doi.org/10.1016/j.jtbi.2008.04.011	journal	September 2008
Fibrosis in connective tissue disease: the role of the myofibroblast and fibroblast-epithelial cell interactions Krieg, Thomas; Abraham, David; Lafyatis, Robert Arthritis Research & Therapy, Vol. 9, Issue Suppl 2 https://doi.org/10.1186/ar2188	journal	January 2007
TGF-β1 as an Enhancer of Fas-Mediated Apoptosis of Lung Epithelial Cells Hagimoto, Naoki; Kuwano, Kazuyoshi; Inoshima, Ichiro The Journal of Immunology, Vol. 168, Issue 12 https://doi.org/10.4049/jimmunol.168.12.6470	journal	June 2002
Multiscale Computational Modeling Reveals a Critical Role for TNF-α Receptor 1 Dynamics in Tuberculosis Granuloma Formation Fallahi-Sichani, Mohammad; El-Kebir, Mohammed; Marino, Simeone The Journal of Immunology, Vol. 186, Issue 6 https://doi.org/10.4049/jimmunol.1003299	journal	February 2011
Prostaglandin E ₂ Synthesis and Suppression of Fibroblast Proliferation by Alveolar Epithelial Cells Is Cyclooxygenase-2–Dependent Lama, Vibha; Moore, Bethany B.; Christensen, Paul American Journal of Respiratory Cell and Molecular Biology, Vol. 27, Issue 6 https://doi.org/10.1165/rcmb.4857	journal	December 2002
Systems Pharmacology Approach Toward the Design of Inhaled Formulations of Rifampicin and Isoniazid for Treatment of Tuberculosis: Design of Inhaled Formulations for Treatment of TB Cilfone, Na; Pienaar, E.; Thurber, Gm CPT: Pharmacometrics & Systems Pharmacology, Vol. 4, Issue 3 https://doi.org/10.1002/psp4.22	journal	March 2015
Regulation of Immune Responses by Tgf-β Letterio, John J.; Roberts, Anita B. Annual Review of Immunology, Vol. 16, Issue 1 https://doi.org/10.1146/annurev.immunol.16.1.137	journal	April 1998
Alpha-Smooth Muscle Actin Expression Upregulates Fibroblast Contractile Activity Hinz, Boris; Celetta, Giuseppe; Tomasek, James J. Molecular Biology of the Cell, Vol. 12, Issue 9 https://doi.org/10.1091/mbc.12.9.2730	journal	September 2001
Drug-induced pulmonary fibrosis. Adamson, I. Y. Environmental Health Perspectives, Vol. 55 https://doi.org/10.1289/ehp.845525	journal	April 1984
Oxidative stress enhanced the transforming growth factor-β2-induced epithelial-mesenchymal transition through chemokine ligand 1 on ARPE-19 cell Yang, I-Hui; Lee, Jong-Jer; Wu, Pei-Chang Scientific Reports, Vol. 10, Issue 1 https://doi.org/10.1038/s41598-020-60785-x	journal	March 2020
IL-4, IL-13, and dexamethasone augment fibroblast proliferation in asthma Kraft, Monica; Lewis, Christina; Pham, David Journal of Allergy and Clinical Immunology, Vol. 107, Issue 4 https://doi.org/10.1067/mai.2001.113760	journal	April 2001
Idiopathic Pulmonary Fibrosis: Pathogenesis and Therapeutic Approaches Selman, Mois??s; Thannickal, Victor J.; Pardo, Annie Drugs, Vol. 64, Issue 4 https://doi.org/10.2165/00003495-200464040-00005	journal	January 2004
The epithelium in idiopathic pulmonary fibrosis: breaking the barrier Camelo, Ana; Dunmore, Rebecca; Sleeman, Matthew A. Frontiers in Pharmacology, Vol. 4 https://doi.org/10.3389/fphar.2013.00173	journal	January 2014
MOUSE CD1-SPECIFIC NK1 T CELLS: Development, Specificity, and Function Bendelac, Albert; Rivera, Miguel N.; Park, Se-Ho Annual Review of Immunology, Vol. 15, Issue 1 https://doi.org/10.1146/annurev.immunol.15.1.535	journal	April 1997
Computational Modeling Predicts IL-10 Control of Lesion Sterilization by Balancing Early Host Immunity–Mediated Antimicrobial Responses with Caseation during Mycobacterium tuberculosis Infection Cilfone, Nicholas A.; Ford, Christopher B.; Marino, Simeone The Journal of Immunology, Vol. 194, Issue 2 https://doi.org/10.4049/jimmunol.1400734	journal	December 2014
Role of NADPH oxidases in the redox biology of liver fibrosis Crosas-Molist, Eva; Fabregat, Isabel Redox Biology, Vol. 6 https://doi.org/10.1016/j.redox.2015.07.005	journal	December 2015
Traveling Wave Model to Interpret a Wound-Healing Cell Migration Assay for Human Peritoneal Mesothelial Cells Maini, Philip K.; McElwain, D. L. Sean; Leavesley, David I. Tissue Engineering, Vol. 10, Issue 3-4 https://doi.org/10.1089/107632704323061834	journal	March 2004
Fibroblasts in fibrosis: novel roles and mediators Kendall, Ryan T.; Feghali-Bostwick, Carol A. Frontiers in Pharmacology, Vol. 5 https://doi.org/10.3389/fphar.2014.00123	journal	May 2014
Multi-Scale Modeling Predicts a Balance of Tumor Necrosis Factor-α and Interleukin-10 Controls the Granuloma Environment during Mycobacterium tuberculosis Infection Cilfone, Nicholas A.; Perry, Cory R.; Kirschner, Denise E. PLoS ONE, Vol. 8, Issue 7 https://doi.org/10.1371/journal.pone.0068680	journal	July 2013
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. Vanhee, D.; Gosset, P.; Wallaert, B. American Journal of Respiratory and Critical Care Medicine, Vol. 150, Issue 4 https://doi.org/10.1164/ajrccm.150.4.7921435	journal	October 1994
Isolation and primary culture of murine alveolar type II cells. Corti, M.; Brody, A. R.; Harrison, J. H. American Journal of Respiratory Cell and Molecular Biology, Vol. 14, Issue 4 https://doi.org/10.1165/ajrcmb.14.4.8600933	journal	April 1996
Evaluation of health-related quality-of-life and dyspnea scales in patients with idiopathic pulmonary fibrosis. Correlation with pulmonary function tests Tzanakis, Nikolaos; Samiou, Maria; Lambiri, Irini European Journal of Internal Medicine, Vol. 16, Issue 2 https://doi.org/10.1016/j.ejim.2004.09.013	journal	April 2005
A critical function for TGF-β signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells Liu, Yongzhong; Zhang, Pin; Li, Jun Nature Immunology, Vol. 9, Issue 6 https://doi.org/10.1038/ni.1607	journal	April 2008
Involvement of Epithelial Cell Apoptosis in Interstitial Lung Diseases Kuwano, Kazuyoshi Internal Medicine, Vol. 47, Issue 5 https://doi.org/10.2169/internalmedicine.47.0713	journal	January 2008
A Novel, Non-Prostanoid EP2 Receptor-Selective Prostaglandin E2 Agonist Stimulates Local Bone Formation and Enhances Fracture Healing Li, Mei; Ke, Hua Zhu; Qi, Hong Journal of Bone and Mineral Research, Vol. 18, Issue 11 https://doi.org/10.1359/jbmr.2003.18.11.2033	journal	November 2003
Biochemical Pathways of Caspase Activation During Apoptosis Budihardjo, Imawati; Oliver, Holt; Lutter, Michael Annual Review of Cell and Developmental Biology, Vol. 15, Issue 1 https://doi.org/10.1146/annurev.cellbio.15.1.269	journal	November 1999
Is Nox4 a key regulator of the activated state of fibroblasts in systemic sclerosis? Böhm, Markus; Dosoki, Heba; Kerkhoff, Claus Experimental Dermatology, Vol. 23, Issue 9 https://doi.org/10.1111/exd.12497	journal	September 2014
Induction of apoptosis by Smad3 and down-regulation of Smad3 expression in response to TGF-β in human normal lung epithelial cells Yanagisawa, Kiyoshi; Osada, Hirotaka; Masuda, Akira Oncogene, Vol. 17, Issue 13 https://doi.org/10.1038/sj.onc.1202052	journal	October 1998
Cellular Mechanisms of Fatal Early-Onset Autoimmunity in Mice with the T Cell-Specific Targeting of Transforming Growth Factor-β Receptor Marie, Julien C.; Liggitt, Denny; Rudensky, Alexander Y. Immunity, Vol. 25, Issue 3 https://doi.org/10.1016/j.immuni.2006.07.012	journal	September 2006
Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts Desmoulière, A.; Geinoz, A.; Gabbiani, F. Journal of Cell Biology, Vol. 122, Issue 1 https://doi.org/10.1083/jcb.122.1.103	journal	July 1993
Health-related quality of life in patients with idiopathic pulmonary fibrosis. What is the main contributing factor? Nishiyama, O.; Taniguchi, H.; Kondoh, Y. Respiratory Medicine, Vol. 99, Issue 4 https://doi.org/10.1016/j.rmed.2004.09.005	journal	April 2005
Recent Developments in Myofibroblast Biology Hinz, Boris; Phan, Sem H.; Thannickal, Victor J. The American Journal of Pathology, Vol. 180, Issue 4 https://doi.org/10.1016/j.ajpath.2012.02.004	journal	April 2012
Combining experiments with multi-cell agent-based modeling to study biological tissue patterning Thorne, B. C.; Bailey, A. M.; Peirce, S. M. Briefings in Bioinformatics, Vol. 8, Issue 4 https://doi.org/10.1093/bib/bbm024	journal	March 2007
Pathogenesis, current treatments and future directions for idiopathic pulmonary fibrosis Loomis-King, Hillary; Flaherty, Kevin R.; Moore, Bethany B. Current Opinion in Pharmacology, Vol. 13, Issue 3 https://doi.org/10.1016/j.coph.2013.03.015	journal	June 2013
Myofibroblast Differentiation by Transforming Growth Factor-β1 Is Dependent on Cell Adhesion and Integrin Signaling via Focal Adhesion Kinase Thannickal, Victor J.; Lee, Daniel Y.; White, Eric S. Journal of Biological Chemistry, Vol. 278, Issue 14 https://doi.org/10.1074/jbc.m208544200	journal	January 2003
Deficient repair response of IPF fibroblasts in a co-culture model of epithelial injury and repair Prasad, Sony; Hogaboam, Cory M.; Jarai, Gabor Fibrogenesis & Tissue Repair, Vol. 7, Issue 1 https://doi.org/10.1186/1755-1536-7-7	journal	January 2014
Pirfenidone: an update on clinical trial data and insights from everyday practice Kreuter, M. European Respiratory Review, Vol. 23, Issue 131 https://doi.org/10.1183/09059180.00008513	journal	February 2014
Identification of specific EP receptors responsible for the hemodynamic effects of PGE₂ Audoly, Laurent P.; Tilley, Stephen L.; Goulet, Jennifer American Journal of Physiology-Heart and Circulatory Physiology, Vol. 277, Issue 3 https://doi.org/10.1152/ajpheart.1999.277.3.h924	journal	September 1999
A New Hope for Idiopathic Pulmonary Fibrosis Hunninghake, Gary M. New England Journal of Medicine, Vol. 370, Issue 22 https://doi.org/10.1056/nejme1403448	journal	May 2014
Regulation of immunity by self-reactive T cells Kronenberg, Mitchell; Rudensky, Alexander Nature, Vol. 435, Issue 7042 https://doi.org/10.1038/nature03725	journal	June 2005
Normal Human Lung Epithelial Cells Inhibit Transforming Growth Factor-β Induced Myofibroblast Differentiation via Prostaglandin E2 Epa, Amali P.; Thatcher, Thomas H.; Pollock, Stephen J. PLOS ONE, Vol. 10, Issue 8 https://doi.org/10.1371/journal.pone.0135266	journal	August 2015
Integration of TGF- β - and EGFR-based signaling pathways using an agent-based model of epithelial restitution: An agent-based model of epithelial restitution Stern, Jordan R.; Christley, Scott; Zaborina, Olga Wound Repair and Regeneration, Vol. 20, Issue 6 https://doi.org/10.1111/j.1524-475X.2012.00852.x	journal	October 2012
Embryonic expression pattern of TGF beta type-1 RNA suggests both paracrine and autocrine mechanisms of action Lehnert, Sigrid A.; Akhurst, Rosemary J. Development, Vol. 104, Issue 2 https://doi.org/10.1242/dev.104.2.263	journal	October 1988
The effects of matrix stiffness and RhoA on the phenotypic plasticity of smooth muscle cells in a 3-D biosynthetic hydrogel system Peyton, Shelly R.; Kim, Peter D.; Ghajar, Cyrus M. Biomaterials, Vol. 29, Issue 17 https://doi.org/10.1016/j.biomaterials.2008.02.005	journal	June 2008
TGF-β type II receptor–deficient thymocytes develop normally but demonstrate increased CD8+ proliferation in vivo Levéen, Per; Carlsén, Maria; Makowska, Anna Blood, Vol. 106, Issue 13 https://doi.org/10.1182/blood-2005-05-1871	journal	December 2005
Synergy between Individual TNF-Dependent Functions Determines Granuloma Performance for Controlling Mycobacterium tuberculosis Infection Ray, J. Christian J.; Flynn, JoAnne L.; Kirschner, Denise E. The Journal of Immunology, Vol. 182, Issue 6 https://doi.org/10.4049/jimmunol.0802297	journal	March 2009
Prostaglandin E Receptors Sugimoto, Yukihiko; Narumiya, Shuh Journal of Biological Chemistry, Vol. 282, Issue 16 https://doi.org/10.1074/jbc.r600038200	journal	February 2007
Identifying Mechanisms of Homeostatic Signaling in Fibroblast Differentiation Warsinske, Hayley C.; Ashley, Shanna L.; Linderman, Jennifer J. Bulletin of Mathematical Biology, Vol. 77, Issue 8 https://doi.org/10.1007/s11538-015-0096-2	journal	August 2015
T Cell-Produced Transforming Growth Factor-β1 Controls T Cell Tolerance and Regulates Th1- and Th17-Cell Differentiation Li, Ming O.; Wan, Yisong Y.; Flavell, Richard A. Immunity, Vol. 26, Issue 5 https://doi.org/10.1016/j.immuni.2007.03.014	journal	May 2007
Tissue repair and the dynamics of the extracellular matrix Midwood, Kim S.; Williams, Leyla Valenick; Schwarzbauer, Jean E. The International Journal of Biochemistry & Cell Biology, Vol. 36, Issue 6 https://doi.org/10.1016/j.biocel.2003.12.003	journal	June 2004
Incidence and Prevalence of Idiopathic Pulmonary Fibrosis Raghu, Ganesh; Weycker, Derek; Edelsberg, John American Journal of Respiratory and Critical Care Medicine, Vol. 174, Issue 7 https://doi.org/10.1164/rccm.200602-163oc	journal	October 2006
Wound healing: an overview of acute, fibrotic and delayed healing Diegelmann, Robert, F. Frontiers in Bioscience, Vol. 9, Issue 1-3 https://doi.org/10.2741/1184	journal	January 2004
Stimulation of prostaglandin (PG) F2α and PGE2 release by tumour necrosis factor-α and interleukin-1α in cultured human luteal phase endometrial cells Chen, D. -B.; Yang, Z. -M.; Le, S. -P. Human Reproduction, Vol. 10, Issue 10 https://doi.org/10.1093/oxfordjournals.humrep.a135790	journal	October 1995
Agent-Based Computational Modeling of Wounded Epithelial Cell Monolayers Walker, D. C.; Hill, G.; Wood, S. M. IEEE Transactions on Nanobioscience, Vol. 3, Issue 3 https://doi.org/10.1109/tnb.2004.833680	journal	September 2004
Pirfenidone: A Novel Anti-fibrotic Agent and Progressive Chronic Allograft Rejection Dosanjh, A.; Ikonen, T.; Wan, B. Pulmonary Pharmacology & Therapeutics, Vol. 15, Issue 5 https://doi.org/10.1006/pupt.2002.0367	journal	October 2002
Pharmacological treatment of idiopathic pulmonary fibrosis – preclinical and clinical studies of pirfenidone, nintedanib, and N-acetylcysteine Myllärniemi, Marjukka; Kaarteenaho, Riitta European Clinical Respiratory Journal, Vol. 2, Issue 1 https://doi.org/10.3402/ecrj.v2.26385	journal	January 2015
Cell, Isoform, and Environment Factors Shape Gradients and Modulate Chemotaxis Chang, S. Laura; Cavnar, Stephen P.; Takayama, Shuichi PLOS ONE, Vol. 10, Issue 4 https://doi.org/10.1371/journal.pone.0123450	journal	April 2015
Identifying control mechanisms of granuloma formation during M. tuberculosis infection using an agent-based model Segovia-Juarez, Jose L.; Ganguli, Suman; Kirschner, Denise Journal of Theoretical Biology, Vol. 231, Issue 3 https://doi.org/10.1016/j.jtbi.2004.06.031	journal	December 2004
Inhibition of Integrin αvβ6, an Activator of Latent Transforming Growth Factor-β, Prevents Radiation-induced Lung Fibrosis Puthawala, Khalid; Hadjiangelis, Nicos; Jacoby, Steven C. American Journal of Respiratory and Critical Care Medicine, Vol. 177, Issue 1 https://doi.org/10.1164/rccm.200706-806oc	journal	January 2008
PGE ₂ inhibition of TGF-β1-induced myofibroblast differentiation is Smad-independent but involves cell shape and adhesion-dependent signaling Thomas, Peedikayil E.; Peters-Golden, Marc; White, Eric S. American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol. 293, Issue 2 https://doi.org/10.1152/ajplung.00489.2006	journal	August 2007
The clinical significance of 5% change in vital capacity in patients with idiopathic pulmonary fibrosis: extended analysis of the pirfenidone trial Taniguchi, Hiroyuki; Kondoh, Yasuhiro; Ebina, Masahito Respiratory Research, Vol. 12, Issue 1 https://doi.org/10.1186/1465-9921-12-93	journal	December 2011
The relative balance of GM-CSF and TGF-β1 regulates lung epithelial barrier function Overgaard, Christian E.; Schlingmann, Barbara; Dorsainvil White, StevenClaude American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol. 308, Issue 12 https://doi.org/10.1152/ajplung.00042.2014	journal	June 2015
The Wound Healing Process: An Overview of the Cellular and Molecular Mechanisms Velnar, T.; Bailey, T.; Smrkolj, V. Journal of International Medical Research, Vol. 37, Issue 5 https://doi.org/10.1177/147323000903700531	journal	October 2009
PGE2 receptor EP2 mediates the antagonistic effect of COX‐2 on TGF‐β signaling during mammary tumorigenesis Tian, Maozhen; Schiemann, William P. The FASEB Journal, Vol. 24, Issue 4 https://doi.org/10.1096/fj.09-141341	journal	November 2009
Myofibroblasts contribute to but are not necessary for wound contraction Ibrahim, Mohamed M.; Chen, Lei; Bond, Jennifer E. Laboratory Investigation, Vol. 95, Issue 12 https://doi.org/10.1038/labinvest.2015.116	journal	September 2015
Pirfenidone for the treatment of idiopathic pulmonary fibrosis Xaubet, Antoni; Serrano-Mollar, Anna; Ancochea, Julio Expert Opinion on Pharmacotherapy, Vol. 15, Issue 2 https://doi.org/10.1517/14656566.2014.867328	journal	November 2013
Redox processes inform multivariate transdifferentiation trajectories associated with TGFβ-induced epithelial–mesenchymal transition Prasanphanich, Adam F.; Arencibia, C. Andrew; Kemp, Melissa L. Free Radical Biology and Medicine, Vol. 76 https://doi.org/10.1016/j.freeradbiomed.2014.07.032	journal	November 2014
IL-4 and IL-13 induce myofibroblastic phenotype of human lung fibroblasts through c-Jun NH2-terminal kinase–dependent pathway Hashimoto, Shu; Gon, Yasuhiro; Takeshita, Ikuko Journal of Allergy and Clinical Immunology, Vol. 107, Issue 6 https://doi.org/10.1067/mai.2001.114702	journal	June 2001
Potential Action of IL-4 and IL-13 as Fibrogenic Factors on Lung Fibroblasts in vitro Saito, Akira; Okazaki, Hitoshi; Sugawara, Isamu International Archives of Allergy and Immunology, Vol. 132, Issue 2 https://doi.org/10.1159/000073718	journal	January 2003
Quality of life of idiopathic pulmonary fibrosis patients de Vries, J.; Kessels, B. L. J.; Drent, M. European Respiratory Journal, Vol. 17, Issue 5 https://doi.org/10.1183/09031936.01.17509540	journal	May 2001
TGF-β-induced EMT: mechanisms and implications for fibrotic lung disease Willis, Brigham C.; Borok, Zea American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol. 293, Issue 3 https://doi.org/10.1152/ajplung.00163.2007	journal	September 2007
Quality of life and dyspnoea in patients treated with bosentan for idiopathic pulmonary fibrosis (BUILD-1) Raghu, G.; King, T. E.; Behr, J. European Respiratory Journal, Vol. 35, Issue 1 https://doi.org/10.1183/09031936.00188108	journal	August 2009
Consequences of altered TGF-β expression and responsiveness in breast cancer: evidence for autocrine and paracrine effects Tobin, Stephen W.; Douville, Karen; Benbow, Ulrike Oncogene, Vol. 21, Issue 1 https://doi.org/10.1038/sj.onc.1205026	journal	January 2002
The Myofibroblast Hinz, Boris; Phan, Sem H.; Thannickal, Victor J. The American Journal of Pathology, Vol. 170, Issue 6 https://doi.org/10.2353/ajpath.2007.070112	journal	June 2007
Agent‐based models in translational systems biology An, Gary; Mi, Qi; Dutta‐Moscato, Joyeeta Wiley Interdisciplinary Reviews: Systems Biology and Medicine, Vol. 1, Issue 2 https://doi.org/10.1002/wsbm.45	journal	September 2009
Selective inhibition of growth-related gene expression in murine keratinocytes by transforming growth factor beta. Coffey, R. J.; Bascom, C. C.; Sipes, N. J. Molecular and Cellular Biology, Vol. 8, Issue 8 https://doi.org/10.1128/MCB.8.8.3088	journal	August 1988
Diminished Prostaglandin E ₂ Contributes to the Apoptosis Paradox in Idiopathic Pulmonary Fibrosis Maher, Toby M.; Evans, Iona C.; Bottoms, Stephen E. American Journal of Respiratory and Critical Care Medicine, Vol. 182, Issue 1 https://doi.org/10.1164/rccm.200905-0674oc	journal	July 2010
Health-related Quality of Life in Patients with Idiopathic Pulmonary Fibrosis -Cross-sectional and Longitudinal Study- Tomioka, Hiromi; Imanaka, Kazufumi; Hashimoto, Kimio Internal Medicine, Vol. 46, Issue 18 https://doi.org/10.2169/internalmedicine.46.6218	journal	January 2007
Epithelial repair mechanisms in the lung Crosby, Lynn M.; Waters, Christopher M. American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol. 298, Issue 6 https://doi.org/10.1152/ajplung.00361.2009	journal	June 2010
Factors Affecting Wound Healing Guo, S.; DiPietro, L. A. Journal of Dental Research, Vol. 89, Issue 3 https://doi.org/10.1177/0022034509359125	journal	February 2010
Bone marrow transplantation alters lung antigen-presenting cells to promote TH17 response and the development of pneumonitis and fibrosis following gammaherpesvirus infection Zhou, X.; Loomis-King, H.; Gurczynski, S. J. Mucosal Immunology, Vol. 9, Issue 3 https://doi.org/10.1038/mi.2015.85	journal	September 2015
Idiopathic pulmonary fibrosis: multiple causes and multiple mechanisms? Maher, T. M.; Wells, A. U.; Laurent, G. J. European Respiratory Journal, Vol. 30, Issue 5 https://doi.org/10.1183/09031936.00069307	journal	November 2007
The role of airway epithelial cells and innate immune cells in chronic respiratory disease Holtzman, Michael J.; Byers, Derek E.; Alexander-Brett, Jennifer Nature Reviews Immunology, Vol. 14, Issue 10 https://doi.org/10.1038/nri3739	journal	September 2014
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. Wakefield, L. M.; Winokur, T. S.; Hollands, R. S. Journal of Clinical Investigation, Vol. 86, Issue 6 https://doi.org/10.1172/jci114932	journal	December 1990
Airway Epithelial Cells: Current Concepts and Challenges Crystal, R. G.; Randell, S. H.; Engelhardt, J. F. Proceedings of the American Thoracic Society, Vol. 5, Issue 7 https://doi.org/10.1513/pats.200805-041hr	journal	September 2008
Multiscale agent-based cancer modeling Zhang, Le; Wang, Zhihui; Sagotsky, Jonathan A. Journal of Mathematical Biology, Vol. 58, Issue 4-5 https://doi.org/10.1007/s00285-008-0211-1	journal	September 2008
State of the art in the diagnosis and management of interstitial lung disease Buzan, Maria T. A.; Pop, Carmen Monica Medicine and Pharmacy Reports, Vol. 88, Issue 2 https://doi.org/10.15386/cjmed-457	journal	April 2015
Strategies for Efficient Numerical Implementation of Hybrid Multi-scale Agent-Based Models to Describe Biological Systems Cilfone, Nicholas A.; Kirschner, Denise E.; Linderman, Jennifer J. Cellular and Molecular Bioengineering, Vol. 8, Issue 1 https://doi.org/10.1007/s12195-014-0363-6	journal	November 2014
Collagen I matrix turnover is regulated by fibronectin polymerization Shi, Feng; Harman, Jennifer; Fujiwara, Keigi American Journal of Physiology-Cell Physiology, Vol. 298, Issue 5 https://doi.org/10.1152/ajpcell.00341.2009	journal	May 2010
Efficacy of Nintedanib in Idiopathic Pulmonary Fibrosis across Prespecified Subgroups in INPULSIS Costabel, Ulrich; Inoue, Yoshikazu; Richeldi, Luca American Journal of Respiratory and Critical Care Medicine, Vol. 193, Issue 2 https://doi.org/10.1164/rccm.201503-0562OC	journal	January 2016
Broad Therapeutic Efficacy of Nintedanib in Idiopathic Pulmonary Fibrosis Wells, Athol U.; Rosas, Ivan O. American Journal of Respiratory and Critical Care Medicine, Vol. 193, Issue 2 https://doi.org/10.1164/rccm.201510-2052ed	journal	January 2016
Synergistic Induction of Cyclooxygenase-2 by Transforming Growth Factor-β1 and Epidermal Growth Factor Inhibits Apoptosis in Epithelial Cells Saha, Debabrata; Datta, Pran K.; Sheng, Hongmiao Neoplasia, Vol. 1, Issue 6 https://doi.org/10.1038/sj.neo.7900051	journal	December 1999
Emerging Patterns in Tumor Systems: Simulating the Dynamics of Multicellular Clusters with an Agent-based Spatial Agglomeration Model Mansury, Yuri; Kimura, Mark; Lobo, Jose Journal of Theoretical Biology, Vol. 219, Issue 3 https://doi.org/10.1006/jtbi.2002.3131	journal	December 2002
A Phase 3 Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis King, Talmadge E.; Bradford, Williamson Z.; Castro-Bernardini, Socorro New England Journal of Medicine, Vol. 370, Issue 22 https://doi.org/10.1056/NEJMoa1402582	journal	May 2014
Sensitivity Analyses of the Change in FVC in a Phase 3 Trial of Pirfenidone for Idiopathic Pulmonary Fibrosis Lederer, David J.; Bradford, Williamson Z.; Fagan, Elizabeth A. Chest, Vol. 148, Issue 1 https://doi.org/10.1378/chest.14-2817	journal	July 2015
Health-Related Quality of Life and 6 Min Walk Distance in Patients with Idiopathic Pulmonary Fibrosis Verma, Geetika; Marras, Theodore; Chowdhury, Noori Canadian Respiratory Journal, Vol. 18, Issue 5 https://doi.org/10.1155/2011/109635	journal	January 2011
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General Principles of Wound Healing Witte, Maria B.; Barbul, Adrian Surgical Clinics of North America, Vol. 77, Issue 3 https://doi.org/10.1016/S0039-6109(05)70566-1	journal	June 1997
Health-related quality of life in patients with idiopathic pulmonary fibrosis: a systematic review Swigris, J. J. Thorax, Vol. 60, Issue 7 https://doi.org/10.1136/thx.2004.035220	journal	July 2005
Viral Infection in Acute Exacerbation of Idiopathic Pulmonary Fibrosis Wootton, Sharon Chao; Kim, Dong Soon; Kondoh, Yasuhiro American Journal of Respiratory and Critical Care Medicine, Vol. 183, Issue 12 https://doi.org/10.1164/rccm.201010-1752oc	journal	June 2011
Blockade of TGF-β inhibits mammary tumor cell viability, migration, and metastases Muraoka, Rebecca S.; Dumont, Nancy; Ritter, Christoph A. Journal of Clinical Investigation, Vol. 109, Issue 12 https://doi.org/10.1172/jci0215234	journal	June 2002
Regulation of local immunity by airway epithelial cells Mayer, Anja K.; Dalpke, Alexander H. Archivum Immunologiae et Therapiae Experimentalis, Vol. 55, Issue 6 https://doi.org/10.1007/s00005-007-0041-7	journal	December 2007
Alveolar epithelial cell inhibition of fibroblast proliferation is regulated by MCP-1/CCR2 and mediated by PGE ₂ Moore, Bethany B.; Peters-Golden, Marc; Christensen, Paul J. American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol. 284, Issue 2 https://doi.org/10.1152/ajplung.00168.2002	journal	February 2003
Agent-based model of inflammation and wound healing: insights into diabetic foot ulcer pathology and the role of transforming growth factor-β1 Mi, Qi; Rivière, Beatrice; Clermont, Gilles Wound Repair and Regeneration, Vol. 15, Issue 5 https://doi.org/10.1111/j.1524-475x.2007.00271.x	journal	September 2007
What Differentiates Normal Lung Repair and Fibrosis?: Inflammation, Resolution of Repair, and Fibrosis Strieter, R. M. Proceedings of the American Thoracic Society, Vol. 5, Issue 3 https://doi.org/10.1513/pats.200710-160dr	journal	April 2008
Comparison of two questionnaires which measure the health-related quality of life of idiopathic pulmonary fibrosis patients Zimmermann, C. S.; Carvalho, C. R. F.; Silveira, K. R. Brazilian Journal of Medical and Biological Research, Vol. 40, Issue 2 https://doi.org/10.1590/s0100-879x2007000200004	journal	January 2007
TGF-β1 inhibition of c-myc transcription and growth in keratinocytes is abrogated by viral transforming proteins with pRB binding domains Pietenpol, Jennifer A.; Stein, Roland W.; Moran, Elizabeth Cell, Vol. 61, Issue 5 https://doi.org/10.1016/0092-8674(90)90188-k	journal	June 1990
Selective inhibition of growth-related gene expression in murine keratinocytes by transforming growth factor beta Coffey, R. J.; Bascom, C. C.; Sipes, N. J. Molecular and Cellular Biology, Vol. 8, Issue 8 https://doi.org/10.1128/mcb.8.8.3088-3093.1988	journal	August 1988
The effect of transforming growth factor-beta on cell proliferation and collagen formation by lung fibroblasts. Fine, A.; Goldstein, R. H. Journal of Biological Chemistry, Vol. 262, Issue 8 https://doi.org/10.1016/S0021-9258(18)61441-3	journal	March 1987
The Differential Effect of Prostaglandin E2 on Transforming Growth Factor-β and Insulin-induced Collagen Formation in Lung Fibroblasts Fine, A.; Poliks, C. F.; Donahue, L. P. Journal of Biological Chemistry, Vol. 264, Issue 29 https://doi.org/10.1016/S0021-9258(18)71448-8	journal	October 1989

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59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
pulmonary fibrosis
transforming growth factor beta1
fibroblasts
epithelial cells
agent-based modeling
prostaglandin E2
IPF
therapeutics for fibrosis
growth-factor-beta
quality-of-life
mycobacterium-tuberculosis infection
agent-based model
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tgf-beta
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lung fibroblasts
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