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

Abstract

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 identifymore » 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.« less

Authors:
 [1];  [2];  [2];  [3];  [4];  [1]
  1. Univ. of Michigan Medical School, Ann Arbor, MI (United States). Dept. of Microbiology and Immunology
  2. Univ. of Michigan Medical School, Ann Arbor, MI (United States). Dept. of Internal Medicine
  3. Univ. of Michigan, Ann Arbor, MI (United States). Dept. of Chemical Engineering
  4. Univ. of Michigan Medical School, Ann Arbor, MI (United States). Dept. of Microbiology and Immunology, Dept. of Internal Medicine
Publication Date:
Research Org.:
Univ. of Michigan Medical School, Ann Arbor, MI (United States)
Sponsoring Org.:
USDOE Office of Science (SC), National Energy Research Scientific Computing Center
OSTI Identifier:
1285867
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Frontiers in Pharmacology
Additional Journal Information:
Journal Volume: 7; Journal ID: ISSN 1663-9812
Publisher:
Frontiers Research Foundation
Country of Publication:
United States
Language:
English
Subject:
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; muscle actin expression; tgf-beta; transforming growth-factor-beta-1; lung fibroblasts; t-cells; myofibroblast differentiation

Citation Formats

Warsinske, Hayley C., Wheaton, Amanda K., Kim, Kevin K., Linderman, Jennifer J., Moore, Bethany B., and Kirschner, Denise E. Computational modeling predicts simultaneous targeting of fibroblasts and epithelial cells is necessary for treatment of pulmonary fibrosis. United States: N. p., 2016. Web. doi:10.3389/fphar.2016.00183.
Warsinske, Hayley C., Wheaton, Amanda K., Kim, Kevin K., Linderman, Jennifer J., Moore, Bethany B., & Kirschner, Denise E. Computational modeling predicts simultaneous targeting of fibroblasts and epithelial cells is necessary for treatment of pulmonary fibrosis. United States. https://doi.org/10.3389/fphar.2016.00183
Warsinske, Hayley C., Wheaton, Amanda K., Kim, Kevin K., Linderman, Jennifer J., Moore, Bethany B., and Kirschner, Denise E. 2016. "Computational modeling predicts simultaneous targeting of fibroblasts and epithelial cells is necessary for treatment of pulmonary fibrosis". United States. https://doi.org/10.3389/fphar.2016.00183. https://www.osti.gov/servlets/purl/1285867.
@article{osti_1285867,
title = {Computational modeling predicts simultaneous targeting of fibroblasts and epithelial cells is necessary for treatment of pulmonary fibrosis},
author = {Warsinske, Hayley C. and Wheaton, Amanda K. and Kim, Kevin K. and Linderman, Jennifer J. and Moore, Bethany B. and Kirschner, Denise E.},
abstractNote = {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.},
doi = {10.3389/fphar.2016.00183},
url = {https://www.osti.gov/biblio/1285867}, journal = {Frontiers in Pharmacology},
issn = {1663-9812},
number = ,
volume = 7,
place = {United States},
year = {Thu Jun 23 00:00:00 EDT 2016},
month = {Thu Jun 23 00:00:00 EDT 2016}
}

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journal, April 1996


Evaluation of health-related quality-of-life and dyspnea scales in patients with idiopathic pulmonary fibrosis. Correlation with pulmonary function tests
journal, April 2005


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journal, December 2002


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PGE2 receptor EP2 mediates the antagonistic effect of COX‐2 on TGF‐β signaling during mammary tumorigenesis
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  • American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol. 308, Issue 12
  • https://doi.org/10.1152/ajplung.00042.2014

The role of airway epithelial cells and innate immune cells in chronic respiratory disease
journal, September 2014


Involvement of Epithelial Cell Apoptosis in Interstitial Lung Diseases
journal, January 2008


Multiscale agent-based cancer modeling
journal, September 2008


Alveolar epithelial cell inhibition of fibroblast proliferation is regulated by MCP-1/CCR2 and mediated by PGE 2
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Biochemical Pathways of Caspase Activation During Apoptosis
journal, November 1999


Health-related Quality of Life in Patients with Idiopathic Pulmonary Fibrosis -Cross-sectional and Longitudinal Study-
journal, January 2007


State of the art in the diagnosis and management of interstitial lung disease
journal, April 2015


Pirfenidone: A Novel Anti-fibrotic Agent and Progressive Chronic Allograft Rejection
journal, October 2002


Collagen I matrix turnover is regulated by fibronectin polymerization
journal, May 2010


Fibroblasts in fibrosis: novel roles and mediators
journal, May 2014


What Differentiates Normal Lung Repair and Fibrosis?: Inflammation, Resolution of Repair, and Fibrosis
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Pathogenesis, current treatments and future directions for idiopathic pulmonary fibrosis
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Comparison of two questionnaires which measure the health-related quality of life of idiopathic pulmonary fibrosis patients
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Wound healing: an overview of acute, fibrotic and delayed healing
journal, January 2004


Prostaglandin E 2 Synthesis and Suppression of Fibroblast Proliferation by Alveolar Epithelial Cells Is Cyclooxygenase-2–Dependent
journal, December 2002


Strategies for Efficient Numerical Implementation of Hybrid Multi-scale Agent-Based Models to Describe Biological Systems
journal, November 2014


Selective inhibition of growth-related gene expression in murine keratinocytes by transforming growth factor beta
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Identifying Mechanisms of Homeostatic Signaling in Fibroblast Differentiation
journal, August 2015


Embryonic expression pattern of TGF beta type-1 RNA suggests both paracrine and autocrine mechanisms of action
journal, October 1988


Works referencing / citing this record:

In Vitro Granuloma Models of Tuberculosis: Potential and Challenges
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Agent‐based models of inflammation in translational systems biology: A decade later
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Multiscale Coupling of an Agent-Based Model of Tissue Fibrosis and a Logic-Based Model of Intracellular Signaling
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