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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:
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. Thu . "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},
journal = {Frontiers in Pharmacology},
number = ,
volume = 7,
place = {United States},
year = {2016},
month = {6}
}

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